05abmdr Xdr Tuberculosis Seminar

7/29/2019 05abmdr Xdr Tuberculosis Seminar

http://slidepdf.com/reader/full/05abmdr-xdr-tuberculosis-seminar 1/71

MODERATOR : DR PANKAJ ABROL

PRESENTED BY: DR VIRENDER

VERMA

MDR & XDR TUBERCULOSIS



MDR & XDR TUBERCULOSIS

Definition

Epidemiology

Etiology

Diagnosis

Treatment

Special situation



Introduction

Mycobacterium tuberculosis has been present in the human

population since antiquity

1882 - Robert Koch discovered Mycobacterium

tuberculosis



Introduction (Contd..)

Sanatorium - The first step against TB.

Measures available to doctors were still modest

Improve social and sanitary conditions

Reduction of the lung volume( Thoracoplasty ) Radiation

1943 - Streptomycin

1963 - Rifampicin



Introduction (Contd..)

Resistance to Streptomycin emerged in 85% cases

Mid-1990 - Most countries registered MDR-TB

2006 – XDR – TB term was coined

BMJ 1948;2:1009 – 1015

N Engl J Med 1993;328:521-6

Morb Mortal Wkly Rep 2006; 55: 301 – 05



Definition

Mono Resistance: Resistant to one drug

Poly-Resistance: Resistant to more than 1 drug

MDR-TB: Resistant to at least isoniazid and rifampicin

with or without resistance to other drugs XDR-TB: MDR-TB + any one of the fluoroquinolones +

one of three injectable second-line drugs (Amikacin,

Capreomycin or Kanamycin)

MMWR 2006;55:1176WHO



Epidemiology

An estimated 9.2 million new cases of TB in 2006 (139

per 100 000 population)

4.1 million new smear-positive cases (44% of the total)

0.7 million HIV-positive cases (8% of the total)

An estimated 14.4 million prevalent cases

Estimated 1.5 million deaths from TB in HIV-negative

people

Estimated 0.2 million death among people infected withHIV.

Semin Respir Crit Care Med 2008;29:481 –

491



EpidemiologyEstimated number of new TB cases

Asia accounts for 55% of global cases, and Africa

accounts for 31%

India ranks 1st

Incidence-168/1lkh pop/yr

Prevalance-299/1lkh pop/yr

WHO REPORT 2008 | GLOBAL TUBERCULOSIS CONTROL

Highest no of

cases



Epidemiology(Contd…)

An estimated 489,139 cases of MDR-TB in 2006

Accounts for 4.8% of all TB cases

Increase of 12% since 2004 and 56% since 2000

China and India carry approximately 50% of the global

burden of MDR-TB

.

Semin Respir Crit Care Med 2008;29:481 –

491



MDR PREVALENCE HIGHER THAN 5.0%AMONG NEW CASES 2002-2007

22.3%

WHO/IUATLD Drug Resistance Surveillance. 2008



MDR PREVALANCE HIGHER THAN 30% AMONGPREVIOUSLY TREATED CASES, 2002-2007

60.0%




MDR prevalence in south east Asian region




Epidemiology(Contd..)

The overall prevalence of XDR-TB is 2%

7% of total MDR – TB cases are XDR-TB

Countries conducting routine surveillance- XDR represent between 7% &34% of MDR isolates

The Global MDR-TB & XDR-TB Res onse Plan 2007 – 2008

The WHO/IUATLD Global Project on Anti-tuberculosis DrugResistance Surveillance 2002-2007



Till June 2008, 49 country have reported confirmed XDR-TB cases to WHO



Prevalence of drug resistancein new cases

Adapted from, Sharma et al TUBERCULOSIS



Prevalence of drug resistance inpreviously treated patient

Adapted from, Sharma et al TUBERCULOSIS



Drug resistant data fromsurvelance sites

Adapted from, Sharma et al. TUBERCULOSIS



Epidemiology(Contd…)

In India an estimated 110 132 cases of MDR-TB in 2006

Accounts for 4.8% of all TB cases

Prevalence among new cases - 2.8%

Prevalence among treated cases -17.2%.

