Drug Resistant Tuberculosis

71
Drug Resistant Tuberculosis Emerging Human Concern Dr.T.V.Rao MD Dr.T.V.Rao MD 1

description

Drug Resistant Tuberculosis

Transcript of Drug Resistant Tuberculosis

Page 1: Drug Resistant Tuberculosis

Drug Resistant Tuberculosis

Emerging Human Concern

DrTVRao MD

DrTVRao MD 1

HISTORY ofTuberculosis

Tuberculosis Is an Ancient Disease Identified as Spinal Tuberculosis in Egyptian Mummies History dates to 1550 ndash 1080 BC Identified by PCR

DrTVRao MD 2

A Tribute to Robert Koch Discoverer of Mycobacterium

Tuberculosis

DrTVRao MD 3

Historical Background

Neolithic Time 2400 BC - Egyptian

mummies spinal columns 460 BC

Hippocrates Greece First clinical description

Phthisis Consumption (I am wasting away)

500-1500 AD Roman occupation of

Europe it spread to Britain

1650-1900 AD White plague of Europe

causing one in five deaths

DrTVRao MD 4

Diagnostic discoveries

24th March 1882 (Robert Koch) TB Day Discovery of staining

technique that identified Tuberculosis bacillus

Definite diagnosis made possible 1890 (Robert Koch)

Tuberculin discovered Diagnostic use when

injected into skin 1895 (Roentgen)

Discovery of X-rays Early diagnosis of

pulmonary disease

DrTVRao MD 5

From Tuberculosis to Tuberculin

Failure of Robert Koch Tuberculin therapy

did in fact work in Kochs laboratory even though it failed to do so almost anywhere else his reliance an animal experiments which essentially differed from what many of his contemporaries many differed with his ideas

DrTVRao MD 6

Global Status

Nine million people suffer from tuberculosis

Two million people die each year

Tuberculosis accounts for one-third of AIDS deaths world wide every year

DrTVRao MD 7

USAID Report on Tuberculosis in India

India has more new tuberculosis (TB) cases annually than any other country ranking first among the 22 high-burden TB countries worldwide according to the World Health Organizationrsquos (WHOrsquos) Global TB Report 2009 TB remains one of the leading infectious causes of mortality in India causing more than 331000 deaths in 2007 There were approximately 196 million new TB cases in India in 2007 representing more than 21 per cent of all TB cases worldwide

DrTVRao MD 8

1908-1920 (Chalmette and Guerin) Vaccine (BCG)

Attenuated strain Mycobacterium Bovis

1943 Streptomycin developed

20th November 1944 Critically ill TB patient injected

dramatically recovered

Pharmacological discoveries

DrTVRao MD 9

Selman Abraham Waksman Nobel Prize for his discovery in

1952

DrTVRao MD 10

Pharmacological discoveries

1956-1960 Combination therapy of INH and PZA

cures TB1955 Cycloserine1962 Ethambutol 1963 Rifampicin1970-1977

Combination of Rifampicin and Isoniazid adopted as International regime for treatment of TB DrTVRao MD 11

No one is Immune to TuberculosisNot only infects poor but famous

too

DrTVRao MD 12

Multi Drug Resistant

TuberculosisMDR-TB

DrTVRao MD 13

Definition

MDR-TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs

Single Isoniazid or Rifampicin resistance is not MDR - TB

MDR TB is a laboratory diagnosis

DrTVRao MD 14

Classification of Drugs 3 Groups depending upon the degree

of effectiveness and potential side effects First Line (Primary agents)

are the most effective and have lowest toxicity Isoniazid Rifampin

Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino

salicylic acid Streptomycin Ethambutol Third Line

are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine

DrTVRao MD 15

Basic concepts ndash Keep facts

Primary (Initial) resistanceTB patientrsquos initial Mycobacterium

tuberculosis population resistant to drugs

Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial

population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16

When to suspect MDR TB

Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy

Treatment failure and interruption cases

Close contacts of MDR tuberculosis cases

Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17

What is extensively drug resistant tuberculosis (XDR TB)

Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18

Why XDR - TB a grave concern

Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective

XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB

DrTVRao MD 19

Global Estimates

Classification

Estimated Number of Cases

Estimated Number of

Deaths

All forms TB

88 million 16 million

MDR TB 424000 116000

XDR TB 27000 16000

DrTVRao MD 20

Extensively Drug-Resistant Mycobacterium tuberculosis

India

The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases

DrTVRao MD 21

Drug susceptible TBsect

MDR-TB

1990sect

XDR-TB

2006sect

Total DR

Resistance to HampR ndash

Treatable with 2nd line drugs

Resistance to 2nd line drugs ndashTreatment options seriously restricted

Resistance to all available drugs ndash

No treatment options

or limited resistance manageable with 4 drug regimen - DOTS

Are we Returning to a Pre-antibiotic Era

DrTVRao MD 22

Genesis of MDR TB

Resistance is a man-made amplification of a natural phenomenon

Inadequate drug delivery is main cause of secondary drug resistance

Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains

MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked

DrTVRao MD 23

Factors Contributing to Development

and Spread of MDR and XDR TB Weak TB programs (DOTS)

Low completioncure rates Lack of treatment follow up and

patient support Unreliable drug supply Diagnostic delay

Absent or inadequate infection control measures

Uncontrolled use of 2nd line drugs Fluroquinolones

DrTVRao MD 24

INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis

Regulators of peroxide response

Mechanism of resistance

DrTVRao MD 25

RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)

Reduced Cell wall permeability

Mechanism of resistance

DrTVRao MD 26

Gene location associated Drug-Resistant

Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas

A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A

Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33

DrTVRao MD 27

Current Scientific Documentations on Drug Resistance in

Tuberculosis

DrTVRao MD 28

Alarming Rise of Resistant TuberculosisWHO Report on

Anti-TB Drug Resistance

490000 new cases of MDR-TB each year with gt110000 deaths1

Accounts for 5 of 9 million new cases of TB2

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

XDR-TB reported by as many as 49 countries (by June 2008)3

Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4

Around 40000 XDR-TB cases emerge every year1

1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

DrTVRao MD 29

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 2: Drug Resistant Tuberculosis

HISTORY ofTuberculosis

Tuberculosis Is an Ancient Disease Identified as Spinal Tuberculosis in Egyptian Mummies History dates to 1550 ndash 1080 BC Identified by PCR

DrTVRao MD 2

A Tribute to Robert Koch Discoverer of Mycobacterium

Tuberculosis

DrTVRao MD 3

Historical Background

Neolithic Time 2400 BC - Egyptian

mummies spinal columns 460 BC

Hippocrates Greece First clinical description

Phthisis Consumption (I am wasting away)

500-1500 AD Roman occupation of

Europe it spread to Britain

1650-1900 AD White plague of Europe

causing one in five deaths

DrTVRao MD 4

Diagnostic discoveries

24th March 1882 (Robert Koch) TB Day Discovery of staining

technique that identified Tuberculosis bacillus

Definite diagnosis made possible 1890 (Robert Koch)

Tuberculin discovered Diagnostic use when

injected into skin 1895 (Roentgen)

Discovery of X-rays Early diagnosis of

pulmonary disease

DrTVRao MD 5

From Tuberculosis to Tuberculin

Failure of Robert Koch Tuberculin therapy

did in fact work in Kochs laboratory even though it failed to do so almost anywhere else his reliance an animal experiments which essentially differed from what many of his contemporaries many differed with his ideas

DrTVRao MD 6

Global Status

Nine million people suffer from tuberculosis

Two million people die each year

Tuberculosis accounts for one-third of AIDS deaths world wide every year

DrTVRao MD 7

USAID Report on Tuberculosis in India

India has more new tuberculosis (TB) cases annually than any other country ranking first among the 22 high-burden TB countries worldwide according to the World Health Organizationrsquos (WHOrsquos) Global TB Report 2009 TB remains one of the leading infectious causes of mortality in India causing more than 331000 deaths in 2007 There were approximately 196 million new TB cases in India in 2007 representing more than 21 per cent of all TB cases worldwide

DrTVRao MD 8

1908-1920 (Chalmette and Guerin) Vaccine (BCG)

Attenuated strain Mycobacterium Bovis

1943 Streptomycin developed

20th November 1944 Critically ill TB patient injected

dramatically recovered

Pharmacological discoveries

DrTVRao MD 9

Selman Abraham Waksman Nobel Prize for his discovery in

1952

DrTVRao MD 10

Pharmacological discoveries

1956-1960 Combination therapy of INH and PZA

cures TB1955 Cycloserine1962 Ethambutol 1963 Rifampicin1970-1977

Combination of Rifampicin and Isoniazid adopted as International regime for treatment of TB DrTVRao MD 11

No one is Immune to TuberculosisNot only infects poor but famous

too

DrTVRao MD 12

Multi Drug Resistant

TuberculosisMDR-TB

DrTVRao MD 13

Definition

MDR-TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs

Single Isoniazid or Rifampicin resistance is not MDR - TB

MDR TB is a laboratory diagnosis

DrTVRao MD 14

Classification of Drugs 3 Groups depending upon the degree

of effectiveness and potential side effects First Line (Primary agents)

are the most effective and have lowest toxicity Isoniazid Rifampin

Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino

salicylic acid Streptomycin Ethambutol Third Line

are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine

DrTVRao MD 15

Basic concepts ndash Keep facts

Primary (Initial) resistanceTB patientrsquos initial Mycobacterium

tuberculosis population resistant to drugs

Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial

population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16

When to suspect MDR TB

Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy

Treatment failure and interruption cases

Close contacts of MDR tuberculosis cases

Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17

What is extensively drug resistant tuberculosis (XDR TB)

Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18

Why XDR - TB a grave concern

Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective

XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB

DrTVRao MD 19

Global Estimates

Classification

Estimated Number of Cases

Estimated Number of

Deaths

All forms TB

88 million 16 million

MDR TB 424000 116000

XDR TB 27000 16000

DrTVRao MD 20

Extensively Drug-Resistant Mycobacterium tuberculosis

India

The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases

DrTVRao MD 21

Drug susceptible TBsect

MDR-TB

1990sect

XDR-TB

2006sect

Total DR

Resistance to HampR ndash

Treatable with 2nd line drugs

Resistance to 2nd line drugs ndashTreatment options seriously restricted

Resistance to all available drugs ndash

No treatment options

or limited resistance manageable with 4 drug regimen - DOTS

Are we Returning to a Pre-antibiotic Era

DrTVRao MD 22

Genesis of MDR TB

Resistance is a man-made amplification of a natural phenomenon

Inadequate drug delivery is main cause of secondary drug resistance

Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains

MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked

DrTVRao MD 23

Factors Contributing to Development

and Spread of MDR and XDR TB Weak TB programs (DOTS)

Low completioncure rates Lack of treatment follow up and

patient support Unreliable drug supply Diagnostic delay

Absent or inadequate infection control measures

Uncontrolled use of 2nd line drugs Fluroquinolones

DrTVRao MD 24

INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis

Regulators of peroxide response

Mechanism of resistance

DrTVRao MD 25

RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)

Reduced Cell wall permeability

Mechanism of resistance

DrTVRao MD 26

Gene location associated Drug-Resistant

Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas

A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A

Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33

DrTVRao MD 27

Current Scientific Documentations on Drug Resistance in

Tuberculosis

DrTVRao MD 28

Alarming Rise of Resistant TuberculosisWHO Report on

Anti-TB Drug Resistance

490000 new cases of MDR-TB each year with gt110000 deaths1

Accounts for 5 of 9 million new cases of TB2

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

XDR-TB reported by as many as 49 countries (by June 2008)3

Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4

Around 40000 XDR-TB cases emerge every year1

1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

DrTVRao MD 29

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 3: Drug Resistant Tuberculosis

A Tribute to Robert Koch Discoverer of Mycobacterium

Tuberculosis

DrTVRao MD 3

Historical Background

Neolithic Time 2400 BC - Egyptian

mummies spinal columns 460 BC

Hippocrates Greece First clinical description

Phthisis Consumption (I am wasting away)

500-1500 AD Roman occupation of

Europe it spread to Britain

1650-1900 AD White plague of Europe

causing one in five deaths

DrTVRao MD 4

Diagnostic discoveries

24th March 1882 (Robert Koch) TB Day Discovery of staining

technique that identified Tuberculosis bacillus

Definite diagnosis made possible 1890 (Robert Koch)

Tuberculin discovered Diagnostic use when

injected into skin 1895 (Roentgen)

Discovery of X-rays Early diagnosis of

pulmonary disease

DrTVRao MD 5

From Tuberculosis to Tuberculin

Failure of Robert Koch Tuberculin therapy

did in fact work in Kochs laboratory even though it failed to do so almost anywhere else his reliance an animal experiments which essentially differed from what many of his contemporaries many differed with his ideas

