Antibiotics, Misuse and Consequences

8/3/2019 Antibiotics, Misuse and Consequences

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Dr.T.V.Rao MD

Dr.T.V.Rao MD 1



Virus

Common cold

Diarrhea (99%)

Acute Bronchitis Influenza (flu)

Measles

Chicken Pox AIDS

Rabies

Hepatitis

Bacteria

Urine infections

Strep Throat

Boils/abscesses Gangrene

Some pneumonia

Ear infections (half) Sinus infections (< half)

Bubonic Plague

TuberculosisDr.T.V.Rao MD 2



Bacteria are the cause of the vast

majority of deaths due to infection

in the United States: sepsis,meningitis, pneumonia

Most viral infections get better all by

themselves in 1-3 weeks; nomedications are required: colds, flu,stomach virus

Dr.T.V.Rao MD 3



They don’t help the patient at all

Expense: 75% of outpatient antibiotics are

used for respiratory infections Patient expectations: why no better?

Side effects: diarrhea, rash, allergy

Development of resistance: the

antibiotic won’t work when you really DOneed it for a bacterial infection

Dr.T.V.Rao MD 4



ANTIMICROBIAL AGENT

• Any chemical or drug

used to treat an infectiousdisease, either by

inhibiting or killing thepathogens in vi vo

Dr.T.V.Rao MD 5



The discovery of penicillin has beenattributed to Scottishscientist Alexander

Fleming in 1928 andthe development of penicillin for use as amedicine is attributed

to the Australian NobelLaureate HowardWalter Florey

Dr.T.V.Rao MD 6


http://slidepdf.com/reader/full/antibiotics-misuse-and-consequences 7/67Dr.T.V.Rao MD 7



The term"antibiotic" wascoined by Selman

Waksman in 1942to describe anysubstanceproduced by a

microorganism thatis antagonistic tothe growth of othermicroorganisms in

high dilutionDr.T.V.Rao MD 8



Antimicrobialagents – that areproduced

synthetically buthave actionsimilar to that of antibiotics andare defined aschemotherapeutic agents

Eg Sulphonamides,uinolones.

Dr.T.V.Rao MD 9



Substancesderived from amicroorganism

or producedsynthetically,that destroys or

limits the growthof a livingorganism

Dr.T.V.Rao MD 10



Bacteriostatic - Antimicrobialagents that reversibly inhibitgrowth of bacteria are called as

bacteriostic ( Tetracyclnes,Chloramphenicol )

Bactericidal – Those with an

irreversible lethal action onbacteria are known as bactericidal( Pencillin, Isoniazid )

Dr.T.V.Rao MD 11



1920 1930 1940 1950 1960 1970 1980 1990 2000

ertapenem tigecyclin

daptomicin

linezolidtelithromicin

quinup./dalfop.cefepime

ciprofloxacin

aztreonamnorfloxacinimipenem

cefotaximeclavulanic ac.

cefuroximegentamicin

cefalotina

nalidíxico ac.ampicillinmethicilin

vancomicinrifampin

chlortetracyclinstreptomycin

pencillin G

prontosil

The development

of anti-infectives …

Development of anti-infectives

Dr.T.V.Rao MD 12



Antimicrobial agents are widelyemployed to cure bacterial diseases

Definition of Antibiotic – Antibiotics

are substances that are derived from avarious species of microorganismsand are capable of inhibiting the

growth of other microorganism evenin small concentrations.

Dr.T.V.Rao MD 13



ANTIBIOTICS – Sources

1. Natural

a.Fungi–

penicillin, griseofulvinb.Bacteria – Bacillus sp. (polymixin,

bacitracin) ; Actinomycetes

(tetracycline, chloramphenicol,streptomycin)

2. SyntheticDr.T.V.Rao MD 14



ANTIMICROBIAL AGENT

Ideal Qualities:

1. kill or inhibit the growth of pathogens

2. cause no damage to the host

3. cause no allergic reaction to the host

4. stable when stored in solid or liquid form

5. remain in specific tissues in the body long enough

to be effective

6. kill the pathogens before they mutate and becomeresistant to it

Dr.T.V.Rao MD 15



Although a large number of antibiotics exist, they fall into

only a few classes with an even more limited number oftargets.

–β-lactams (penicillins) –cell wall biosynthesis

–Glycopeptide (vancomycin) –cell wall biosynthesis

–Aminoglycosides (gentamycin) –protein synthesis

–Macrolides (erythromycin) –protein synthesis

–Quinolones (ciprofloxacin) –nucleic acid synthesis

–Sulfonamides (sulfamethoxazole) –folic acid metabolism

Dr.T.V.Rao MD 16



Is an antibiotic necessary ?