For XDR - 7.4% & 9.3% among MDR-TB

WHO REPORT 2008 | GLOBAL TUBERCULOSIS CONTROL



Aiims Data

Primary MDR- 6%

Acquired MDR- 24%

XDR- 4%

Aiims microbiology department



Molecular basis

Drug resistance can be achieved by.

Barrier methods

Degrading or inactivating

enzyme Drug target modifications

MDR-TB reflects step wise accumulation of individual

mutation

Spontaneous mutations leading to resistance occur atrandom

Natural resistance

Resistance to ATT

Tubercle 1987; 68:5 –

18Lancet 1994; 344:293 – 8



Mechanism of drug action

National Institute of Allergy And Infectious Disease



Mechanisms of drug resistance

Thorax 1998;53:793 –

797



WEIGHTED MEAN OF RESISTANCETO SPECIFIC DRUGS

The WHO/IUATLD Global Project on Anti-tuberculosisDrug Resistance Surveillance 2002-2007

In new cases In previously treated cases



Amplifier effect of short coursechemotherapy

Semin Respir Crit Care Med 2008;29:499 – 524



Host factor

The frequencies of DRB1∗01and of DQB1∗0502

significantly decreased in the MDR-TB

DRB1∗14 occurred in 30.9% of MDR cases 6.8% in the

drug sensitive cases Patients with HLA-DRB1∗14 have a eight-fold risk of

developing MDR-TB

Odd ratio = 8.2

Sharma S K et al. I nfection, Genetics and Evolution 3 (2003) 183-188



Agent factor

The most wide spread Mycobacterium tuberculosis strains

are of Beijing family

W-Beijing genotype strong association with multidrug

resistance Method - Restriction fragment length polymorphism

(RFLP) analysis of IS6110 insertion

World wide prevalent

Int J Tuberc Lung Dis 2005; 9:646 –

653



Factors related to previoustreatment

MDR-TB is a man-made phenomenon

poor treatment, poor drugs and poor adherence lead to the

development of MDR-TB.

Most powerful predictor of presence of MDR-TB is ahistory of previous treatment

In management most common error is adding single drug to

failing regimen

Indian J Med Res 2004; 120:354 – 376



Causes of inadequate treatment

Lambregts et al. Tubercle and Lung Disease 1995: 76; 455-458



l f



Supranational reference LaboratoryNetwork

TRC




Who should go for drug sensitivity test?

A TB patient who fails an RNTCP Category I or III

treatment regimen

Any RNTCP Category II patient who is sputum smear

positive at the end of the fourth month of treatment or later. Concurrent illness such as epilepsy, alcoholism, renal and

hepatic problems, psychiatric illness

Excluded

Under 15 years of age; Having had >1 mth t/t with second-line anti-TB drug.

MDR Suspect

RNTCP DOTS-Plus Guidelines,2008



Laboratory aspect

Sputum should be good and satisfactory

Specimen should be transported as soon as possible

If delay

Refrigeration

Preservation -1% Cetyl Pyridinium Chloride (CPC) + 2%

NaCl

Sputum container labelled as BIO- HAZARD

Homogenisation and decontamination

Inoculation and incubation




Methods of Drug susceptibility

Conventional method

Culture uses Lowenstein-Jensen (LJ) or 7H11 solid media

Takes long time - 6-8 week

Sensitivity limited by availability of bacilli in sample

Methods

Absolute Concentration Method

The Resistance Ratio Method

Proportion Method



Proportion method

Method of choice: Recommended by DOTS-Plus

10-fold dilutions of inoculum are planted on both control

and drug – containing media

Resistant portion as a percentage of the total populationtested

CRITERIA OF RESISTANCE

Any strain with 1% (the critical proportion) of bacilli

resistant to any of the four drugs



Phage-based tests

Luciferase reporter phages

Infected bacteria emit light

Results in 2 days post culture

Limited reports of clinical application

FAST Plaque TB-RMP test

Plaques of lysed cells counted

Results in 2-3 days

Cannot be used for children or HIV-positive patients

S Afr Med J . 2007;97:858-863

J Infect. 2005;51:175-187.



