Rationalism of Antibiotic Therapy

8/8/2019 Rationalism of Antibiotic Therapy

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Rationalism of

Antibiotic TherapyConsequences of Misuse

Dr.T.V.Rao MD

Dr.T.V.Rao MD



ANTIMICROBIAL AGENT

Any chemical or drug used

to treat an infectious disease,either by inhibiting or killing

the pathogens in vivo

Dr.T.V.Rao MD





Discovery of Pencillin

Awarded Nobel Prize

Dr.T.V.Rao MD



Selman Waksman

The term "antibiotic"was coined by Selman Waksman in 1942 to

describe anysubstance producedby a microorganism that is antagonistic to

the growth of othermicroorganisms in high dilution

Dr.T.V.Rao MD



Chemotherapeutic Agents

Antimicrobial agents

that are produced

synthetically but have

action similar to that of antibiotics and are

def ined as

chemotherapeutic

agents

Eg Sulphonamides,

Q uinolones.

Dr.T.V.Rao MD



Def inition

Bacteriostatic - Antimicrobial agents that

reversibly inhibit growth of bacteria are called

as bacteriostic ( Tetracyclnes, Chloramphenicol )

Bactericidal Those with an irreversible lethal

action on bacteria are known as bactericidal (

Pencillin, Isoniazid )

Dr.T.V.Rao MD



1920 1930 1940 1950 1960 1970 1980 1990 2000

ertapenemtigecyclin

dapto

micinlinezolidtelithromicin

quinup./dalfop.cef epime

ciprof loxacinaztreonam

norf loxacinimipenem

cefotaximeclavulanic ac.

cef uroximegentamicin

cefalotinanalidí xico ac.

ampicillinmethicilin

vancomicinrifampin

chlortetracyclin

streptomycinpencillin G

prontosil

The development

of anti-infectives

Development of anti-infectives

Dr.T.V.Rao MD





ANTIBIOTICS

Substances derivedfrom amicroorganism or

producedsynthetically, thatdestroys or limitsthe growth of a

living organism

Dr.T.V.Rao MD



ANTIBIOTICS ± Sources

1. Natural

a.Fungi ± penicillin, griseofulvin

b.Bacteria ± Bac illus sp.(polymixin, bacitracin) ;

Act inomy cetes (tetracycline,chloramphenicol,streptomycin)

2. Synthetic Dr.T.V.Rao MD



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 enoughto be effective

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

Dr.T.V.Rao MD



Basic Classes of Antibiotics

Although a large number of antibiotics exist, they fall into only a few classes with

an even more limited number of targets.

-lactams (penicillins) cell wall biosynthesis

Glycopeptides (vancomycin) cell wall biosynthesis

Aminoglycosides (gentamycin) protein synthesis

Macrolides (erythromycin) protein synthesis

Quinolones (ciprofloxacin) nucleic acid synthesis

Sulfonamides (sulfamethoxazole) folic acid metabolismDr.T.V.Rao MD



Prescribing an antibiotic

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



Is an antibiotic necessary ?

Useful only for the treatment of bacterialinfections

Not all fevers are due to infection

Not all infections are due to bacteria

There is no evidence that antibioticswill prevent secondary bacterial

infection in patients with viralinfection

Dr.T.V.Rao MD



Choice of regimen

Oral vs parenteral

Traditional view

serious = parenteral

previous lack of broad spectrum oral antibiotics with reliable bioavailability

Improved oral agents

higher and more persistent serum and tissue levels

for certain inf ections as good as parenteral

Dr.T.V.Rao MD



Advantages of oral treatment

Eliminates risks of complications associated

with intravascular lines

Shorter duration of hospital stay

Savings in nursing time

Savings in overall costs

Dr.T.V.Rao MD



Antimicrobial Resistance: Antimicrobial Resistance:

Key Prevention StrategiesKey Prevention Strategies

Optimize Use

Prevent Transmission

Prevent Infection

Effective Diagnosis & Treatment

Pathogen Antimicrobial-Resistant Pathogen

AntimicrobialResistance

AntimicrobialUse

Infection

Campaign to Prevent Antimicrobial Resistance in Healthcare Settings

Susceptible Pathogen

Dr.T.V.Rao MD



Emerging Resistance

Antibiotic resistance is aconsequence of evolution via natural selection. The antibiotic action is an environmental pressure; those bacteria which have a mutation allowing them to survive will live on to

reproduce. They will then pass this trait to theiroff spring, which will be af ully resistant generation.