What is the most appropriate

antibiotic ?What dose, frequency, route and

duration ?

Is the treatment effective ?

Dr.T.V.Rao MD 17



Useful only for the treatment of bacterialinfections

Not all fevers are due to infection

Not all infections are due to bacteriaThere is no evidence that

antibiotics will prevent

secondary bacterial infection inpatients with viral infection

Dr.T.V.Rao MD 18



Oral vs parenteralTraditional view “serious = parenteral”

previous lack of broad spectrum oralantibiotics with reliable bioavailability

Improved oral agents higher and more persistent serum and

tissue levels for certain infections as good as

parenteral

Dr.T.V.Rao MD 19



Eliminates risks of complications associated

with intravascular linesShorter duration of hospitalstay

Savings in nursing timeSavings in overall costs

Dr.T.V.Rao MD 20



New Resistant Bacteria

Susceptible Bacteria

Resistant Bacteria

Resistance Gene Transfer

Dr.T.V.Rao MD 21



Mechanisms of Resistance

Enzymatic

degradation

Decreased entry

Efflux pump

Altered target site

Bypass pathway

Dr.T.V.Rao MD 22



Antimicrobial Resistance:

Key Prevention Strategies

Optimize Use

Prevent

Transmission

Prevent

Infection

Effective Diagnosis & Treatment

PathogenAntimicrobial-Resistant Pathogen

AntimicrobialResistance

Antimicrobial Use

Infection

Campaign to Prevent Antimicrobial Resistance in Healthcare Settings

Susceptible Pathogen

Dr.T.V.Rao MD 23



Antibiotic resistance isa consequence of evolution via naturalselection. Theantibiotic action is an

environmentalpressure; thosebacteria which have amutation allowingthem to survive willlive on to reproduce.

They will then pass thistrait to their offspring,which will be a fullyresistant generation.

Dr.T.V.Rao MD 24



Dr.T.V.Rao MD 25



Dr.T.V.Rao MD 26



Dr.T.V.Rao MD 27



48% of all antibiotics by weight is added toanimal feeds to promote growth. Results in low,sub therapeutic levels which are thought to

promote resistance. Farm families who own chickens feed

tetracycline have an increased incidence of tetracycline resistant fecal flora

Chickens at Spanish supermarkets have >90% of cultured campylobacter resistant to quinolones

39% of enterococci in the fecal flora of pigsfrom the Netherlands is resistant to vancomycinvs 0% in Sweden. (Sweden bans antibioticadditives in animal feed) Dr.T.V.Rao MD 28



Several studies havedemonstrated thatpatterns of antibioticusage greatly affect the

number of resistantorganisms whichdevelop. Overuse of broad-spectrumantibiotics, such as

second- and third-generationCephalosporins,generate resistant

strains. Dr.T.V.Rao MD 29



The resistant strains arise eitherby mutation and selection or bygenetic exchange in which

sensitive organisms receive thegenetic material ( part of DNA)from the resistant organisms and

the part of DNA carries with it theinformation of mode of inducingresistance against one or multiplen imi r i l n . Dr.T.V.Rao MD 30



RESISTANCE

ACQUISITION OF BACTERIAL RESISTANCE

ACQUIRED RESISTANCE

Species develop ability to resist an

antimicrobial drug to which it is as awhole naturally susceptible

Two mechanisms:

1. Mutational – chromosomal

2. Genetic exchange – transformation, transduction,

conjugation Dr.T.V.Rao MD 31



The greatest possibility of evil in self-medication is the use of too small doses sothat instead of clearing up infection, themicrobes are educated to resist penicillinand a host of penicillin-fast organisms isbread out which can be passed to otherindividuals and from them to other until

they reach someone who gets a septicemiaor a pneumonia which penicillin cannotsave.

. Sir AlexanderFlemming

Dr.T.V.Rao MD 32



1980s –ESBL producing GN bacteria 1990 Vancomycin resistantEnterococci emerged

2000 VISA (intermediate levelresistance)

2002-VRSA (high level resistance)

2002- Linezolid resistant enterococciand Staphylococci reported

Dr.T.V.Rao MD 33



Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes

AmpicillinThird-GenerationCephalosporins

1963

1965

TEM-1E coli S paratyphi

1970s

TEM-1Reported in28 Gram-NegativeSpecies

1980s1983

ESBLinUnitedStates

1987

ESBL inEurope

2000

>120 ESBLsWorldwide

Dr.T.V.Rao MD 34



Resistance to Antibiotics

•Bacteria (and viruses) are very resourceful creatures and they havedeveloped resistance mechanisms to essentially every antibiotic that hasbeen developed.

•Moreover, increased use of antibiotics results in increased resistance (th

paradox of antibiotics).

