Rationalism of Antibiotic

Therapy

Consequences of MisuseConsequences of Misuse

Dr.T.V.Rao MD

Dr.T.V.Rao MD

ANTIMICROBIAL AGENT

• Any chemical or drug used to treat an infectious disease, treat an infectious disease,

either by inhibiting or killing the pathogens in vivo

Dr.T.V.Rao MD

Beginning of Antibiotics with Discovery of

Pencillin

• The discovery of penicillin

has been attributed to

Scottish scientist

Alexander Fleming in 1928

and the development of and the development of

penicillin for use as a

medicine is attributed to

the Australian Nobel

Laureate Howard Walter

Florey.

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 any substance produced by a produced by a microorganism that is antagonistic to the growth of other microorganisms in high dilution

Dr.T.V.Rao MD

Chemotherapeutic AgentsChemotherapeutic AgentsChemotherapeutic AgentsChemotherapeutic Agents

• Antimicrobial agents –

that are produced

synthetically but have

action similar to that of

antibiotics and are antibiotics and are

defined as

chemotherapeutic agents

• Eg Sulphonamides,

Quinolones.

Dr.T.V.Rao MD

Definition

• Bacteriostatic - Antimicrobial agents that

reversibly inhibit growth of bacteria are called as

bacteriostic ( Tetracyclnes, Chloramphenicol )

• Bactericidal – Those with an irreversible lethal • Bactericidal – Those with an irreversible lethal

action on bacteria are known as bactericidal (

Pencillin, Isoniazid )

Dr.T.V.Rao MD

ertapenem tigecyclin daptomicin

linezolidtelithromicin

quinup./dalfop.cefepime

ciprofloxacinaztreonam

norfloxacinimipenem

cefotaximeclavulanic ac.

cefuroxime

The development

of anti-infectives …

Development of anti-infectives

1920 1930 1940 1950 1960 1970 1980 1990 2000

cefuroximegentamicin

cefalotinanalidíxico ac.

ampicillinmethicilin

vancomicinrifampin

chlortetracyclinstreptomycin

pencillin Gprontosil

Dr.T.V.Rao MD

Uses of Antimicrobial Agents

• Antimicrobial agents are widely employed to cure

bacterial diseases

• Definition of Antibiotic – Antibiotics are

substances that are derived from a various species substances that are derived from a various species

of microorganisms and are capable of inhibiting

the growth of other microorganism even in small

concentrations.

Dr.T.V.Rao MD

ANTIBIOTICS

• Substances derived from a microorganism or produced synthetically, that synthetically, that destroys or limits the growth of a living organism

Dr.T.V.Rao MD

ANTIBIOTICS – Sources

1. Natural

a.Fungi – penicillin, griseofulvin

b.Bacteria – Bacillus sp. (polymixin, bacitracin) ; Actinomycetes (tetracycline, chloramphenicol, streptomycin)

2. SyntheticDr.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 host3. 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 tobe 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.

–β-lactams (penicillins) –cell wall biosynthesis–β-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 ?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 bacterial infections

� Not all fevers are due to infection

� Not all infections are due to bacteria� Not all infections are due to bacteria

�There is no evidence that antibiotics will prevent secondary bacterial infection in patients with viral infection

Dr.T.V.Rao MD

Choice of regimen

� Oral vs parenteral

� Traditional view

� “serious = parenteral”

� previous lack of broad spectrum oral antibiotics

with reliable bioavailabilitywith 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

Advantages of oral treatment

� Eliminates risks of complications associated with

intravascular lines

� Shorter duration of hospital stay

� Savings in nursing time� Savings in nursing time

� Savings in overall costs

Dr.T.V.Rao MD

Antimicrobial Resistance:Antimicrobial Resistance:

Key Prevention StrategiesKey Prevention Strategies

PreventTransmission

PreventInfection

PathogenAntimicrobial-Resistant Pathogen

Campaign to Prevent Antimicrobial Resistance in Healthcare Settings

Susceptible Pathogen

Optimize UseEffectiveDiagnosis& Treatment

Antimicrobial Resistance

Antimicrobial Use

Infection

Dr.T.V.Rao MD

Emerging Resistance

• Antibiotic resistance is a consequence of evolution via natural selection. The antibiotic action is an environmental pressure; those bacteria which have a environmental pressure; those bacteria which have a mutation allowing them to survive will live on to reproduce. They will then pass this trait to their offspring, which will be a fully resistant generation.