Dr.T.V.Rao MD



Irrational Use of Third Generation

Cephalosporins Several studies have demonstrated that patterns of antibiotic usage greatly aff ect the number of resistant organisms which develop.Overuse of broad-spectrum antibiotics, such

as second- and third-generation Cephalosporins, generate resistant strains.

Dr.T.V.Rao MD



Origin of Drug Resistant Strains

The resistant strains arise either by mutation

and selection or by genetic exchange in which

sensitive organisms receive the genetic

material ( part of DNA) from the resistant

organisms and the part of DNA carries with it

the information of mode of inducing

resistance against one or multiple antimicrobial agents.

Dr.T.V.Rao MD



RESISTANCE

ACQUISITION OF BACTERIAL RESISTANCE

ACQUIRED RESISTANCE

Species develop ability to resist anantimicrobial drug to which it is as awhole naturally susceptible

Two mechanisms:

1. Mutational ± chromosomal

2. Genetic exchange ±transformation, transduction,

conjugationDr.T.V.Rao MD



Self Medication

The greatest possibility of evil in self-medication is

the use of too small doses so that instead of

clearing up infection, the microbes are educated to

resist penicillin and a host of penicillin-fastorganisms is bread out which can be passed to

other individuals and from them to other until they

reach someone who gets a septicemia or a

pneumonia which penicillin cannot save.

. Sir AlexanderFlemming

Dr.T.V.Rao MD



Historical aspects

1980s ESBL producing GN bacteria

1990 Vancomycin resistant Enterococci

emerged2000 VISA (intermediate level resistance)

2002-VRSA (high level resistance)

2002- Linezolid resistant enterococci andStaphylococci reported

Dr.T.V.Rao MD



Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes

AmpicillinThird-Generation

Cephalosporins

1963

1965

TEM-1

E coli

S paratyphi

1970s

TEM-1

Reported in

28 Gram-

Negative

Species

1980s1983

ESBL

in

United

States

1987

ESBL in

Europe

2000

>120 ESBLs

Worldwide

Dr.T.V.Rao MD



Resistance to Antibiotics

Bacteria (and viruses) are very resourcef ul creatures and they have developed resistanmechanisms to essentially every antibiotic that has been developed.

Moreover, increased use of antibiotics results in increased resistance (the 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 diff icult for the antibiotic to get into the cell

5.Actively remove the antibiotic from the cellDr.T.V.Rao MD



P lasmids

Plasmid seem to be ubiquitous in bacteria, Mayencode genetic information for properties

1 Resistance to Antibiotics

2 Bacteriocins production3 Enterotoxin production4 Enhanced pathogen city5 Reduced Sensitivity to

mutagens6 Degrade complex organic molecules

T.V.Rao MD

Dr.T.V.Rao MD



Resistance Transfer Factor

RTF

Plasmids helps to spread multiple drug resistance

Discovered in 1959 Japan

Inf ections caused due to Shigella spread resistance to

following Antibiotics

Sulphonamides

Streptomycin

Choramphenicol,

Tetracycline

Dr.T.V.Rao MD



RTF

Shigella + E.coli excreted in the stool

resistant to several drugs in vivo and vitro

Plasmid mediated transmitted by

Conjugation Episomes spread the

resistance

Dr.T.V.Rao MD



Transposons and R factor

R forms may have evolved as a collection of Transposons

Each carrying Genes that conf ers resistance to one orseveral Antibiotics

Seen in Plasmids,

Microorganisms

Animals

Laboratory Manipulations are called as Genetic Engineering

Dr.T.V.Rao MD



Plasmid Mediated Drug

resistanceSulphonamides --- Reduce permeability

Erythromycin ---- Modif ication of ribosome's

Tetracyclnes ----- Reduced permeabilityChloramphenicol ---- Acetylation of drug

Streptomycin ----- Adenylation of drug

Pencillin ----- Hydrolysis of lactum ring

Dr.T.V.Rao MD



RESISTANCE

ACQUIRED RESISTANCE ± EXAMPLES:

1. R esistance (R ) plasmids

Transmitted by conjugation

2. mecA gene

Codes for a PBP with low affinityfor F-lactam antibiotics

Methicillin-resistant S. aureus

Dr.T.V.Rao MD



RESISTANCE

ORIGIN 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



RESISTANCE

GENETIC

1. Chromosomal

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

20 to spontaneous mutation in a locusthat controls susceptibility to a givendrug due to mutation in gene that

codes for either:

a. drug target

b. transport system in the membranethat controls drug uptake

Dr.T.V.Rao MD



RESISTANCE

GENETIC

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



< 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



RESISTANCE

LIMITATION 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 resistant tothe drug (e.g. INH + R ifampicin)

3. Limit the use of a valuable drug avoidexposure of the organism to the drug

Dr.T.V.Rao MD



What Is Antimicrobial Stewardship?