Others

Microscopic-Observation Drug-Susceptibility assay

(MODS)

DST for first line drugs

Report within 7 days

Simple, rapid & low cost

Nitrate reductase assay

Sensitivity and specificity ≥ 90%.

Colorimetric method

For isoniazid and rifampicin

N Engl J Med. 2006;355:1539-1550Antimicrob Agents Chemother. 2003;47:3616-3619.



Molecular method

DNA sequencing

Most accurate and reliable method for mutation detection

Detect both previously recognized and unrecognized mutations

For rifampicin only

The Line Probe assay (LiPA)

Detect rpoB mutations of rifampicin

Result in less than 48 hours

J Clin Microbiol. 2007;45:2635-2640



GenoType® MTBDR test

•Test available

within one day

•Sensitivity- 98.8%

•specificity - 100%

J Clin Microbiol 2005; 43: 3699-3703



Diagnosis(Contd..)

DNA microarrays

Based on the principle of hybridization

Detect Rifampicin resistance only

Analysis large amounts of DNA sequences

Molecular beacons

Sensitive enough to detect 2 bacilli,

Results in 3 hours

Single-strand conformation polymorphism (SSCP)

Fluorescence resonance energy transfer (FRET) probes

Genome Res 1998;8:435-48.Methods Mol Biol 2003;212:111-28



Difficulty in testing susceptibility of2nd line drugs

In vitro drug instability

Drug loss due to protein binding

Heat inactivation

Incomplete dissolution Filter sterilization

Varying drug potency

Critical concentration very close to the minimal inhibitory

concentration (MIC)

Guidelines for mangt of DR-TB Update 2008 WHO



Prevention

Self administered therapy is inferior to DOTS

Fixed dose combination (FDC) can be a cost effective

strategy, only somewhat inferior to DOTS

DOTS the most cost effective intervention in the control of

TB

DOTS the most cost effective prevention for MDR &

XDR- TB

Int. J . Tuberc. Lung Dis. 2000; 4: 201 –

7



DOTS in MDR – TB:

cure rate: ≤ 60%

recurrence rate: ≥ 28%

J AMA 2000; 283: 2537 – 45.

Int. J . Tuberc. Lung Dis. 2002; 6: 858 –

64.WHO/HTM/TB/2006.361



Programme strategies

Standardized treatment

On the basis of DRS data

All patients receive the same regimen

Empirical treatment Individually designed

Based on history of antituberculosis treatment &DRS data

Individualized treatment

Based on history of antituberculosis treatment & DST



Basic principles

Patient suspected of drug resistance, must under go culture

& DST

Patient should immediately started with treatment

A single drug should never be added to failing regimen

Drugs with potential cross resistance should never be used

At least 3 previously unused drugs to which there is in vitro

susceptibility , must be employed

Based on the history of drugs taken

Minimum duration is 18 months post culture conversion



Classes of antitubercular drugs

guidelines for the programmatic mngmt of DR tuberculosis. who 2008

Use any available



Use any available

Group 1: First-line oral agents

Plus one of theseGroup 2: Injectable agents

Plus one of these

Group3: Fluoroquinolones

Pick one or more of

Group 4: Second-line oral

bacteriostatic agents

Consider use of these

Group 5: Drugs of unclear role in

DR-TB treatment

MDR TB suspect referred from MO-PHI to DTO



MDR TB suspect referred from MO PHI to DTO

with

• Copy of the Cat II (and Cat I/III) Rx card

• Request for culture and DST form

• Drug-o-gram

DTO confirms suspect and sends sputum

samples to IRL with• Request for culture and DST form

• Drug-o-gram

Enter in Culture and DST register at DTC

Culture and DST results

communicated to

the DTO electronically

continuesCat II

treatment

Non MDR

TB MDR TB

• Patient traced by DTO with the help of MO-TC

and STS.