DrTVRao MD 6

Global Status

Nine million people suffer from tuberculosis

Two million people die each year

Tuberculosis accounts for one-third of AIDS deaths world wide every year

DrTVRao MD 7

USAID Report on Tuberculosis in India

India has more new tuberculosis (TB) cases annually than any other country ranking first among the 22 high-burden TB countries worldwide according to the World Health Organizationrsquos (WHOrsquos) Global TB Report 2009 TB remains one of the leading infectious causes of mortality in India causing more than 331000 deaths in 2007 There were approximately 196 million new TB cases in India in 2007 representing more than 21 per cent of all TB cases worldwide

DrTVRao MD 8

1908-1920 (Chalmette and Guerin) Vaccine (BCG)

Attenuated strain Mycobacterium Bovis

1943 Streptomycin developed

20th November 1944 Critically ill TB patient injected

dramatically recovered

Pharmacological discoveries

DrTVRao MD 9

Selman Abraham Waksman Nobel Prize for his discovery in

1952

DrTVRao MD 10

Pharmacological discoveries

1956-1960 Combination therapy of INH and PZA

cures TB1955 Cycloserine1962 Ethambutol 1963 Rifampicin1970-1977

Combination of Rifampicin and Isoniazid adopted as International regime for treatment of TB DrTVRao MD 11

No one is Immune to TuberculosisNot only infects poor but famous

too

DrTVRao MD 12

Multi Drug Resistant

TuberculosisMDR-TB

DrTVRao MD 13

Definition

MDR-TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs

Single Isoniazid or Rifampicin resistance is not MDR - TB

MDR TB is a laboratory diagnosis

DrTVRao MD 14

Classification of Drugs 3 Groups depending upon the degree

of effectiveness and potential side effects First Line (Primary agents)

are the most effective and have lowest toxicity Isoniazid Rifampin

Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino

salicylic acid Streptomycin Ethambutol Third Line

are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine

DrTVRao MD 15

Basic concepts ndash Keep facts

Primary (Initial) resistanceTB patientrsquos initial Mycobacterium

tuberculosis population resistant to drugs

Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial

population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16

When to suspect MDR TB

Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy

Treatment failure and interruption cases

Close contacts of MDR tuberculosis cases

Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17

What is extensively drug resistant tuberculosis (XDR TB)

Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18

Why XDR - TB a grave concern

Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective

XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB

DrTVRao MD 19

Global Estimates

Classification

Estimated Number of Cases

Estimated Number of

Deaths

All forms TB

88 million 16 million

MDR TB 424000 116000

XDR TB 27000 16000

DrTVRao MD 20

Extensively Drug-Resistant Mycobacterium tuberculosis

India

The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases

DrTVRao MD 21

Drug susceptible TBsect

MDR-TB

1990sect

XDR-TB

2006sect

Total DR

Resistance to HampR ndash

Treatable with 2nd line drugs

Resistance to 2nd line drugs ndashTreatment options seriously restricted

Resistance to all available drugs ndash

No treatment options

or limited resistance manageable with 4 drug regimen - DOTS

Are we Returning to a Pre-antibiotic Era

DrTVRao MD 22

Genesis of MDR TB

Resistance is a man-made amplification of a natural phenomenon

Inadequate drug delivery is main cause of secondary drug resistance

Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains

MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked

DrTVRao MD 23

Factors Contributing to Development

and Spread of MDR and XDR TB Weak TB programs (DOTS)

Low completioncure rates Lack of treatment follow up and

patient support Unreliable drug supply Diagnostic delay

Absent or inadequate infection control measures

Uncontrolled use of 2nd line drugs Fluroquinolones

DrTVRao MD 24

INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis

Regulators of peroxide response

Mechanism of resistance

DrTVRao MD 25

RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)

Reduced Cell wall permeability

Mechanism of resistance

DrTVRao MD 26

Gene location associated Drug-Resistant

Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas

A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A

Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33

DrTVRao MD 27

Current Scientific Documentations on Drug Resistance in

Tuberculosis

DrTVRao MD 28

Alarming Rise of Resistant TuberculosisWHO Report on

Anti-TB Drug Resistance

490000 new cases of MDR-TB each year with gt110000 deaths1

Accounts for 5 of 9 million new cases of TB2

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

XDR-TB reported by as many as 49 countries (by June 2008)3

Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4

Around 40000 XDR-TB cases emerge every year1

1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

DrTVRao MD 29

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 4: Drug Resistant Tuberculosis

Historical Background

Neolithic Time 2400 BC - Egyptian

mummies spinal columns 460 BC

Hippocrates Greece First clinical description

Phthisis Consumption (I am wasting away)

500-1500 AD Roman occupation of

Europe it spread to Britain

1650-1900 AD White plague of Europe

causing one in five deaths

DrTVRao MD 4

Diagnostic discoveries

24th March 1882 (Robert Koch) TB Day Discovery of staining

technique that identified Tuberculosis bacillus

Definite diagnosis made possible 1890 (Robert Koch)

Tuberculin discovered Diagnostic use when

injected into skin 1895 (Roentgen)

Discovery of X-rays Early diagnosis of

pulmonary disease

DrTVRao MD 5

From Tuberculosis to Tuberculin

Failure of Robert Koch Tuberculin therapy

did in fact work in Kochs laboratory even though it failed to do so almost anywhere else his reliance an animal experiments which essentially differed from what many of his contemporaries many differed with his ideas

DrTVRao MD 6

Global Status

Nine million people suffer from tuberculosis

Two million people die each year

Tuberculosis accounts for one-third of AIDS deaths world wide every year

DrTVRao MD 7

USAID Report on Tuberculosis in India

India has more new tuberculosis (TB) cases annually than any other country ranking first among the 22 high-burden TB countries worldwide according to the World Health Organizationrsquos (WHOrsquos) Global TB Report 2009 TB remains one of the leading infectious causes of mortality in India causing more than 331000 deaths in 2007 There were approximately 196 million new TB cases in India in 2007 representing more than 21 per cent of all TB cases worldwide

DrTVRao MD 8

1908-1920 (Chalmette and Guerin) Vaccine (BCG)

Attenuated strain Mycobacterium Bovis

1943 Streptomycin developed

20th November 1944 Critically ill TB patient injected

dramatically recovered

Pharmacological discoveries

DrTVRao MD 9

Selman Abraham Waksman Nobel Prize for his discovery in

1952

DrTVRao MD 10

Pharmacological discoveries

1956-1960 Combination therapy of INH and PZA

cures TB1955 Cycloserine1962 Ethambutol 1963 Rifampicin1970-1977

Combination of Rifampicin and Isoniazid adopted as International regime for treatment of TB DrTVRao MD 11

No one is Immune to TuberculosisNot only infects poor but famous

too

DrTVRao MD 12

Multi Drug Resistant

TuberculosisMDR-TB

DrTVRao MD 13

Definition

MDR-TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs

Single Isoniazid or Rifampicin resistance is not MDR - TB

MDR TB is a laboratory diagnosis

DrTVRao MD 14

Classification of Drugs 3 Groups depending upon the degree

of effectiveness and potential side effects First Line (Primary agents)

are the most effective and have lowest toxicity Isoniazid Rifampin

Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino

salicylic acid Streptomycin Ethambutol Third Line

are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine

DrTVRao MD 15

Basic concepts ndash Keep facts

Primary (Initial) resistanceTB patientrsquos initial Mycobacterium

tuberculosis population resistant to drugs

Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial

population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16

When to suspect MDR TB

Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy

Treatment failure and interruption cases

Close contacts of MDR tuberculosis cases

Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17

What is extensively drug resistant tuberculosis (XDR TB)

Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18

Why XDR - TB a grave concern

Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective

XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB

DrTVRao MD 19

Global Estimates

Classification

Estimated Number of Cases

Estimated Number of

Deaths

All forms TB

88 million 16 million

MDR TB 424000 116000

XDR TB 27000 16000

DrTVRao MD 20

Extensively Drug-Resistant Mycobacterium tuberculosis

India

The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases

DrTVRao MD 21

Drug susceptible TBsect

MDR-TB

1990sect

XDR-TB

2006sect

Total DR

Resistance to HampR ndash

Treatable with 2nd line drugs

Resistance to 2nd line drugs ndashTreatment options seriously restricted

Resistance to all available drugs ndash

No treatment options

or limited resistance manageable with 4 drug regimen - DOTS

Are we Returning to a Pre-antibiotic Era

DrTVRao MD 22

Genesis of MDR TB

Resistance is a man-made amplification of a natural phenomenon

Inadequate drug delivery is main cause of secondary drug resistance

Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains

MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked

DrTVRao MD 23

Factors Contributing to Development

and Spread of MDR and XDR TB Weak TB programs (DOTS)

Low completioncure rates Lack of treatment follow up and

patient support Unreliable drug supply Diagnostic delay

Absent or inadequate infection control measures

Uncontrolled use of 2nd line drugs Fluroquinolones

DrTVRao MD 24

INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis

Regulators of peroxide response

Mechanism of resistance

DrTVRao MD 25

RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)

Reduced Cell wall permeability

Mechanism of resistance

DrTVRao MD 26

Gene location associated Drug-Resistant

Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas

A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A

Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33

DrTVRao MD 27

Current Scientific Documentations on Drug Resistance in

Tuberculosis

DrTVRao MD 28

Alarming Rise of Resistant TuberculosisWHO Report on

Anti-TB Drug Resistance

490000 new cases of MDR-TB each year with gt110000 deaths1

Accounts for 5 of 9 million new cases of TB2

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

XDR-TB reported by as many as 49 countries (by June 2008)3

Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4

Around 40000 XDR-TB cases emerge every year1

1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

DrTVRao MD 29

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 5: Drug Resistant Tuberculosis

Diagnostic discoveries

24th March 1882 (Robert Koch) TB Day Discovery of staining

technique that identified Tuberculosis bacillus

Definite diagnosis made possible 1890 (Robert Koch)

Tuberculin discovered Diagnostic use when

injected into skin 1895 (Roentgen)

Discovery of X-rays Early diagnosis of

pulmonary disease

DrTVRao MD 5

From Tuberculosis to Tuberculin

Failure of Robert Koch Tuberculin therapy

did in fact work in Kochs laboratory even though it failed to do so almost anywhere else his reliance an animal experiments which essentially differed from what many of his contemporaries many differed with his ideas

DrTVRao MD 6

Global Status

Nine million people suffer from tuberculosis

Two million people die each year

Tuberculosis accounts for one-third of AIDS deaths world wide every year

DrTVRao MD 7

USAID Report on Tuberculosis in India

India has more new tuberculosis (TB) cases annually than any other country ranking first among the 22 high-burden TB countries worldwide according to the World Health Organizationrsquos (WHOrsquos) Global TB Report 2009 TB remains one of the leading infectious causes of mortality in India causing more than 331000 deaths in 2007 There were approximately 196 million new TB cases in India in 2007 representing more than 21 per cent of all TB cases worldwide

DrTVRao MD 8

1908-1920 (Chalmette and Guerin) Vaccine (BCG)

Attenuated strain Mycobacterium Bovis

1943 Streptomycin developed

20th November 1944 Critically ill TB patient injected

dramatically recovered

Pharmacological discoveries

DrTVRao MD 9

Selman Abraham Waksman Nobel Prize for his discovery in

1952

DrTVRao MD 10

Pharmacological discoveries

1956-1960 Combination therapy of INH and PZA

cures TB1955 Cycloserine1962 Ethambutol 1963 Rifampicin1970-1977

Combination of Rifampicin and Isoniazid adopted as International regime for treatment of TB DrTVRao MD 11

No one is Immune to TuberculosisNot only infects poor but famous

too

DrTVRao MD 12

Multi Drug Resistant

TuberculosisMDR-TB

DrTVRao MD 13

Definition

MDR-TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs

Single Isoniazid or Rifampicin resistance is not MDR - TB

MDR TB is a laboratory diagnosis

DrTVRao MD 14

Classification of Drugs 3 Groups depending upon the degree

of effectiveness and potential side effects First Line (Primary agents)

are the most effective and have lowest toxicity Isoniazid Rifampin

Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino

salicylic acid Streptomycin Ethambutol Third Line

are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine

DrTVRao MD 15

Basic concepts ndash Keep facts

Primary (Initial) resistanceTB patientrsquos initial Mycobacterium

tuberculosis population resistant to drugs

Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial

population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16

When to suspect MDR TB

Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy

Treatment failure and interruption cases

Close contacts of MDR tuberculosis cases

Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17

What is extensively drug resistant tuberculosis (XDR TB)

Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18

Why XDR - TB a grave concern

Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective

XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB

DrTVRao MD 19

Global Estimates

Classification

Estimated Number of Cases

Estimated Number of

Deaths

All forms TB

88 million 16 million

MDR TB 424000 116000

XDR TB 27000 16000

DrTVRao MD 20

Extensively Drug-Resistant Mycobacterium tuberculosis

India

The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases

DrTVRao MD 21

Drug susceptible TBsect

MDR-TB

1990sect

XDR-TB

2006sect

Total DR

Resistance to HampR ndash

Treatable with 2nd line drugs

Resistance to 2nd line drugs ndashTreatment options seriously restricted

Resistance to all available drugs ndash

No treatment options

or limited resistance manageable with 4 drug regimen - DOTS

Are we Returning to a Pre-antibiotic Era

DrTVRao MD 22

Genesis of MDR TB

Resistance is a man-made amplification of a natural phenomenon

Inadequate drug delivery is main cause of secondary drug resistance

Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains

MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked

DrTVRao MD 23

Factors Contributing to Development

and Spread of MDR and XDR TB Weak TB programs (DOTS)

Low completioncure rates Lack of treatment follow up and

patient support Unreliable drug supply Diagnostic delay

Absent or inadequate infection control measures

Uncontrolled use of 2nd line drugs Fluroquinolones

DrTVRao MD 24

INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis

Regulators of peroxide response

Mechanism of resistance

DrTVRao MD 25

RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)

Reduced Cell wall permeability

Mechanism of resistance

DrTVRao MD 26

Gene location associated Drug-Resistant

Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas

A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A

Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33

DrTVRao MD 27

Current Scientific Documentations on Drug Resistance in

Tuberculosis

DrTVRao MD 28

Alarming Rise of Resistant TuberculosisWHO Report on

Anti-TB Drug Resistance

490000 new cases of MDR-TB each year with gt110000 deaths1

Accounts for 5 of 9 million new cases of TB2

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

XDR-TB reported by as many as 49 countries (by June 2008)3

Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4

Around 40000 XDR-TB cases emerge every year1

1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

DrTVRao MD 29

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 6: Drug Resistant Tuberculosis

From Tuberculosis to Tuberculin

Failure of Robert Koch Tuberculin therapy

did in fact work in Kochs laboratory even though it failed to do so almost anywhere else his reliance an animal experiments which essentially differed from what many of his contemporaries many differed with his ideas

DrTVRao MD 6

Global Status

Nine million people suffer from tuberculosis

Two million people die each year

Tuberculosis accounts for one-third of AIDS deaths world wide every year

DrTVRao MD 7

USAID Report on Tuberculosis in India

India has more new tuberculosis (TB) cases annually than any other country ranking first among the 22 high-burden TB countries worldwide according to the World Health Organizationrsquos (WHOrsquos) Global TB Report 2009 TB remains one of the leading infectious causes of mortality in India causing more than 331000 deaths in 2007 There were approximately 196 million new TB cases in India in 2007 representing more than 21 per cent of all TB cases worldwide

DrTVRao MD 8

1908-1920 (Chalmette and Guerin) Vaccine (BCG)

Attenuated strain Mycobacterium Bovis

1943 Streptomycin developed

20th November 1944 Critically ill TB patient injected

dramatically recovered

Pharmacological discoveries

DrTVRao MD 9

Selman Abraham Waksman Nobel Prize for his discovery in

1952

DrTVRao MD 10

Pharmacological discoveries

1956-1960 Combination therapy of INH and PZA

cures TB1955 Cycloserine1962 Ethambutol 1963 Rifampicin1970-1977

Combination of Rifampicin and Isoniazid adopted as International regime for treatment of TB DrTVRao MD 11

No one is Immune to TuberculosisNot only infects poor but famous

too

DrTVRao MD 12

Multi Drug Resistant

TuberculosisMDR-TB

DrTVRao MD 13

Definition

MDR-TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs

Single Isoniazid or Rifampicin resistance is not MDR - TB

MDR TB is a laboratory diagnosis

DrTVRao MD 14

Classification of Drugs 3 Groups depending upon the degree

of effectiveness and potential side effects First Line (Primary agents)

are the most effective and have lowest toxicity Isoniazid Rifampin

Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino

salicylic acid Streptomycin Ethambutol Third Line

are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine

DrTVRao MD 15

Basic concepts ndash Keep facts

Primary (Initial) resistanceTB patientrsquos initial Mycobacterium

tuberculosis population resistant to drugs

Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial

population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16

When to suspect MDR TB

Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy

Treatment failure and interruption cases

Close contacts of MDR tuberculosis cases

Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17

What is extensively drug resistant tuberculosis (XDR TB)

Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18

Why XDR - TB a grave concern

Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective

XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB

DrTVRao MD 19

Global Estimates

Classification

Estimated Number of Cases

Estimated Number of

Deaths

All forms TB

88 million 16 million

MDR TB 424000 116000

XDR TB 27000 16000

DrTVRao MD 20

Extensively Drug-Resistant Mycobacterium tuberculosis

India

The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases

DrTVRao MD 21

Drug susceptible TBsect

MDR-TB

1990sect

XDR-TB

2006sect

Total DR

Resistance to HampR ndash

Treatable with 2nd line drugs

Resistance to 2nd line drugs ndashTreatment options seriously restricted

Resistance to all available drugs ndash

No treatment options

or limited resistance manageable with 4 drug regimen - DOTS

Are we Returning to a Pre-antibiotic Era

DrTVRao MD 22

Genesis of MDR TB

Resistance is a man-made amplification of a natural phenomenon

Inadequate drug delivery is main cause of secondary drug resistance

Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains

MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked

DrTVRao MD 23

Factors Contributing to Development

and Spread of MDR and XDR TB Weak TB programs (DOTS)

Low completioncure rates Lack of treatment follow up and

patient support Unreliable drug supply Diagnostic delay

Absent or inadequate infection control measures

Uncontrolled use of 2nd line drugs Fluroquinolones

DrTVRao MD 24

INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis

Regulators of peroxide response

Mechanism of resistance

DrTVRao MD 25

RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)

Reduced Cell wall permeability

Mechanism of resistance

DrTVRao MD 26

Gene location associated Drug-Resistant

Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas

A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A

Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33

DrTVRao MD 27

Current Scientific Documentations on Drug Resistance in

Tuberculosis

DrTVRao MD 28

Alarming Rise of Resistant TuberculosisWHO Report on

Anti-TB Drug Resistance

490000 new cases of MDR-TB each year with gt110000 deaths1

Accounts for 5 of 9 million new cases of TB2

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

XDR-TB reported by as many as 49 countries (by June 2008)3

Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4

Around 40000 XDR-TB cases emerge every year1

1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

DrTVRao MD 29

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 7: Drug Resistant Tuberculosis

Global Status

Nine million people suffer from tuberculosis

Two million people die each year

Tuberculosis accounts for one-third of AIDS deaths world wide every year

DrTVRao MD 7

USAID Report on Tuberculosis in India

India has more new tuberculosis (TB) cases annually than any other country ranking first among the 22 high-burden TB countries worldwide according to the World Health Organizationrsquos (WHOrsquos) Global TB Report 2009 TB remains one of the leading infectious causes of mortality in India causing more than 331000 deaths in 2007 There were approximately 196 million new TB cases in India in 2007 representing more than 21 per cent of all TB cases worldwide

DrTVRao MD 8

1908-1920 (Chalmette and Guerin) Vaccine (BCG)

Attenuated strain Mycobacterium Bovis

1943 Streptomycin developed

20th November 1944 Critically ill TB patient injected

dramatically recovered

Pharmacological discoveries

DrTVRao MD 9

Selman Abraham Waksman Nobel Prize for his discovery in

1952

DrTVRao MD 10

Pharmacological discoveries

1956-1960 Combination therapy of INH and PZA

cures TB1955 Cycloserine1962 Ethambutol 1963 Rifampicin1970-1977

Combination of Rifampicin and Isoniazid adopted as International regime for treatment of TB DrTVRao MD 11

No one is Immune to TuberculosisNot only infects poor but famous

too

DrTVRao MD 12

Multi Drug Resistant

TuberculosisMDR-TB

DrTVRao MD 13

Definition

MDR-TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs

Single Isoniazid or Rifampicin resistance is not MDR - TB

MDR TB is a laboratory diagnosis

DrTVRao MD 14

Classification of Drugs 3 Groups depending upon the degree

of effectiveness and potential side effects First Line (Primary agents)

are the most effective and have lowest toxicity Isoniazid Rifampin

Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino

salicylic acid Streptomycin Ethambutol Third Line

are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine

DrTVRao MD 15

Basic concepts ndash Keep facts

Primary (Initial) resistanceTB patientrsquos initial Mycobacterium

tuberculosis population resistant to drugs

Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial

population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16

When to suspect MDR TB

Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy

Treatment failure and interruption cases

Close contacts of MDR tuberculosis cases

Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17

What is extensively drug resistant tuberculosis (XDR TB)

Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18

Why XDR - TB a grave concern

Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective

XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB

DrTVRao MD 19

Global Estimates

Classification

Estimated Number of Cases

Estimated Number of

Deaths

All forms TB

88 million 16 million

MDR TB 424000 116000

XDR TB 27000 16000

DrTVRao MD 20

Extensively Drug-Resistant Mycobacterium tuberculosis

India

The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases

DrTVRao MD 21

Drug susceptible TBsect

MDR-TB

1990sect

XDR-TB

2006sect

Total DR

Resistance to HampR ndash

Treatable with 2nd line drugs

Resistance to 2nd line drugs ndashTreatment options seriously restricted

Resistance to all available drugs ndash

No treatment options

or limited resistance manageable with 4 drug regimen - DOTS

Are we Returning to a Pre-antibiotic Era

DrTVRao MD 22

Genesis of MDR TB

Resistance is a man-made amplification of a natural phenomenon

Inadequate drug delivery is main cause of secondary drug resistance

Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains

MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked

DrTVRao MD 23

Factors Contributing to Development

and Spread of MDR and XDR TB Weak TB programs (DOTS)

Low completioncure rates Lack of treatment follow up and

patient support Unreliable drug supply Diagnostic delay

Absent or inadequate infection control measures

Uncontrolled use of 2nd line drugs Fluroquinolones

DrTVRao MD 24

INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis

Regulators of peroxide response

Mechanism of resistance

DrTVRao MD 25

RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)

Reduced Cell wall permeability

Mechanism of resistance

DrTVRao MD 26

Gene location associated Drug-Resistant

Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas

A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A

Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33

DrTVRao MD 27

Current Scientific Documentations on Drug Resistance in

Tuberculosis

DrTVRao MD 28

Alarming Rise of Resistant TuberculosisWHO Report on

Anti-TB Drug Resistance

490000 new cases of MDR-TB each year with gt110000 deaths1

Accounts for 5 of 9 million new cases of TB2

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

XDR-TB reported by as many as 49 countries (by June 2008)3

Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4

Around 40000 XDR-TB cases emerge every year1

1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

DrTVRao MD 29

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 8: Drug Resistant Tuberculosis

USAID Report on Tuberculosis in India

India has more new tuberculosis (TB) cases annually than any other country ranking first among the 22 high-burden TB countries worldwide according to the World Health Organizationrsquos (WHOrsquos) Global TB Report 2009 TB remains one of the leading infectious causes of mortality in India causing more than 331000 deaths in 2007 There were approximately 196 million new TB cases in India in 2007 representing more than 21 per cent of all TB cases worldwide

DrTVRao MD 8

1908-1920 (Chalmette and Guerin) Vaccine (BCG)

Attenuated strain Mycobacterium Bovis

1943 Streptomycin developed

20th November 1944 Critically ill TB patient injected

dramatically recovered

Pharmacological discoveries

DrTVRao MD 9

Selman Abraham Waksman Nobel Prize for his discovery in

1952

DrTVRao MD 10

Pharmacological discoveries

1956-1960 Combination therapy of INH and PZA

cures TB1955 Cycloserine1962 Ethambutol 1963 Rifampicin1970-1977

Combination of Rifampicin and Isoniazid adopted as International regime for treatment of TB DrTVRao MD 11

No one is Immune to TuberculosisNot only infects poor but famous

too

DrTVRao MD 12

Multi Drug Resistant

TuberculosisMDR-TB

DrTVRao MD 13

Definition

MDR-TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs

Single Isoniazid or Rifampicin resistance is not MDR - TB

MDR TB is a laboratory diagnosis

DrTVRao MD 14

Classification of Drugs 3 Groups depending upon the degree

of effectiveness and potential side effects First Line (Primary agents)

are the most effective and have lowest toxicity Isoniazid Rifampin

Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino

salicylic acid Streptomycin Ethambutol Third Line

are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine

DrTVRao MD 15

Basic concepts ndash Keep facts

Primary (Initial) resistanceTB patientrsquos initial Mycobacterium

tuberculosis population resistant to drugs

Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial

population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16

When to suspect MDR TB

Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy

Treatment failure and interruption cases

Close contacts of MDR tuberculosis cases

Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17

What is extensively drug resistant tuberculosis (XDR TB)

Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18

Why XDR - TB a grave concern

Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective

XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB

DrTVRao MD 19

Global Estimates

Classification

Estimated Number of Cases

Estimated Number of

Deaths

All forms TB

88 million 16 million

MDR TB 424000 116000

XDR TB 27000 16000

DrTVRao MD 20

Extensively Drug-Resistant Mycobacterium tuberculosis

India

The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases

DrTVRao MD 21

Drug susceptible TBsect

MDR-TB

1990sect

XDR-TB

2006sect

Total DR

Resistance to HampR ndash

Treatable with 2nd line drugs

Resistance to 2nd line drugs ndashTreatment options seriously restricted

Resistance to all available drugs ndash

No treatment options

or limited resistance manageable with 4 drug regimen - DOTS

Are we Returning to a Pre-antibiotic Era

DrTVRao MD 22

Genesis of MDR TB

Resistance is a man-made amplification of a natural phenomenon

Inadequate drug delivery is main cause of secondary drug resistance

Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains

MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked

DrTVRao MD 23

Factors Contributing to Development

and Spread of MDR and XDR TB Weak TB programs (DOTS)

Low completioncure rates Lack of treatment follow up and

patient support Unreliable drug supply Diagnostic delay

Absent or inadequate infection control measures

Uncontrolled use of 2nd line drugs Fluroquinolones

DrTVRao MD 24

INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis

Regulators of peroxide response

Mechanism of resistance

DrTVRao MD 25

RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)

Reduced Cell wall permeability

Mechanism of resistance

DrTVRao MD 26

Gene location associated Drug-Resistant

Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas

A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A

Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33

DrTVRao MD 27

Current Scientific Documentations on Drug Resistance in

Tuberculosis

DrTVRao MD 28

Alarming Rise of Resistant TuberculosisWHO Report on

Anti-TB Drug Resistance

490000 new cases of MDR-TB each year with gt110000 deaths1

Accounts for 5 of 9 million new cases of TB2

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

XDR-TB reported by as many as 49 countries (by June 2008)3

Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4

Around 40000 XDR-TB cases emerge every year1

1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

DrTVRao MD 29

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 9: Drug Resistant Tuberculosis

1908-1920 (Chalmette and Guerin) Vaccine (BCG)

Attenuated strain Mycobacterium Bovis

1943 Streptomycin developed

20th November 1944 Critically ill TB patient injected

dramatically recovered

Pharmacological discoveries

DrTVRao MD 9

Selman Abraham Waksman Nobel Prize for his discovery in

1952

DrTVRao MD 10

Pharmacological discoveries

1956-1960 Combination therapy of INH and PZA

cures TB1955 Cycloserine1962 Ethambutol 1963 Rifampicin1970-1977

Combination of Rifampicin and Isoniazid adopted as International regime for treatment of TB DrTVRao MD 11

No one is Immune to TuberculosisNot only infects poor but famous

too

DrTVRao MD 12

Multi Drug Resistant

TuberculosisMDR-TB

DrTVRao MD 13

Definition

MDR-TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs

Single Isoniazid or Rifampicin resistance is not MDR - TB

MDR TB is a laboratory diagnosis

DrTVRao MD 14

Classification of Drugs 3 Groups depending upon the degree

of effectiveness and potential side effects First Line (Primary agents)

are the most effective and have lowest toxicity Isoniazid Rifampin

Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino

salicylic acid Streptomycin Ethambutol Third Line

are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine

DrTVRao MD 15

Basic concepts ndash Keep facts

Primary (Initial) resistanceTB patientrsquos initial Mycobacterium

tuberculosis population resistant to drugs

Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial

population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16

When to suspect MDR TB

Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy

Treatment failure and interruption cases

Close contacts of MDR tuberculosis cases

Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17

What is extensively drug resistant tuberculosis (XDR TB)

Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18

Why XDR - TB a grave concern

Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective

XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB

DrTVRao MD 19

Global Estimates

Classification

Estimated Number of Cases

Estimated Number of

Deaths

All forms TB

88 million 16 million

MDR TB 424000 116000

XDR TB 27000 16000

DrTVRao MD 20

Extensively Drug-Resistant Mycobacterium tuberculosis

India

The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases

DrTVRao MD 21

Drug susceptible TBsect

MDR-TB

1990sect

XDR-TB

2006sect

Total DR

Resistance to HampR ndash

Treatable with 2nd line drugs

Resistance to 2nd line drugs ndashTreatment options seriously restricted

Resistance to all available drugs ndash

No treatment options

or limited resistance manageable with 4 drug regimen - DOTS

Are we Returning to a Pre-antibiotic Era

DrTVRao MD 22

Genesis of MDR TB

Resistance is a man-made amplification of a natural phenomenon

Inadequate drug delivery is main cause of secondary drug resistance

Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains

MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked

DrTVRao MD 23

Factors Contributing to Development

and Spread of MDR and XDR TB Weak TB programs (DOTS)

Low completioncure rates Lack of treatment follow up and

patient support Unreliable drug supply Diagnostic delay

Absent or inadequate infection control measures

Uncontrolled use of 2nd line drugs Fluroquinolones

DrTVRao MD 24

INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis

Regulators of peroxide response

Mechanism of resistance

DrTVRao MD 25

RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)

Reduced Cell wall permeability

Mechanism of resistance

DrTVRao MD 26

Gene location associated Drug-Resistant

Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas

A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A

Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33

DrTVRao MD 27

Current Scientific Documentations on Drug Resistance in

Tuberculosis

DrTVRao MD 28

Alarming Rise of Resistant TuberculosisWHO Report on

Anti-TB Drug Resistance

490000 new cases of MDR-TB each year with gt110000 deaths1

Accounts for 5 of 9 million new cases of TB2

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

XDR-TB reported by as many as 49 countries (by June 2008)3

Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4

Around 40000 XDR-TB cases emerge every year1

1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

DrTVRao MD 29

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 10: Drug Resistant Tuberculosis

Selman Abraham Waksman Nobel Prize for his discovery in

1952

DrTVRao MD 10

Pharmacological discoveries

1956-1960 Combination therapy of INH and PZA

cures TB1955 Cycloserine1962 Ethambutol 1963 Rifampicin1970-1977

Combination of Rifampicin and Isoniazid adopted as International regime for treatment of TB DrTVRao MD 11

No one is Immune to TuberculosisNot only infects poor but famous

too

DrTVRao MD 12

Multi Drug Resistant

TuberculosisMDR-TB

DrTVRao MD 13

Definition

MDR-TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs

Single Isoniazid or Rifampicin resistance is not MDR - TB

MDR TB is a laboratory diagnosis

DrTVRao MD 14

Classification of Drugs 3 Groups depending upon the degree

of effectiveness and potential side effects First Line (Primary agents)

are the most effective and have lowest toxicity Isoniazid Rifampin

Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino

salicylic acid Streptomycin Ethambutol Third Line

are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine

DrTVRao MD 15

Basic concepts ndash Keep facts

Primary (Initial) resistanceTB patientrsquos initial Mycobacterium

tuberculosis population resistant to drugs

Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial

population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16

When to suspect MDR TB

Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy

Treatment failure and interruption cases

Close contacts of MDR tuberculosis cases

Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17

What is extensively drug resistant tuberculosis (XDR TB)

Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18

Why XDR - TB a grave concern

Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective

XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB

DrTVRao MD 19

Global Estimates

Classification

Estimated Number of Cases

Estimated Number of

Deaths

All forms TB

88 million 16 million

MDR TB 424000 116000

XDR TB 27000 16000

DrTVRao MD 20

Extensively Drug-Resistant Mycobacterium tuberculosis

India

The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases

DrTVRao MD 21

Drug susceptible TBsect

MDR-TB

1990sect

XDR-TB

2006sect

Total DR

Resistance to HampR ndash

Treatable with 2nd line drugs

Resistance to 2nd line drugs ndashTreatment options seriously restricted

Resistance to all available drugs ndash

No treatment options

or limited resistance manageable with 4 drug regimen - DOTS

Are we Returning to a Pre-antibiotic Era

DrTVRao MD 22

Genesis of MDR TB

Resistance is a man-made amplification of a natural phenomenon

Inadequate drug delivery is main cause of secondary drug resistance

Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains

MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked

DrTVRao MD 23

Factors Contributing to Development

and Spread of MDR and XDR TB Weak TB programs (DOTS)

Low completioncure rates Lack of treatment follow up and

patient support Unreliable drug supply Diagnostic delay

Absent or inadequate infection control measures

Uncontrolled use of 2nd line drugs Fluroquinolones

DrTVRao MD 24

INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis

Regulators of peroxide response

Mechanism of resistance

DrTVRao MD 25

RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)

Reduced Cell wall permeability

Mechanism of resistance

DrTVRao MD 26

Gene location associated Drug-Resistant

Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas

A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A

Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33

DrTVRao MD 27

Current Scientific Documentations on Drug Resistance in

Tuberculosis

DrTVRao MD 28

Alarming Rise of Resistant TuberculosisWHO Report on

Anti-TB Drug Resistance

490000 new cases of MDR-TB each year with gt110000 deaths1

Accounts for 5 of 9 million new cases of TB2

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

XDR-TB reported by as many as 49 countries (by June 2008)3

Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4

Around 40000 XDR-TB cases emerge every year1

1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

DrTVRao MD 29

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 11: Drug Resistant Tuberculosis

Pharmacological discoveries

1956-1960 Combination therapy of INH and PZA

cures TB1955 Cycloserine1962 Ethambutol 1963 Rifampicin1970-1977

Combination of Rifampicin and Isoniazid adopted as International regime for treatment of TB DrTVRao MD 11

No one is Immune to TuberculosisNot only infects poor but famous

too

DrTVRao MD 12

Multi Drug Resistant

TuberculosisMDR-TB

DrTVRao MD 13

Definition

MDR-TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs

Single Isoniazid or Rifampicin resistance is not MDR - TB

MDR TB is a laboratory diagnosis

DrTVRao MD 14

Classification of Drugs 3 Groups depending upon the degree

of effectiveness and potential side effects First Line (Primary agents)

are the most effective and have lowest toxicity Isoniazid Rifampin

Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino

salicylic acid Streptomycin Ethambutol Third Line

are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine

DrTVRao MD 15

Basic concepts ndash Keep facts

Primary (Initial) resistanceTB patientrsquos initial Mycobacterium

tuberculosis population resistant to drugs

Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial

population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16

When to suspect MDR TB

Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy

Treatment failure and interruption cases

Close contacts of MDR tuberculosis cases

Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17

What is extensively drug resistant tuberculosis (XDR TB)

Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18

Why XDR - TB a grave concern

Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective

XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB

DrTVRao MD 19

Global Estimates

Classification

Estimated Number of Cases

Estimated Number of

Deaths

All forms TB

88 million 16 million

MDR TB 424000 116000

XDR TB 27000 16000

DrTVRao MD 20

Extensively Drug-Resistant Mycobacterium tuberculosis

India

The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases

DrTVRao MD 21

Drug susceptible TBsect

MDR-TB

1990sect

XDR-TB

2006sect

Total DR

Resistance to HampR ndash

Treatable with 2nd line drugs

Resistance to 2nd line drugs ndashTreatment options seriously restricted

Resistance to all available drugs ndash

No treatment options

or limited resistance manageable with 4 drug regimen - DOTS

Are we Returning to a Pre-antibiotic Era

DrTVRao MD 22

Genesis of MDR TB

Resistance is a man-made amplification of a natural phenomenon

Inadequate drug delivery is main cause of secondary drug resistance

Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains

MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked

DrTVRao MD 23

Factors Contributing to Development

and Spread of MDR and XDR TB Weak TB programs (DOTS)

Low completioncure rates Lack of treatment follow up and

patient support Unreliable drug supply Diagnostic delay

Absent or inadequate infection control measures

Uncontrolled use of 2nd line drugs Fluroquinolones

DrTVRao MD 24

INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis

Regulators of peroxide response

Mechanism of resistance

DrTVRao MD 25

RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)

Reduced Cell wall permeability

Mechanism of resistance

DrTVRao MD 26

Gene location associated Drug-Resistant

Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas

A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A

Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33

DrTVRao MD 27

Current Scientific Documentations on Drug Resistance in

Tuberculosis

DrTVRao MD 28

Alarming Rise of Resistant TuberculosisWHO Report on

Anti-TB Drug Resistance

490000 new cases of MDR-TB each year with gt110000 deaths1

Accounts for 5 of 9 million new cases of TB2

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

XDR-TB reported by as many as 49 countries (by June 2008)3

Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4

Around 40000 XDR-TB cases emerge every year1

1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

DrTVRao MD 29

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 12: Drug Resistant Tuberculosis