A comination of inf ection control and antimicrobial management

Mandatory inf ection control compliance

Selection of antimicrobials from each class of drugs that 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

Dellit TH, et al. C lin Infect Dis. 2007;44:159-177.

Dr.T.V.Rao MD



IDSA Guidelines Def inition of

Antimicrobial Stewardship

Antimicrobial stewardship is an activity that

promotes

The appropriate selection of antimicrobials

The appropriate dosing of antimicrobials

The appropriate route and duration of

antimicrobial therapy

Dr.T.V.Rao MD



The Primary Goal of

Antimicrobial Stewardship The primary goal of antimicrobial stewardship is to

Optimize clinical outcomes while minimizing unintended

consequences 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



The Primary Goal of

Antimicrobial Stewardship The primary goal of antimicrobial stewardship is to

Optimize clinical outcomes while minimizing unintended

consequences 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



< 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





Inappropriate dose - ineff ective concentration of antibiotics at site of

inf ection

Inappropriate route - ineff ective concentration of antibiotics at site of

inf ection

Inappropriate duration

Inappropriate Drug Regimen

Dr.T.V.Rao MD



Multi Drug resistant pathogens

If a bacterium carries several

resistance genes, it is called

multiresistant or, informally, asuperbug. The term antimicrobial

resistance is sometimes use to

explicitly encompass organisms otherthan bacteria

Dr.T.V.Rao MD



Antibiotic Resistance

Threat to Humans and Animals

Antibiotic resistance has become a serious

problem in both developed and

underdeveloped nations. By 1984 half of

those with active tuberculosis in the United

States had a strain that resisted at least one

antibiotic.In certain settings, such as hospitals

and some childcare location

Dr.T.V.Rao MD



Dr.T.V.Rao MD



Between 1962 and 2000, no major classes of

antibiotics were introduced

Fischbach MA and Walsh CT Science 2009

Dr.T.V.Rao MD



Physicians Can Impact

Other clinicians

Patients

Optimize patient evaluationAdopt judicious antibiotic

prescribing practicesImmunize patients

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

Dr.T.V.Rao MD



Antibiotic Pressure and Resistance in Bacteria:

C onclusions

Bacteria evolve resistance to antibiotics in

response to environmental pressure exerted

by the use of antibiotics.

Many of these bacteria are signif icant

pathogens.

Our responsibility to our community is to use

antibiotics prudently, for appropriate

indications.

Dr.T.V.Rao MD



12 Steps to Prevent AntimicrobialResistance

12 Break the chain11 Isolate the pathogen

10 Stop treatment when cured9 Know when to say no to vanco

8 Treat inf ection, not colonization7 Treat inf ection, not contamination

6 Use local data5 Practice antimicrobial control

4 Access the experts3 Target the pathogen

2 Get the catheters out1 Vaccinate

Prevent Transmission

Use Antimicrobials Wisely

Diagnose & Treat Effectively

Prevent Inf ections

Campaign to Prevent Antimicrobial Resistance in Healthcare Settings

Dr.T.V.Rao MD



Conclusions

Antibiotic resistance is a major problem

world-wide

Resistance is inevitable with use

No new class of antibiotic introduced over

the last two decades

Appropriate use is the only way of prolonging the useful life of an antibiotic

Dr.T.V.Rao MD



Are we ov erusing Antibiotics

Dr.T.V.Rao MD



Choose the Appropriate

Antibiotic

Think before

prescribingAre we using

Right drug

for the Rightbug ?

Dr.T.V.Rao MD



The e-programme created by Dr.T.V.Rao MDfor teaching the Medical Graduates in the

Developing world.

Email

[email protected]

Dr T V Rao MD

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Rationalism of Antibiotic Therapy