•The basic resistance mechanisms are quite simple:

1.Modify the antibiotic

2.Modify the target of the antibiotic

3.Destroy the antibiotic

4.Make it more difficult for the antibiotic to get into the cell

Dr.T.V.Rao MD 35



Plasmid seem to be ubiquitous inbacteria, May encode geneticinformation for properties

1 Resistance to Antibiotics2 Bacteriocins production3 Enterotoxin production4 Enhanced pathogen city

5 Reduced Sensitivity tomutagens

6 Degrade complex organic

molecules Dr.T.V.Rao MD 36



Plasmids – helps to spread multiple drugresistance

Discovered in 1959 Japan

Infections caused due to Shigella spreadresistance to following Antibiotics

Sulphonamides

Streptomycin

Choramphenicol,Tetracycline

Dr.T.V.Rao MD 37



Shigella + E.coli

excreted in thestool resistant to

several drugs invivo and vitro

Plasmid mediated –transmitted by

Conjugation Episomes spread

the resistance

Dr.T.V.Rao MD 38



R forms may have evolved as a collection of

Transposons Each carrying Genes that confers resistance

to one or several Antibiotics Seen in Plasmids,

MicroorganismsAnimals

Laboratory Manipulations are called asGenetic Engineering

Dr.T.V.Rao MD 39



Sulphonamides --- Reduce permeability

Erythromycin ---- Modification of ribosome's

Tetracyclnes ----- Reduced permeability

Chloramphenicol ---- Acetylation of drug

Streptomycin ----- Adenylation of drug

Pencillin ----- Hydrolysis of lactum ring

Dr.T.V.Rao MD 40



Therapeutic failures and relapse Facilitates spread in the hospitalunder “antibiotic pressure”

Need to use more costly andtoxic agents

The emergence of untreatablepathogens

Dr.T.V.Rao MD 41



RESISTANCE

ACQUIRED RESISTANCE – EXAMPLES:

1. Resistance (R) plasmids

Transmitted by conjugation

2. mecA gene

Codes for a PBP with low affinityfor -lactam antibiotics

Methicillin-resistant S. aureus

Dr.T.V.Rao MD 42



RESISTANCEORIGIN OF DRUG RESISTANCE

NON-GENETIC

1. Metabolically inactive organisms maybe phenotypically resistant to drugs

– M. tuberculosis

2. Loss of specific target structure for adrug for several generations

3. Organism infects host at sites whereantimicrobials are excluded or arenot active – aminoglycosides (e.g.Gentamicin) vs. Salmonella entericfevers intracellular

Dr.T.V.Rao MD 43



RESISTANCE

GENETIC

1. Chromosomal

Occurs at a frequency of 10-12 to 10-7

2

0

to spontaneous mutation in a locusthat controls susceptibility to a givendrug due to mutation in gene thatcodes for either:

a. drug targetb. transport system in the membrane

that controls drug uptake

Dr.T.V.Rao MD 44



RESISTANCEGENETIC

2. Extrachromosomal

a. Plasmid-mediated

Occurs in many different species, esp. gram(-) rods

Mediate resistance to multiple drugs

Can replicate independently of bacterialchromosome many copies

Can be transferred not only to cells of thesame species but also to other species andgenera

Dr.T.V.Rao MD 45



1Smith TL et al. N Engl J Med. 1999;340:493-501. 2Martone WJ. Infect Control Hosp Epidemiol . 1998;19:539-545.3Hiramatsu K et al. J Antimicrob Chemother . 1997;40:135-136. 4CDC. MMWR Morb Mortal Wkly Rep. 2002;51:565-567.

1975 1995 1990 1985 1980 P a t h

o g e n s R e s i s t a n t t o A n t i b i o t i c s ( % )

10090

80

70

60

5040

30

20

10

1996 2000

MRSA = methicillin-resistant Staphylococcus

aureus

VRE = vancomycin-resistant enterococci

GISA = glycopeptide-intermediate S aureus

VRSA = vancomycin-resistant S aureus MRSA1

VRE2

GISA3

Year 2002

VRSA4

Dr.T.V.Rao MD 46



< Inappropriate specimen selection and

collection

< Inappropriate clinical tests

< Failure to use stains/smears

< Failure to use cultures and

susceptibility tests

Practices Contributing to

Misuse of Antibiotics

Dr.T.V.Rao MD 47



RESISTANCELIMITATION OF DRUG RESISTANCE

1. Maintain sufficiently high levels of thedrug in the tissues inhibit original

population and first-step mutants.

2. Simultaneous administration of twodrugs that do not give cross-resistance

delay emergence of mutants resistantto the drug (e.g. INH + Rifampicin)

3. Limit the use of a valuable drug avoid

exposure of the organism to the drug Dr.T.V.Rao MD 48



What Is Antimicrobial Stewardship?