No one is Immune to TuberculosisNot only infects poor but famous

too

DrTVRao MD 12

Multi Drug Resistant

TuberculosisMDR-TB

DrTVRao MD 13

Definition

MDR-TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs

Single Isoniazid or Rifampicin resistance is not MDR - TB

MDR TB is a laboratory diagnosis

DrTVRao MD 14

Classification of Drugs 3 Groups depending upon the degree

of effectiveness and potential side effects First Line (Primary agents)

are the most effective and have lowest toxicity Isoniazid Rifampin

Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino

salicylic acid Streptomycin Ethambutol Third Line

are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine

DrTVRao MD 15

Basic concepts ndash Keep facts

Primary (Initial) resistanceTB patientrsquos initial Mycobacterium

tuberculosis population resistant to drugs

Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial

population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16

When to suspect MDR TB

Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy

Treatment failure and interruption cases

Close contacts of MDR tuberculosis cases

Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17

What is extensively drug resistant tuberculosis (XDR TB)

Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18

Why XDR - TB a grave concern

Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective

XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB

DrTVRao MD 19

Global Estimates

Classification

Estimated Number of Cases

Estimated Number of

Deaths

All forms TB

88 million 16 million

MDR TB 424000 116000

XDR TB 27000 16000

DrTVRao MD 20

Extensively Drug-Resistant Mycobacterium tuberculosis

India

The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases

DrTVRao MD 21

Drug susceptible TBsect

MDR-TB

1990sect

XDR-TB

2006sect

Total DR

Resistance to HampR ndash

Treatable with 2nd line drugs

Resistance to 2nd line drugs ndashTreatment options seriously restricted

Resistance to all available drugs ndash

No treatment options

or limited resistance manageable with 4 drug regimen - DOTS

Are we Returning to a Pre-antibiotic Era

DrTVRao MD 22

Genesis of MDR TB

Resistance is a man-made amplification of a natural phenomenon

Inadequate drug delivery is main cause of secondary drug resistance

Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains

MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked

DrTVRao MD 23

Factors Contributing to Development

and Spread of MDR and XDR TB Weak TB programs (DOTS)

Low completioncure rates Lack of treatment follow up and

patient support Unreliable drug supply Diagnostic delay

Absent or inadequate infection control measures

Uncontrolled use of 2nd line drugs Fluroquinolones

DrTVRao MD 24

INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis

Regulators of peroxide response

Mechanism of resistance

DrTVRao MD 25

RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)

Reduced Cell wall permeability

Mechanism of resistance

DrTVRao MD 26

Gene location associated Drug-Resistant

Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas

A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A

Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33

DrTVRao MD 27

Current Scientific Documentations on Drug Resistance in

Tuberculosis

DrTVRao MD 28

Alarming Rise of Resistant TuberculosisWHO Report on

Anti-TB Drug Resistance

490000 new cases of MDR-TB each year with gt110000 deaths1

Accounts for 5 of 9 million new cases of TB2

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

XDR-TB reported by as many as 49 countries (by June 2008)3

Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4

Around 40000 XDR-TB cases emerge every year1

1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

DrTVRao MD 29

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 13: Drug Resistant Tuberculosis

Multi Drug Resistant

TuberculosisMDR-TB

DrTVRao MD 13

Definition

MDR-TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs

Single Isoniazid or Rifampicin resistance is not MDR - TB

MDR TB is a laboratory diagnosis

DrTVRao MD 14

Classification of Drugs 3 Groups depending upon the degree

of effectiveness and potential side effects First Line (Primary agents)

are the most effective and have lowest toxicity Isoniazid Rifampin

Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino

salicylic acid Streptomycin Ethambutol Third Line

are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine

DrTVRao MD 15

Basic concepts ndash Keep facts

Primary (Initial) resistanceTB patientrsquos initial Mycobacterium

tuberculosis population resistant to drugs

Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial

population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16

When to suspect MDR TB

Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy

Treatment failure and interruption cases

Close contacts of MDR tuberculosis cases

Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17

What is extensively drug resistant tuberculosis (XDR TB)

Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18

Why XDR - TB a grave concern

Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective

XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB

DrTVRao MD 19

Global Estimates

Classification

Estimated Number of Cases

Estimated Number of

Deaths

All forms TB

88 million 16 million

MDR TB 424000 116000

XDR TB 27000 16000

DrTVRao MD 20

Extensively Drug-Resistant Mycobacterium tuberculosis

India

The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases

DrTVRao MD 21

Drug susceptible TBsect

MDR-TB

1990sect

XDR-TB

2006sect

Total DR

Resistance to HampR ndash

Treatable with 2nd line drugs

Resistance to 2nd line drugs ndashTreatment options seriously restricted

Resistance to all available drugs ndash

No treatment options

or limited resistance manageable with 4 drug regimen - DOTS

Are we Returning to a Pre-antibiotic Era

DrTVRao MD 22

Genesis of MDR TB

Resistance is a man-made amplification of a natural phenomenon

Inadequate drug delivery is main cause of secondary drug resistance

Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains

MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked

DrTVRao MD 23

Factors Contributing to Development

and Spread of MDR and XDR TB Weak TB programs (DOTS)

Low completioncure rates Lack of treatment follow up and

patient support Unreliable drug supply Diagnostic delay

Absent or inadequate infection control measures

Uncontrolled use of 2nd line drugs Fluroquinolones

DrTVRao MD 24

INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis

Regulators of peroxide response

Mechanism of resistance

DrTVRao MD 25

RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)

Reduced Cell wall permeability

Mechanism of resistance

DrTVRao MD 26

Gene location associated Drug-Resistant

Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas

A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A

Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33

DrTVRao MD 27

Current Scientific Documentations on Drug Resistance in

Tuberculosis

DrTVRao MD 28

Alarming Rise of Resistant TuberculosisWHO Report on

Anti-TB Drug Resistance

490000 new cases of MDR-TB each year with gt110000 deaths1

Accounts for 5 of 9 million new cases of TB2

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

XDR-TB reported by as many as 49 countries (by June 2008)3

Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4

Around 40000 XDR-TB cases emerge every year1

1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

DrTVRao MD 29

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 14: Drug Resistant Tuberculosis

Definition

MDR-TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs

Single Isoniazid or Rifampicin resistance is not MDR - TB

MDR TB is a laboratory diagnosis

DrTVRao MD 14

Classification of Drugs 3 Groups depending upon the degree

of effectiveness and potential side effects First Line (Primary agents)

are the most effective and have lowest toxicity Isoniazid Rifampin

Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino

salicylic acid Streptomycin Ethambutol Third Line

are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine

DrTVRao MD 15

Basic concepts ndash Keep facts

Primary (Initial) resistanceTB patientrsquos initial Mycobacterium

tuberculosis population resistant to drugs

Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial

population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16

When to suspect MDR TB

Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy

Treatment failure and interruption cases

Close contacts of MDR tuberculosis cases

Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17

What is extensively drug resistant tuberculosis (XDR TB)

Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18

Why XDR - TB a grave concern

Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective

XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB

DrTVRao MD 19

Global Estimates

Classification

Estimated Number of Cases

Estimated Number of

Deaths

All forms TB

88 million 16 million

MDR TB 424000 116000

XDR TB 27000 16000

DrTVRao MD 20

Extensively Drug-Resistant Mycobacterium tuberculosis

India

The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases

DrTVRao MD 21

Drug susceptible TBsect

MDR-TB

1990sect

XDR-TB

2006sect

Total DR

Resistance to HampR ndash

Treatable with 2nd line drugs

Resistance to 2nd line drugs ndashTreatment options seriously restricted

Resistance to all available drugs ndash

No treatment options

or limited resistance manageable with 4 drug regimen - DOTS

Are we Returning to a Pre-antibiotic Era

DrTVRao MD 22

Genesis of MDR TB

Resistance is a man-made amplification of a natural phenomenon

Inadequate drug delivery is main cause of secondary drug resistance

Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains

MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked

DrTVRao MD 23

Factors Contributing to Development

and Spread of MDR and XDR TB Weak TB programs (DOTS)

Low completioncure rates Lack of treatment follow up and

patient support Unreliable drug supply Diagnostic delay

Absent or inadequate infection control measures

Uncontrolled use of 2nd line drugs Fluroquinolones

DrTVRao MD 24

INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis

Regulators of peroxide response

Mechanism of resistance

DrTVRao MD 25

RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)

Reduced Cell wall permeability

Mechanism of resistance

DrTVRao MD 26

Gene location associated Drug-Resistant

Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas

A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A

Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33

DrTVRao MD 27

Current Scientific Documentations on Drug Resistance in

Tuberculosis

DrTVRao MD 28

Alarming Rise of Resistant TuberculosisWHO Report on

Anti-TB Drug Resistance

490000 new cases of MDR-TB each year with gt110000 deaths1

Accounts for 5 of 9 million new cases of TB2

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

XDR-TB reported by as many as 49 countries (by June 2008)3

Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4

Around 40000 XDR-TB cases emerge every year1

1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

DrTVRao MD 29

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 15: Drug Resistant Tuberculosis

Classification of Drugs 3 Groups depending upon the degree

of effectiveness and potential side effects First Line (Primary agents)

are the most effective and have lowest toxicity Isoniazid Rifampin

Second LineLess effective and more toxic effectsinclude (in no particular order) p-amino

salicylic acid Streptomycin Ethambutol Third Line

are least effective and most toxic Amikacin Kanamycin Capreomycin Viomycin Kanamycin Cycloserine

DrTVRao MD 15

Basic concepts ndash Keep facts

Primary (Initial) resistanceTB patientrsquos initial Mycobacterium

tuberculosis population resistant to drugs

Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial

population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16

When to suspect MDR TB

Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy

Treatment failure and interruption cases

Close contacts of MDR tuberculosis cases

Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17

What is extensively drug resistant tuberculosis (XDR TB)

Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18

Why XDR - TB a grave concern

Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective

XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB

DrTVRao MD 19

Global Estimates

Classification

Estimated Number of Cases

Estimated Number of

Deaths

All forms TB

88 million 16 million

MDR TB 424000 116000

XDR TB 27000 16000

DrTVRao MD 20

Extensively Drug-Resistant Mycobacterium tuberculosis

India

The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases

DrTVRao MD 21

Drug susceptible TBsect

MDR-TB

1990sect

XDR-TB

2006sect

Total DR

Resistance to HampR ndash

Treatable with 2nd line drugs

Resistance to 2nd line drugs ndashTreatment options seriously restricted

Resistance to all available drugs ndash

No treatment options

or limited resistance manageable with 4 drug regimen - DOTS

Are we Returning to a Pre-antibiotic Era

DrTVRao MD 22

Genesis of MDR TB

Resistance is a man-made amplification of a natural phenomenon

Inadequate drug delivery is main cause of secondary drug resistance

Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains

MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked

DrTVRao MD 23

Factors Contributing to Development

and Spread of MDR and XDR TB Weak TB programs (DOTS)

Low completioncure rates Lack of treatment follow up and

patient support Unreliable drug supply Diagnostic delay

Absent or inadequate infection control measures

Uncontrolled use of 2nd line drugs Fluroquinolones

DrTVRao MD 24

INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis

Regulators of peroxide response

Mechanism of resistance

DrTVRao MD 25

RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)

Reduced Cell wall permeability

Mechanism of resistance

DrTVRao MD 26

Gene location associated Drug-Resistant

Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas

A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A

Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33

DrTVRao MD 27

Current Scientific Documentations on Drug Resistance in

Tuberculosis

DrTVRao MD 28

Alarming Rise of Resistant TuberculosisWHO Report on

Anti-TB Drug Resistance

490000 new cases of MDR-TB each year with gt110000 deaths1

Accounts for 5 of 9 million new cases of TB2

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

XDR-TB reported by as many as 49 countries (by June 2008)3

Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4

Around 40000 XDR-TB cases emerge every year1

1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

DrTVRao MD 29

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 16: Drug Resistant Tuberculosis

Basic concepts ndash Keep facts

Primary (Initial) resistanceTB patientrsquos initial Mycobacterium

tuberculosis population resistant to drugs

Secondary (Acquired) resistanceDrug-resistant M tuberculosis in initial

population selected by inappropriate drug use (inadequate treatment or non-adherence) DrTVRao MD 16

When to suspect MDR TB

Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy

Treatment failure and interruption cases

Close contacts of MDR tuberculosis cases

Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17

What is extensively drug resistant tuberculosis (XDR TB)

Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18

Why XDR - TB a grave concern

Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective

XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB

DrTVRao MD 19

Global Estimates

Classification

Estimated Number of Cases

Estimated Number of

Deaths

All forms TB

88 million 16 million

MDR TB 424000 116000

XDR TB 27000 16000

DrTVRao MD 20

Extensively Drug-Resistant Mycobacterium tuberculosis

India

The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases

DrTVRao MD 21

Drug susceptible TBsect

MDR-TB

1990sect

XDR-TB

2006sect

Total DR

Resistance to HampR ndash

Treatable with 2nd line drugs

Resistance to 2nd line drugs ndashTreatment options seriously restricted

Resistance to all available drugs ndash

No treatment options

or limited resistance manageable with 4 drug regimen - DOTS

Are we Returning to a Pre-antibiotic Era

DrTVRao MD 22

Genesis of MDR TB

Resistance is a man-made amplification of a natural phenomenon

Inadequate drug delivery is main cause of secondary drug resistance

Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains

MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked

DrTVRao MD 23

Factors Contributing to Development

and Spread of MDR and XDR TB Weak TB programs (DOTS)