• Patient counselled and referred to DOTS Plus

site

Continue

Cat II




RNTCP CATEGORY IV REGIMEN

6 (9) Km Ofx Eto Cs Z E / 18 Ofx Eto Cs E




Surgery

Indications

Localized disease

High probability of failure or relapse with medical therapy

3 months chemotherapy prior to surgery

Bilateral disease does not preclude surgical intervention,

unless extensive

Excellent cure rates ≥90% with post-surgery chemotherapy

Clin. Chest Med. 1997; 18: 123 – 30

Ann. Thorac. Surg. 2005; 79:959 –

63



Surgery(Contd..)

Poor prognosis

Low BMI (<18.5 kg/m2)

Bacillary resistance to ofloxacin

Cavitation beyond the range of surgical resection

Complications: Respiratory failure, Bronchopleural fistula,

Infections, Empyema, wound

Adjunctive surgical procedures : Myoplasty, Omentoplasty,

Thoracoplasty

Eur Respir. J . 2006; 28: 576 –

80



Immunotherapy

Mycobacterium vaccae

Mycobacterium w

Cytokine therapy

interferon-g

Interferon-α

Interleukin-2 (IL-2)

Others

Thalidomide Transfer factor

Pentoxifylline Inhibitors of transforming Imiquimod growth factor-

Levamisole Interleukin-12

Clin. Exp. Immunol. 2005; 141:541 – 8.

Respir. Med. 2001; 95: 444 –

7.



Exploratory approach

Local instillation of antimycobacterial agent

Plant products: cerulenin, transcinnamic acid, Flourensia

etc

Imipenem in murine model New delivery system: liposomes, solid lipid nano particles

Int. J . Antimicrob. Agents 2007; 29: 338 –

40



Newer therapy

The American J ournal of Medicine (2008) 121, 835-844



Infection control measures

Administrative controls

Reduced hospitalisation

Rapid drug-susceptibility assays

Detention for confirmed XDR tuberculosis patients

Environmental controls

Airborne Infection Isolation (AII) room

High-Efficiency Particulate Air (HEPA) Filter

Ultraviolet germicidal irradiation (UVGI)

Personal respiratory protection

Respirator

Surgical masks for patient

MMWR December 30, 2005 / 54 (RR17); 1-141



Treatment outcomes

Short course chemotherapy is ineffective for controlling

established MDR-TB

Cure rate ≤ 60%

Recurrence rate ≥ 28%

Cure rates up to 75% can be achieved with individualized

regimen

XDR-TB co infected with HIV, mortality is very high

Kwazulu Natal study 52 out of 53 XDR cases died

Sharma S K et al.Indian J Chest Dis Allied Sci. 1996 38(2):73-9N Engl J Med 1993; 328: 527

– 32



Outcome(contd..)

Total 801 patients referred among this 651 tested

651 patients tested XDR-TB - 48 (7.4%)

MDR-TB- 603 (92.6%)

Use of Comprehensive treatment with5 drugs (incl

fluoroquinolone and injectables) at highest tolerated dose,

T/t >2 years, drug susceptibility done to design and adjust

regimens. Cured or completed the treatment

XDR-TB- 29 (60.4%)

MDR-TB – 400 (66.3%)

N Engl J Med 2008;359:563-74



Outcomes(contd..)

N Engl J Med 2008;359:563-74

St d f bli ti T f DR TB T t t O t

Cure rates



Study, year of publication Type of DR-TB Treatment Outcome

Goble et al, 1993

Sharma et al, 1996

Park et al , 1998

Yew et al, 2000

Tahaoglu et al, 2001

Mitnick et al, 2003

Nathanson et al, 2006

Gandhi et al, 2006

Sharma, 2007

Mitnick et al, 2008

MDR-TB [ n = 171]

MDR-TB [ n = 19]

MDR-TB [ n = 107]

MDR-TB [ n = 63]

MDR-TB [ n = 158]

MDR-TB [ n = 75]

MDR-TB [ n = 1047]

XDR-TB [ n = 53]

MDR-TB [ n = 172]

XDR-TB [ n = 1]

XDR-TB [ n =48]

MDR-TB [ n = 603]