• A combination of infection control and antimicrobial

management• Mandatory infection control compliance • Selection of antimicrobials from each class of drugsthat does

the least collateral damage• Collateral damage issues include – MRSA– ESBLs– C difficile

– Stable derepression– MBLs and other carbapenemases– VRE• Appropriate de-escalation when culture results are

available Dr.T.V.Rao MD 49



IDSA Guidelines – Definition ofAntimicrobial Stewardship

• Antimicrobial stewardship is anactivity that promotes

– The appropriate selection of antimicrobials

– The appropriate dosing of

antimicrobials

– The appropriate route and durationof antimicrobial therapy

Dr.T.V.Rao MD 50



The Primary Goal of

Antimicrobial Stewardship• The primary goal of antimicrobial stewardship is to

– Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

• Unintended consequences include the following – Toxicity

– The selection of pathogenic organisms, such as C difficile

– The emergence of resistant pathogens

Dr.T.V.Rao MD 51



The Primary Goal of

Antimicrobial Stewardship• The primary goal of antimicrobial stewardship is to

– Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use

• Unintended consequences include the following – Toxicity

– The selection of pathogenic organisms, such as C difficile

– The emergence of resistant pathogens

Dr.T.V.Rao MD 52



< Inappropriate specimen selection and

collection

< Inappropriate clinical tests

< Failure to use stains/smears

< Failure to use cultures and

susceptibility tests

Practices Contributing to

Misuse of Antibiotics

Dr.T.V.Rao MD 53



Use of antibiotics with noclinical indication (eg, for

viral infections)Use of broad spectrumantibiotics when notindicated

Inappropriate choice of

empiric antibiotics

Inappropriate Antibiotic Use

Dr.T.V.Rao MD 54



Inappropriate dose - ineffectiveconcentration of antibiotics at siteof infection

Inappropriate route - ineffectiveconcentration of antibiotics at siteof infection

Inappropriate duration

Inappropriate Drug Regimen

Dr.T.V.Rao MD 55



If a bacterium carries severalresistance genes, it is calledmultiresistant or, informally, a

superbug. The termantimicrobial resistance issometimes use to explicitly

encompass organisms otherthan bacteria

Dr.T.V.Rao MD 56



Antibiotic resistance has become aserious problem in both developedand underdeveloped nations. By

1984 half of those with activetuberculosis in the United States hada strain that resisted at least one

antibiotic.In certain settings, such ashospitals and some childcare location

Dr.T.V.Rao MD 57



Dr.T.V.Rao MD 58



Fischbach MA and Walsh CT Science 2009

Dr.T.V.Rao MD 59



Other clinicians

Patients

Optimize patient evaluationAdopt judicious antibioticprescribing practicesImmunize patients

Optimize consultations withother cliniciansUse infection control measuresEducate others about judicioususe of antibiotics

Dr.T.V.Rao MD 60



Bacteria evolve resistance toantibiotics in response toenvironmental pressure exerted by the

use of antibiotics. Many of these bacteria are significantpathogens.

Our responsibility to our community isto use antibiotics prudently, forappropriate indications.

Dr.T.V.Rao MD 61

Campaign to Prevent Antimicrobial Resistance in Healthcare Settings



12 Steps to Prevent

Antimicrobial Resistance

12 Break the chain11 Isolate the pathogen10 Stop treatment when cured

9 Know when to say “no” to vanco 8 Treat infection, not colonization

7 Treat infection, not contamination6 Use local data

5 Practice antimicrobial control4 Access the experts

3 Target the pathogen2 Get the catheters out

1 Vaccinate

Prevent Transmission

Use Antimicrobials Wisely

Diagnose & Treat

Effectively

Prevent Infections

Dr.T.V.Rao MD 62



Antibiotic resistance is a majorproblem world-wide

Resistance is inevitable with use

No new class of antibioticintroduced over the last twodecades

Appropriate use is the only way ofprolonging the useful life of anantibiotic

Dr.T.V.Rao MD 63



Dr.T.V.Rao MD 64



Surveillance

Prevention and

Control

Research

Product

Development

Agency forHealth Care Research and

QualityDepartment of

Defense

EnvironmentalProtection

Agency

Health CareFinancing

Administration

Health Resources andServices

Administration

Department ofAgriculture

Department ofVeterans Affairs

Dr.T.V.Rao MD 65



Think before

prescribing Are

we using Right

drug for the

Right bug ?

Dr.T.V.Rao MD 66



Created by Dr.T.V.Rao MD for

Medical Professionals in the

Developing WorldEmail

[email protected]

Antibiotics, Misuse and Consequences

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