Low completioncure rates Lack of treatment follow up and

patient support Unreliable drug supply Diagnostic delay

Absent or inadequate infection control measures

Uncontrolled use of 2nd line drugs Fluroquinolones

DrTVRao MD 24

INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis

Regulators of peroxide response

Mechanism of resistance

DrTVRao MD 25

RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)

Reduced Cell wall permeability

Mechanism of resistance

DrTVRao MD 26

Gene location associated Drug-Resistant

Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas

A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A

Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33

DrTVRao MD 27

Current Scientific Documentations on Drug Resistance in

Tuberculosis

DrTVRao MD 28

Alarming Rise of Resistant TuberculosisWHO Report on

Anti-TB Drug Resistance

490000 new cases of MDR-TB each year with gt110000 deaths1

Accounts for 5 of 9 million new cases of TB2

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

XDR-TB reported by as many as 49 countries (by June 2008)3

Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4

Around 40000 XDR-TB cases emerge every year1

1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

DrTVRao MD 29

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 17: Drug Resistant Tuberculosis

When to suspect MDR TB

Re-treatment patients whorsquos sputum smear remains positive after three monthsrsquo of intensive therapy

Treatment failure and interruption cases

Close contacts of MDR tuberculosis cases

Positive diagnoses with TB culture and susceptibility testing DrTVRao MD 17

What is extensively drug resistant tuberculosis (XDR TB)

Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18

Why XDR - TB a grave concern

Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective

XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB

DrTVRao MD 19

Global Estimates

Classification

Estimated Number of Cases

Estimated Number of

Deaths

All forms TB

88 million 16 million

MDR TB 424000 116000

XDR TB 27000 16000

DrTVRao MD 20

Extensively Drug-Resistant Mycobacterium tuberculosis

India

The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases

DrTVRao MD 21

Drug susceptible TBsect

MDR-TB

1990sect

XDR-TB

2006sect

Total DR

Resistance to HampR ndash

Treatable with 2nd line drugs

Resistance to 2nd line drugs ndashTreatment options seriously restricted

Resistance to all available drugs ndash

No treatment options

or limited resistance manageable with 4 drug regimen - DOTS

Are we Returning to a Pre-antibiotic Era

DrTVRao MD 22

Genesis of MDR TB

Resistance is a man-made amplification of a natural phenomenon

Inadequate drug delivery is main cause of secondary drug resistance

Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains

MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked

DrTVRao MD 23

Factors Contributing to Development

and Spread of MDR and XDR TB Weak TB programs (DOTS)

Low completioncure rates Lack of treatment follow up and

patient support Unreliable drug supply Diagnostic delay

Absent or inadequate infection control measures

Uncontrolled use of 2nd line drugs Fluroquinolones

DrTVRao MD 24

INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis

Regulators of peroxide response

Mechanism of resistance

DrTVRao MD 25

RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)

Reduced Cell wall permeability

Mechanism of resistance

DrTVRao MD 26

Gene location associated Drug-Resistant

Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas

A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A

Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33

DrTVRao MD 27

Current Scientific Documentations on Drug Resistance in

Tuberculosis

DrTVRao MD 28

Alarming Rise of Resistant TuberculosisWHO Report on

Anti-TB Drug Resistance

490000 new cases of MDR-TB each year with gt110000 deaths1

Accounts for 5 of 9 million new cases of TB2

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

XDR-TB reported by as many as 49 countries (by June 2008)3

Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4

Around 40000 XDR-TB cases emerge every year1

1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

DrTVRao MD 29

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 18: Drug Resistant Tuberculosis

What is extensively drug resistant tuberculosis (XDR TB)

Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB XDR TB is defined as TB which is resistant to isoniazid and rifampin plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (ie amikacin kanamycin or capreomycin)DrTVRao MD 18

Why XDR - TB a grave concern

Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective

XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB

DrTVRao MD 19

Global Estimates

Classification

Estimated Number of Cases

Estimated Number of

Deaths

All forms TB

88 million 16 million

MDR TB 424000 116000

XDR TB 27000 16000

DrTVRao MD 20

Extensively Drug-Resistant Mycobacterium tuberculosis

India

The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases

DrTVRao MD 21

Drug susceptible TBsect

MDR-TB

1990sect

XDR-TB

2006sect

Total DR

Resistance to HampR ndash

Treatable with 2nd line drugs

Resistance to 2nd line drugs ndashTreatment options seriously restricted

Resistance to all available drugs ndash

No treatment options

or limited resistance manageable with 4 drug regimen - DOTS

Are we Returning to a Pre-antibiotic Era

DrTVRao MD 22

Genesis of MDR TB

Resistance is a man-made amplification of a natural phenomenon

Inadequate drug delivery is main cause of secondary drug resistance

Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains

MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked

DrTVRao MD 23

Factors Contributing to Development

and Spread of MDR and XDR TB Weak TB programs (DOTS)

Low completioncure rates Lack of treatment follow up and

patient support Unreliable drug supply Diagnostic delay

Absent or inadequate infection control measures

Uncontrolled use of 2nd line drugs Fluroquinolones

DrTVRao MD 24

INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis

Regulators of peroxide response

Mechanism of resistance

DrTVRao MD 25

RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)

Reduced Cell wall permeability

Mechanism of resistance

DrTVRao MD 26

Gene location associated Drug-Resistant

Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas

A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A

Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33

DrTVRao MD 27

Current Scientific Documentations on Drug Resistance in

Tuberculosis

DrTVRao MD 28

Alarming Rise of Resistant TuberculosisWHO Report on

Anti-TB Drug Resistance

490000 new cases of MDR-TB each year with gt110000 deaths1

Accounts for 5 of 9 million new cases of TB2

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

XDR-TB reported by as many as 49 countries (by June 2008)3

Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4

Around 40000 XDR-TB cases emerge every year1

1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

DrTVRao MD 29

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 19: Drug Resistant Tuberculosis

Why XDR - TB a grave concern

Because XDR TB is resistant to first-line and second line drugs patients are left with treatment options that are much less effective

XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system These persons are more likely to develop TB disease once they are infected and also have a higher risk of death once they develop TB

DrTVRao MD 19

Global Estimates

Classification

Estimated Number of Cases

Estimated Number of

Deaths

All forms TB

88 million 16 million

MDR TB 424000 116000

XDR TB 27000 16000

DrTVRao MD 20

Extensively Drug-Resistant Mycobacterium tuberculosis

India

The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases

DrTVRao MD 21

Drug susceptible TBsect

MDR-TB

1990sect

XDR-TB

2006sect

Total DR

Resistance to HampR ndash

Treatable with 2nd line drugs

Resistance to 2nd line drugs ndashTreatment options seriously restricted

Resistance to all available drugs ndash

No treatment options

or limited resistance manageable with 4 drug regimen - DOTS

Are we Returning to a Pre-antibiotic Era

DrTVRao MD 22

Genesis of MDR TB

Resistance is a man-made amplification of a natural phenomenon

Inadequate drug delivery is main cause of secondary drug resistance

Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains

MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked

DrTVRao MD 23

Factors Contributing to Development

and Spread of MDR and XDR TB Weak TB programs (DOTS)

Low completioncure rates Lack of treatment follow up and

patient support Unreliable drug supply Diagnostic delay

Absent or inadequate infection control measures

Uncontrolled use of 2nd line drugs Fluroquinolones

DrTVRao MD 24

INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis

Regulators of peroxide response

Mechanism of resistance

DrTVRao MD 25

RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)

Reduced Cell wall permeability

Mechanism of resistance

DrTVRao MD 26

Gene location associated Drug-Resistant

Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas

A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A

Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33

DrTVRao MD 27

Current Scientific Documentations on Drug Resistance in

Tuberculosis

DrTVRao MD 28

Alarming Rise of Resistant TuberculosisWHO Report on

Anti-TB Drug Resistance

490000 new cases of MDR-TB each year with gt110000 deaths1

Accounts for 5 of 9 million new cases of TB2

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

XDR-TB reported by as many as 49 countries (by June 2008)3

Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4

Around 40000 XDR-TB cases emerge every year1

1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

DrTVRao MD 29

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 20: Drug Resistant Tuberculosis

Global Estimates

Classification

Estimated Number of Cases

Estimated Number of

Deaths

All forms TB

88 million 16 million

MDR TB 424000 116000

XDR TB 27000 16000

DrTVRao MD 20

Extensively Drug-Resistant Mycobacterium tuberculosis

India

The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases

DrTVRao MD 21

Drug susceptible TBsect

MDR-TB

1990sect

XDR-TB

2006sect

Total DR

Resistance to HampR ndash

Treatable with 2nd line drugs

Resistance to 2nd line drugs ndashTreatment options seriously restricted

Resistance to all available drugs ndash

No treatment options

or limited resistance manageable with 4 drug regimen - DOTS

Are we Returning to a Pre-antibiotic Era

DrTVRao MD 22

Genesis of MDR TB

Resistance is a man-made amplification of a natural phenomenon

Inadequate drug delivery is main cause of secondary drug resistance

Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains

MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked

DrTVRao MD 23

Factors Contributing to Development

and Spread of MDR and XDR TB Weak TB programs (DOTS)

Low completioncure rates Lack of treatment follow up and

patient support Unreliable drug supply Diagnostic delay

Absent or inadequate infection control measures

Uncontrolled use of 2nd line drugs Fluroquinolones

DrTVRao MD 24

INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis

Regulators of peroxide response

Mechanism of resistance

DrTVRao MD 25

RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)

Reduced Cell wall permeability

Mechanism of resistance

DrTVRao MD 26

Gene location associated Drug-Resistant

Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas

A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A

Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33

DrTVRao MD 27

Current Scientific Documentations on Drug Resistance in

Tuberculosis

DrTVRao MD 28

Alarming Rise of Resistant TuberculosisWHO Report on

Anti-TB Drug Resistance

490000 new cases of MDR-TB each year with gt110000 deaths1

Accounts for 5 of 9 million new cases of TB2

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

XDR-TB reported by as many as 49 countries (by June 2008)3

Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4

Around 40000 XDR-TB cases emerge every year1

1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

DrTVRao MD 29

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 21: Drug Resistant Tuberculosis

Extensively Drug-Resistant Mycobacterium tuberculosis

India

The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal and Amita Jain King Georges Medical University Lucknow India Volume 13 Number 9ndashSeptember 2007 in Emerging Infectious Diseases

DrTVRao MD 21

Drug susceptible TBsect

MDR-TB

1990sect

XDR-TB

2006sect

Total DR

Resistance to HampR ndash

Treatable with 2nd line drugs

Resistance to 2nd line drugs ndashTreatment options seriously restricted

Resistance to all available drugs ndash

No treatment options

or limited resistance manageable with 4 drug regimen - DOTS

Are we Returning to a Pre-antibiotic Era

DrTVRao MD 22

Genesis of MDR TB

Resistance is a man-made amplification of a natural phenomenon

Inadequate drug delivery is main cause of secondary drug resistance

Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains

MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked

DrTVRao MD 23

Factors Contributing to Development

and Spread of MDR and XDR TB Weak TB programs (DOTS)

Low completioncure rates Lack of treatment follow up and

patient support Unreliable drug supply Diagnostic delay

Absent or inadequate infection control measures

Uncontrolled use of 2nd line drugs Fluroquinolones

DrTVRao MD 24

INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis

Regulators of peroxide response

Mechanism of resistance

DrTVRao MD 25

RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)

Reduced Cell wall permeability

Mechanism of resistance

DrTVRao MD 26

Gene location associated Drug-Resistant

Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas

A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A

Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33

DrTVRao MD 27

Current Scientific Documentations on Drug Resistance in

Tuberculosis

DrTVRao MD 28

Alarming Rise of Resistant TuberculosisWHO Report on

Anti-TB Drug Resistance

490000 new cases of MDR-TB each year with gt110000 deaths1

Accounts for 5 of 9 million new cases of TB2

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

XDR-TB reported by as many as 49 countries (by June 2008)3

Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4

Around 40000 XDR-TB cases emerge every year1

1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

DrTVRao MD 29

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 22: Drug Resistant Tuberculosis

Drug susceptible TBsect

MDR-TB

1990sect

XDR-TB

2006sect

Total DR

Resistance to HampR ndash

Treatable with 2nd line drugs

Resistance to 2nd line drugs ndashTreatment options seriously restricted

Resistance to all available drugs ndash

No treatment options

or limited resistance manageable with 4 drug regimen - DOTS

Are we Returning to a Pre-antibiotic Era

DrTVRao MD 22

Genesis of MDR TB

Resistance is a man-made amplification of a natural phenomenon

Inadequate drug delivery is main cause of secondary drug resistance

Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains

MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked

DrTVRao MD 23

Factors Contributing to Development

and Spread of MDR and XDR TB Weak TB programs (DOTS)