65% cured, treatment failure

35%

Sputum conversion in 18 cases

out of 19 82.5% cured, treatment failure

17.5%

81% cured, treatment failure

14.3%, death 4.7%

Cured or completed treatment

77%, default 11%, treatmentfailure 8%, death 4%

83% cured, death 8%

Cured or completed treatment

69.7%, treatment failure 6.7%

52 of the 53 patients died

41.6% cured, treatment failure

38.7%

60.4% with XDR-TB completed

treatment or cured; 66.3% with

MDR-TB completed treatment

or cured Adapted from, Sharma et al TUBERCULOSIS



Poor prognosis

HIV

Extrapulmonary involvement

Low haematocrit

Low BMI

Older age

Alcoholism

Bacillary and treatment characteristics

Extensive drug resistance

Resistance to ofloxacin in vitro

previous treatment

failure to apply appropriate therapy

Poor adherence during treatment



Management of contacts

Identify through contact tracing

If contacts have active disease the culture & DST required

Clinical follow up for a period of at least 2 year

If active disease then prompt MDR-TB regimen WHO not recommended 2nd line drugs as

Suggested regimens

Pyrazinamide plus Ethambutol

Pyrazinamide plus Quinolone

Am J Respir Crit Care Med 2000; 161(4 Pt 2) : 221-47

Guidelines for mangt of DR-TB Update 2008 WHO



MDR & XDR-TB and HIV

African region has high burden for both HIV and TB

TB -Most common opportunistic infection in HIV

Risk of reactivation : 5 to 8 per cent per annum

Cumulative lifetime risk : ≥ 30 % No predisposes for MDR-TB

High risk of mortality, especially when diagnosed late

AIDS 1998; 12 : 191-5

Thorax 2002; 57: 810 –

16



Contd...

Antiretroviral therapy must

Efavirenz is the preferred drug to be used in patients on

ATT

Drug interaction uncommon with 2nd

line drugs ex Fluoroquinolone – Didanosine

Higher rate of adverse drug reaction

Extrapulmonary localization, independent poor prognostic

factor .

Am. J . Respir. Crit. Care Med. 2001; 164



Children

Transmission of MDR-TB from adult patients to children

could occur

Adverse drug reactions are common.

Reasonably good cure rate

Fluoroquinolones- Conflicting evidence

Weight loss / absence of satisfactory weight gain is

suggestive of treatment failure

WHO/HTM/TB/2006.361Hampel B et al. Pediatr. Infect. Dis. J . 1997; 16: 127 – 9



Pregnancy

Not a contraindication for treatment of MDR-TB

Therapy may be delayed until the second trimester

Avoid aminoglycoside

Ethionamide can aggravate nausea and vomiting in pregnant women

Infant formula is good alternatively to breast feeding

Outcome is good

Chest 2003; 123: 953 – 6.



Summary

MDR & XDR tuberculosis pose greater challenge for

effective TB management

Poor treatment, poor drugs and poor adherence lead to the

development of drug resistance

MDR-TB and XDR-TB are pure laboratory diagnosis

Need for new methods for early diagnosis



Summary(Contd..)

DOTS treatment for TB patients is the most cost effective

method of preventing MDR TB

Prompt diagnosis early treatment is prerequisite for all

programmes

Adjuvant therapy should be use whenever possible

Comprehensive and individualized treatment have good

prognosis compared to standardized treatment



Thank you



21-female

•H/O Cough, Shortness of breath for 2

years

• Associated with blackish sputum – only

during menstruation

•Weight loss and reduction in appetite

• ATT – 1 year for this illness

Examination:

•No LAP•Chest: Bilateral crepitations

•CVS and Abdomen: Normal



DIFFERENTIALS:

•Interstitial lung disease –Lymphangiomyomatosis

•Catamenial Lung

• Atypical infections



Fibre-optic bronchoscopy:

Bronchial washing : AFB positive

Culture: Mycobacteria tuberculosisResistance: HRE

Sensitive: Fluoroquinolone, cycloserine,

Streptomycin

05abmdr Xdr Tuberculosis Seminar

Documents

Transcript of 05abmdr Xdr Tuberculosis Seminar