Low completioncure rates Lack of treatment follow up and

patient support Unreliable drug supply Diagnostic delay

Absent or inadequate infection control measures

Uncontrolled use of 2nd line drugs Fluroquinolones

DrTVRao MD 24

INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis

Regulators of peroxide response

Mechanism of resistance

DrTVRao MD 25

RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)

Reduced Cell wall permeability

Mechanism of resistance

DrTVRao MD 26

Gene location associated Drug-Resistant

Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas

A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A

Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33

DrTVRao MD 27

Current Scientific Documentations on Drug Resistance in

Tuberculosis

DrTVRao MD 28

Alarming Rise of Resistant TuberculosisWHO Report on

Anti-TB Drug Resistance

490000 new cases of MDR-TB each year with gt110000 deaths1

Accounts for 5 of 9 million new cases of TB2

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

XDR-TB reported by as many as 49 countries (by June 2008)3

Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4

Around 40000 XDR-TB cases emerge every year1

1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

DrTVRao MD 29

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 23: Drug Resistant Tuberculosis

Genesis of MDR TB

Resistance is a man-made amplification of a natural phenomenon

Inadequate drug delivery is main cause of secondary drug resistance

Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains

MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked

DrTVRao MD 23

Factors Contributing to Development

and Spread of MDR and XDR TB Weak TB programs (DOTS)

Low completioncure rates Lack of treatment follow up and

patient support Unreliable drug supply Diagnostic delay

Absent or inadequate infection control measures

Uncontrolled use of 2nd line drugs Fluroquinolones

DrTVRao MD 24

INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis

Regulators of peroxide response

Mechanism of resistance

DrTVRao MD 25

RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)

Reduced Cell wall permeability

Mechanism of resistance

DrTVRao MD 26

Gene location associated Drug-Resistant

Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas

A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A

Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33

DrTVRao MD 27

Current Scientific Documentations on Drug Resistance in

Tuberculosis

DrTVRao MD 28

Alarming Rise of Resistant TuberculosisWHO Report on

Anti-TB Drug Resistance

490000 new cases of MDR-TB each year with gt110000 deaths1

Accounts for 5 of 9 million new cases of TB2

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

XDR-TB reported by as many as 49 countries (by June 2008)3

Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4

Around 40000 XDR-TB cases emerge every year1

1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

DrTVRao MD 29

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 24: Drug Resistant Tuberculosis

Factors Contributing to Development

and Spread of MDR and XDR TB Weak TB programs (DOTS)

Low completioncure rates Lack of treatment follow up and

patient support Unreliable drug supply Diagnostic delay

Absent or inadequate infection control measures

Uncontrolled use of 2nd line drugs Fluroquinolones

DrTVRao MD 24

INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis

Regulators of peroxide response

Mechanism of resistance

DrTVRao MD 25

RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)

Reduced Cell wall permeability

Mechanism of resistance

DrTVRao MD 26

Gene location associated Drug-Resistant

Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas

A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A

Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33

DrTVRao MD 27

Current Scientific Documentations on Drug Resistance in

Tuberculosis

DrTVRao MD 28

Alarming Rise of Resistant TuberculosisWHO Report on

Anti-TB Drug Resistance

490000 new cases of MDR-TB each year with gt110000 deaths1

Accounts for 5 of 9 million new cases of TB2

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

XDR-TB reported by as many as 49 countries (by June 2008)3

Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4

Around 40000 XDR-TB cases emerge every year1

1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

DrTVRao MD 29

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 25: Drug Resistant Tuberculosis

INHChromosomally mediatedLoss of catalaseperoxidaseMutation in mycolic acid synthesis

Regulators of peroxide response

Mechanism of resistance

DrTVRao MD 25

RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)

Reduced Cell wall permeability

Mechanism of resistance

DrTVRao MD 26

Gene location associated Drug-Resistant

Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas

A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A

Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33

DrTVRao MD 27

Current Scientific Documentations on Drug Resistance in

Tuberculosis

DrTVRao MD 28

Alarming Rise of Resistant TuberculosisWHO Report on

Anti-TB Drug Resistance

490000 new cases of MDR-TB each year with gt110000 deaths1

Accounts for 5 of 9 million new cases of TB2

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

XDR-TB reported by as many as 49 countries (by June 2008)3

Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4

Around 40000 XDR-TB cases emerge every year1

1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

DrTVRao MD 29

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 26: Drug Resistant Tuberculosis

RifampinReduced binding to RNA polymeraseClusters of mutations at ldquoRifampin Resistance Determining Regionrdquo (RRDR)

Reduced Cell wall permeability

Mechanism of resistance

DrTVRao MD 26

Gene location associated Drug-Resistant

Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas

A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A

Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33

DrTVRao MD 27

Current Scientific Documentations on Drug Resistance in

Tuberculosis

DrTVRao MD 28

Alarming Rise of Resistant TuberculosisWHO Report on

Anti-TB Drug Resistance

490000 new cases of MDR-TB each year with gt110000 deaths1

Accounts for 5 of 9 million new cases of TB2

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

XDR-TB reported by as many as 49 countries (by June 2008)3

Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4

Around 40000 XDR-TB cases emerge every year1

1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

DrTVRao MD 29

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 27: Drug Resistant Tuberculosis

Gene location associated Drug-Resistant

Mtuberculosis Drug Gene Isoniazid Kat G Inh A Kas

A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A

Dubaniewicz A et al Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis Int J Infect Dis20004129-33

DrTVRao MD 27

Current Scientific Documentations on Drug Resistance in

Tuberculosis

DrTVRao MD 28

Alarming Rise of Resistant TuberculosisWHO Report on

Anti-TB Drug Resistance

490000 new cases of MDR-TB each year with gt110000 deaths1

Accounts for 5 of 9 million new cases of TB2

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

XDR-TB reported by as many as 49 countries (by June 2008)3

Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4

Around 40000 XDR-TB cases emerge every year1

1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

DrTVRao MD 29

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 28: Drug Resistant Tuberculosis

Current Scientific Documentations on Drug Resistance in

Tuberculosis

DrTVRao MD 28

Alarming Rise of Resistant TuberculosisWHO Report on

Anti-TB Drug Resistance

490000 new cases of MDR-TB each year with gt110000 deaths1

Accounts for 5 of 9 million new cases of TB2

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

XDR-TB reported by as many as 49 countries (by June 2008)3

Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4

Around 40000 XDR-TB cases emerge every year1

1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

DrTVRao MD 29

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 29: Drug Resistant Tuberculosis

Alarming Rise of Resistant TuberculosisWHO Report on

Anti-TB Drug Resistance

490000 new cases of MDR-TB each year with gt110000 deaths1

Accounts for 5 of 9 million new cases of TB2

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

XDR-TB reported by as many as 49 countries (by June 2008)3

Recent WHOIUATLD Global Surveillance report indicated 75 (3014012) of MDR TB to be XDR4

Around 40000 XDR-TB cases emerge every year1

1Tuberculosis MDR-TB amp XDR-TBmdashThe 2008 Report The Stop TB Department WHO2Hargreaves S httpinfectionthelancetcom Vol 8 April 2008 p2203Raviglione MC NEJM 2008359636-84Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

DrTVRao MD 29

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 30: Drug Resistant Tuberculosis

MDR-TB amp XDR-TBTHE 2008 REPORT

of MDR-TB among new TB cases 1994-2007

DrTVRao MD 30

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 31: Drug Resistant Tuberculosis

MDR-TB rates higher than ever (up to 223) particularly in former Soviet Union countries

DrTVRao MD 31

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 32: Drug Resistant Tuberculosis

Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union about 50 of cases resistant to at least one drug about 20 MDR XDR-TB proportions also higher (as high as 24 in

Estonia)1

MDRXDR TB ndash essentially a man-made problem2

High numbers of resistant cases (gt400000 MDR-TB cases every year) due mainly to Underinvestment in basic TB control Poor management of anti-TB drugs Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World Report No 4 The WHOIUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007 World Health Organization 2008 (WHOHTMTB2008394)

2Reichman The Lancet 20083711052-3

DrTVRao MD 32

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 33: Drug Resistant Tuberculosis

The Much Discussed Article on XDR TB in the Lancet

Of the 221 multi-drug resistant (MDR-TB) cases 53 (24) were XDR

Almost all (52 of 53) of the XDR-TB patients died with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected

55 patents had never received anti-TB drugs suggesting primary transmission of XDR pathogen

67 patients had been admitted to the hospital in the preceding 2 years suggesting potential role of nosocomial transmission

Gandhi et al Lancet 20063681575-80DrTVRao MD 33

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 34: Drug Resistant Tuberculosis

Poor mangement of infected lead to grwoing resistance

Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care Problems include incorrect drug prescribing practices by providers poor quality drugs or erratic supply of drugs and also patient non-adherence DrTVRao MD 34

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 35: Drug Resistant Tuberculosis

Susceptibility Testing

1048708 Direct and indirect testing1048708 Primary Drugs testing1048708 Isoniazid1048708 Rifampicin1048708 Ethambutol ()1048708 Pyrizinamide ()

DrTVRao MD 35

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 36: Drug Resistant Tuberculosis

Drug susceptibility testing (DST)

DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment

Accuracy is more important than speed DST results should come from a small

number of well-equipped experienced laboratories who participate and perform well in an international DST quality control scheme

The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

DrTVRao MD 36

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 37: Drug Resistant Tuberculosis

Drug susceptibility Testing

Assessment of growth inhibition on solid media containing various dilutions of the drug in comparison with the test strains

As the method depend observation of growth Results are not available until several weeks after isolation of the organism

DrTVRao MD 37

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 38: Drug Resistant Tuberculosis

Other accredited Methods

Radiometric and Non radiometric methods

Nucleic acid technology ndash effective upto 95 in mutations to rifampicin resistance to gene rpoB gene

DrTVRao MD 38

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 39: Drug Resistant Tuberculosis

Drug susceptibility testing (DST)

As a minimum laboratories supplying DST data should correctly identify resistance to isoniazid and rifampicin in over 90 of quality control samples in two out of the last three quality control roundsDrTVRao MD 39

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 40: Drug Resistant Tuberculosis

Detection of Rifampicin Drug susceptibility testing (DST) is more important

Early identification of mycobacterial growth as M tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB

Laboratories should aim to identify isolates as M tuberculosis complex and perform rifampicin resistance in 90 of isolates within 1-2 working days This is technologically feasible

DrTVRao MD 40

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 41: Drug Resistant Tuberculosis

Drug susceptibility testing

For DST laboratories modern molecular techniques permit the successful identification of isoniazid resistance in at least 75 of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance

DrTVRao MD 41

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 42: Drug Resistant Tuberculosis

Secondary Drugs testing [lack of standardized

methods]

Ofloxacin quinolonesEthionamide KanamycinCapreomycin Ensure quality control and

quality assurance

DrTVRao MD 42

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 43: Drug Resistant Tuberculosis

WHO Controls the Tuberculosis related work

The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)DrTVRao MD 43

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 44: Drug Resistant Tuberculosis

Other WHO-Endorsed Tools

Liquid culture (eg MGIT BacTALERT)

Capilia TB Rapid strip test that detects a TB-

specific antigen from culture

Molecular line probe assays (eg GenoType MTBDRplus INNO-LiPA RifTB) Strip test for detection of TB and

drug-resistance conferring mutations

DrTVRao MD 44

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 45: Drug Resistant Tuberculosis

BacTALERTreg

DrTVRao MD 45

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 46: Drug Resistant Tuberculosis

CDC Updates Guidelines for Nucleic AcidAmplification Techniques to Diagnose

Tuberculosis

NAAT results should be interpreted in conjunction with the AFB smear results

NAAT and smear positive start Rx despite pending culture results PPV 95

Smear negative NAAT positive use clinical judgment to either treat or await culture

DrTVRao MD 46

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 47: Drug Resistant Tuberculosis

Selection from automated systems for molecular and

bacteriological rapid diagnostics

PCRRocheCOBASreg Amplicorreg

amplification kitsRocheCOBASreg LightCyclerreg

(real-time-PCR)RocheCOBASreg TaqMan 48reg(increases the specificity of real-

time-PCR)

DrTVRao MD 47

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 48: Drug Resistant Tuberculosis

Molecular Fingerprinting

26 of 30 (87) XDR TB isolates found to be genetically similar

Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug-resistant strain

DrTVRao MD 48

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 49: Drug Resistant Tuberculosis

Is PCR methods a solution

PCR cant yet replace neither microscopy culturing and competent clinical examination

DrTVRao MD 49

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 50: Drug Resistant Tuberculosis

No testing method replaces Clinical assessment

DrTVRao MD 50

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 51: Drug Resistant Tuberculosis

XDR-TBThe description

of XDR-TB was first used earlier in 2006 following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) DrTVRao MD 51

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 52: Drug Resistant Tuberculosis

How x-MDR generated

Acquired resistance is that which occurs as a result of specific previous treatment The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past while the level of acquired resistance is a measure of on-going TB control measuresDrTVRao MD 52

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 53: Drug Resistant Tuberculosis

Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant to all first line drugs namely Isoniazid and Rifampin and Three or more second line drugs (SLDrsquoS) that are used to treat MDR-TB Thequinalones like Ofloaxin

Or Aminoglycosides like Capreomycin amp

Kanamycin

No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years

DrTVRao MD 53

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 54: Drug Resistant Tuberculosis

Background Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis has been reported in 45 countries including countries with limited resources and a high burden of tuberculosis

DrTVRao MD 54

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 55: Drug Resistant Tuberculosis

DrTVRao MD 55

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 56: Drug Resistant Tuberculosis

Transmissionof X -MDR

Like other forms of TB XDR-TB is spread through the air When a person with infectious TB coughs sneezes talks or spits they propel Mycobacterium into the air

DrTVRao MD 56

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 57: Drug Resistant Tuberculosis

Best options to diagnoseX-MDR tuberculosis

To evaluate drug susceptibility the bacteria need to be cultivated and tested in a suitable laboratory Final diagnosis in this way for TB and especially for XDR-TB may take from 6 to 16 weeks To reduce the time needed for diagnosis new tools for rapid TB diagnosis are urgently needed

DrTVRao MD 57

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 58: Drug Resistant Tuberculosis

When to suspect MDR TB

Patients not showing any reduction

in bacillary population after 3-

months of regular treatment with

Cat II regimen

Sputum positive patients who are

contacts of a known MDR TB

patient

DrTVRao MD 58

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 59: Drug Resistant Tuberculosis

How to evaluate MDR TB

MDR TB is only a laboratory

proved HR resistance

Clinical suspicion should be

followed by lab Confirmation

Laboratories should be quality

controlledTRC

DrTVRao MD 59

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 60: Drug Resistant Tuberculosis

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It can also be contracted without a patient receiving any previous treatment for TB

Mostly associated with HIV positive patients

HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic

Average survival period for patients infected with XDR-TB is 16 days

DrTVRao MD 60

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 61: Drug Resistant Tuberculosis

Responding to MDRXDR-TB

Augment DOTS Program by

New diagnostics

New drugs New vaccines HIV incidence

reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson Lancet 20073702030-432Basu et al Quoted in Porco and Getz Lancet 20073701464-5

DrTVRao MD 61

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 62: Drug Resistant Tuberculosis

Second Line Drug Treatment (SLDrsquos)

Less effective more costly and more toxic 50 cure rate

Four months intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol DrTVRao MD 62

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 63: Drug Resistant Tuberculosis

World Health Organisation (WHO) Guidelines for treatment

of MDR-TB

Strengthen basic TB care to prevent the emergence of drug-resistance

Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission

Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients

Increase investment in laboratory infrastructures to enable better detection and management of resistant cases

DrTVRao MD 63

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 64: Drug Resistant Tuberculosis

Treatment Guidelines

Sensitivity testing for all smear positive specimens

Patient Family and staff counselling amp education

Correct and thorough hand washing protocol and procedure

Personal protection is very important

DrTVRao MD 64

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 65: Drug Resistant Tuberculosis

THE NEW MDR-TB Guidelines

A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions

But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation

Reflect GLC expert consensus and evidence and experience from GLC projects thus far

DrTVRao MD 65

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 66: Drug Resistant Tuberculosis

Effective laboratory Diagnosis

Sputum smear examinations ndash rapid classification of species (atypical mycobacteria common in AIDS)

Culture examinations

Rapid drug sensitivity testingDrTVRao MD 66

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 67: Drug Resistant Tuberculosis

MDR TB and HIV

MDR TB occurs with the same frequency in HIV

patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-

infected patients in congregate settings occurs

leading to lsquooutbreaksrsquo of MDR TB in such settings

Infection control measures absolutely essential in

settings where large number of HIV TB patients stay

togetherDrTVRao MD 67

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 68: Drug Resistant Tuberculosis

Transmission is dependent on closeness and time of contact

In penitentiary care contacts are very close and prolonged ndash culture positive cases can also transmit TB especially to HIV positive population

DrTVRao MD 68

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 69: Drug Resistant Tuberculosis

To Know more on MDR ndashTB Current Guidelines of WHO

Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]

Visit helliphelliphellip WHOHTMTB20116DrTVRao MD 69

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 70: Drug Resistant Tuberculosis

Are there any solutions for effective

Diagnosis in TB

DrTVRao MD 70

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71
Page 71: Drug Resistant Tuberculosis

Programme Created by DrTVRao MD for Medical and Health Care

Workers in the Developing World Email

doctortvraogmailcom

DrTVRao MD 71

  • Drug Resistant Tuberculosis Emerging Human Concern
  • HISTORY of Tuberculosis
  • A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculo
  • Historical Background
  • Diagnostic discoveries
  • From Tuberculosis to Tuberculin Failure of Robert Koch
  • Global Status
  • USAID Report on Tuberculosis in India
  • Pharmacological discoveries
  • Selman Abraham Waksman Nobel Prize for his discovery in
  • Pharmacological discoveries (2)
  • No one is Immune to Tuberculosis Not only infects poor but fam
  • Multi Drug Resistant Tuberculosis MDR-TB
  • Definition
  • Classification of Drugs
  • Basic concepts ndash Keep facts
  • When to suspect MDR TB
  • What is extensively drug resistant tuberculosis (XDR TB)
  • Why XDR - TB a grave concern
  • Slide 20
  • Extensively Drug-Resistant Mycobacterium tuberculosis India
  • Are we Returning to a Pre-antibiotic Era
  • Genesis of MDR TB
  • Factors Contributing to Development and Spre
  • Mechanism of resistance
  • Mechanism of resistance (2)
  • Gene location associated Drug-Resistant
  • Current Scientific Documentations on Drug Resistance in Tubercu
  • Alarming Rise of Resistant Tuberculosis
  • MDR-TB amp XDR-TB THE 2008 REPORT of MDR-TB among new TB cases
  • MDR-TB rates higher than ever (up to 223) particularly in fo
  • Alarming Rise of Resistant TB
  • The Much Discussed Article on XDR TB in the Lancet
  • Poor mangement of infected lead to grwoing resistance
  • Susceptibility Testing
  • Drug susceptibility testing (DST)
  • Drug susceptibility Testing
  • Other accredited Methods
  • Drug susceptibility testing (DST)
  • Detection of Rifampicin Drug susceptibility testing (DST) is m
  • Drug susceptibility testing
  • Secondary Drugs testing [lack of standardized methods]
  • WHO Controls the Tuberculosis related work
  • Other WHO-Endorsed Tools
  • BacTALERTreg
  • CDC Updates Guidelines for Nucleic Acid Amplification Technique
  • Selection from automated systems for molecular and bacteriologi
  • Molecular Fingerprinting
  • Is PCR methods a solution
  • No testing method replaces Clinical assessment
  • XDR-TB
  • How x-MDR generated
  • Extreme Drug resistant Tuberculosis (XDR-TB)
  • Background Extensively drug-resistant tuberculosis
  • Slide 55
  • Transmission of X -MDR
  • Best options to diagnose X-MDR tuberculosis
  • When to suspect MDR TB
  • How to evaluate MDR TB
  • Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS
  • Responding to MDRXDR-TB
  • Second Line Drug Treatment (SLDrsquos)
  • World Health Organisation (WHO) Guidelines for treatment of MDR
  • Treatment Guidelines
  • THE NEW MDR-TB Guidelines
  • Effective laboratory Diagnosis
  • MDR TB and HIV
  • Transmission is dependent on closeness and time of contact
  • To Know more on MDR ndashTB Current Guidelines of WHO
  • Are there any solutions for effective
  • Slide 71

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Extensively Drug Resistant – Tuberculosis B10

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Drug-Resistant Tuberculosis: A Survival Guide for ... · ADVERSE REACTIONS Introduction Treatment of drug-resistant tuberculosis (TB) requires the use of multiple medications and

The emergence of extensively drug-resistant tuberculosis ...

The emergence of extensively drug-resistant tuberculosis ...

Systems biology of drug-resistant tuberculosis The ... · Systems biology of drug-resistant ... Plasmids notably code for resistance to antibiotics. ... the tuberculosis bacteria

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Focus on Drug-Resistant Tuberculosis - Home - The · PDF fileDrug-resistant Tuberculosis FOCUS ON Drug-resistant TB is part of the growing challenge of antimicrobial resistant superbugs

Focus on Drug-Resistant Tuberculosis - Home - The · PDF fileDrug-resistant Tuberculosis FOCUS ON Drug-resistant TB is part of the growing challenge of antimicrobial resistant superbugs

MANAGEMENT OF DRUG-RESISTANT TUBERCULOSIS of drug resistant TB guidelines.pdf · Legal issues around the management of drug-resistant tuberculosis (DR-TB) are complex and have been

MANAGEMENT OF DRUG-RESISTANT TUBERCULOSIS of drug resistant TB guidelines.pdf · Legal issues around the management of drug-resistant tuberculosis (DR-TB) are complex and have been

Management of Drug-resistant Tuberculosis (DR-TB)...Management of Drug-resistant Tuberculosis (DR-TB) Nitipatana Chierakul Division of Respiratory Disease & Tuberculosis Department

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Multi-Drug Resistant Tuberculosis - An Indian Scenario Vol 7 Issue 2 Apr-Jun… · Multi-drug resistant tuberculosis is defined as disease due to M tuberculosis that is resistant

Multi-Drug Resistant Tuberculosis - An Indian Scenario Vol 7 Issue 2 Apr-Jun… · Multi-drug resistant tuberculosis is defined as disease due to M tuberculosis that is resistant

Multi-Drug Resistant tuberculosis: update on epidemic and ... L...2010 Global report on drug resistance surveillance and response Alamty May 2010 Multi-Drug Resistant tuberculosis:

Multi-Drug Resistant tuberculosis: update on epidemic and ... L...2010 Global report on drug resistance surveillance and response Alamty May 2010 Multi-Drug Resistant tuberculosis:

Programmatic Management of Drug-Resistant Tuberculosis: An ...

Programmatic Management of Drug-Resistant Tuberculosis: An ...

Line probe assays for drug- resistant tuberculosis detection

Line probe assays for drug- resistant tuberculosis detection

Nurse Case Management of Drug-Resistant Tuberculosis ...nid... · 5 Nurse Case Management of Drug-Resistant Tuberculosis Webinar May 20, 2015 Curry International Tuberculosis Center

Nurse Case Management of Drug-Resistant Tuberculosis ...nid... · 5 Nurse Case Management of Drug-Resistant Tuberculosis Webinar May 20, 2015 Curry International Tuberculosis Center

MULTI-DRUG RESISTANT TUBERCULOSIS - TB … Multi-Drug Resistant Tuberculosis: A Policy Framework on Decentralised and Deinstitutionalised Management for South Africa will guide provinces

MULTI-DRUG RESISTANT TUBERCULOSIS - TB … Multi-Drug Resistant Tuberculosis: A Policy Framework on Decentralised and Deinstitutionalised Management for South Africa will guide provinces

Risk Factors for Drug-Resistant Tuberculosis · 2014-09-05 · M. Gomes et al. 112 Keywords Tuberculosis, Drug-Resistance, Risk, Diabetes, Portugal 1. Introduction Drug-resistant

Risk Factors for Drug-Resistant Tuberculosis · 2014-09-05 · M. Gomes et al. 112 Keywords Tuberculosis, Drug-Resistance, Risk, Diabetes, Portugal 1. Introduction Drug-resistant

WHO treatment guidelines for drug- resistant tuberculosis

WHO treatment guidelines for drug- resistant tuberculosis

Managing Drug-Resistant Tuberculosis in Pregnancy, Mothers ... · Managing Drug-Resistant Tuberculosis in Pregnancy, Mothers and Newborns James Seddon Postgraduate Course 31st October

Managing Drug-Resistant Tuberculosis in Pregnancy, Mothers ... · Managing Drug-Resistant Tuberculosis in Pregnancy, Mothers and Newborns James Seddon Postgraduate Course 31st October

Drug Resistant Tuberculosis Symposia - The CRUDEM Foundation

Drug Resistant Tuberculosis Symposia - The CRUDEM Foundation

WHO consolidated guidelines on drug-resistant tuberculosis ...

WHO consolidated guidelines on drug-resistant tuberculosis ...

Tuberculosis burden in households of patients with multi drug-resistant and extensively drug-resistant tuberculosis: a retrospective cohort study.

Tuberculosis burden in households of patients with multi drug-resistant and extensively drug-resistant tuberculosis: a retrospective cohort study.

Multi drug and extensive drug resistant tuberculosis

Multi drug and extensive drug resistant tuberculosis