Dr.T.V.Rao MD

Irrational Use of Third Generation

Cephalosporins• Several studies have

demonstrated that patterns of antibiotic usage greatly affect the number of resistant organisms which develop. Overuse of broad-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 Origin of Drug Resistant Origin of Drug Resistant Origin of Drug Resistant StrainsStrainsStrainsStrains

• 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) 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 an antimicrobial drug to which it is as a antimicrobial drug to which it is as a whole naturally susceptible

� Two mechanisms:

1. Mutational – chromosomal

2. Genetic exchange – transformation, transduction, conjugation

Dr.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-fast organisms is bread out which

can be passed to other individuals and from them to 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 emerged

2000 VISA (intermediate level resistance)

2002-VRSA (high level resistance)2002-VRSA (high level resistance)

2002- Linezolid resistant enterococci and

Staphylococci reported

Dr.T.V.Rao MD

Evolution of b-Lactamase

Plasmid-Mediated TEM and SHV Enzymes

AmpicillinThird-Generation

Cephalosporins

1965 1970s 1980s 1987 2000

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 resourceful creatures and they have developed resistance

mechanisms 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:•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

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

Plasmids

• Plasmid seem to be ubiquitous in bacteria, May encode genetic information for properties

1 Resistance to Antibiotics2 Bacteriocins production3 Enterotoxin 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

• Infections caused due to Shigella spread resistance to

following Antibioticsfollowing 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 vitrovitro

• 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 confers resistance to one or several Antibiotics

• Seen in Plasmids,• Seen in Plasmids,

Microorganisms

Animals

Laboratory Manipulations are called as Genetic Engineering

Dr.T.V.Rao MD

Plasmid Mediated Drug resistance

Sulphonamides --- Reduce permeability

Erythromycin ---- Modification of ribosome's

Tetracyclnes ----- Reduced permeability

Chloramphenicol ---- Acetylation of drugChloramphenicol ---- Acetylation of drug

Streptomycin ----- Adenylation of drug

Pencillin ----- Hydrolysis of lactum ring

Dr.T.V.Rao MD

RESISTANCE

ACQUIRED RESISTANCE – EXAMPLES:

1. Resistance (R) plasmids

� Transmitted by conjugation� Transmitted by conjugation

2. mecA gene

� Codes for a PBP with low affinity for β-lactam antibiotics

� Methicillin-resistant S. aureus

Dr.T.V.Rao MD

RESISTANCE

ORIGIN OF DRUG RESISTANCE

NON-GENETIC

1. Metabolically inactive organisms may be phenotypically resistant to drugs – M. tuberculosistuberculosis

2. Loss of specific target structure for a drug for several generations

3. Organism infects host at sites where antimicrobials are excluded or are not active – aminoglycosides (e.g. Gentamicin) vs. Salmonella enteric fevers (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 locus that controls susceptibility to a given drug � due controls susceptibility to a given drug � due

to mutation in gene that codes for either:

a. drug target

b. transport system in the membrane that 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� Mediate resistance to multiple drugs

� Can replicate independently of bacterial chromosome � many copies

� Can be transferred not only to cells of the same species but also to other species and genera

Dr.T.V.Rao MD

< Inappropriate specimen selection and collection

< Inappropriate clinical tests

Practices Contributing to

Misuse of Antibiotics

< Inappropriate clinical tests

< Failure to use stains/smears

< Failure to use cultures and susceptibility tests

Dr.T.V.Rao MD

RESISTANCE

LIMITATION OF DRUG RESISTANCE

1. Maintain sufficiently high levels of the drug in the tissues � inhibit original population

and first-step mutants.and first-step mutants.

2. Simultaneous administration of two drugs that do not give cross-resistance � delay

emergence of mutants resistant to the drug (e.g. INH + Rifampicin)

3. Limit the use of a valuable drug � avoid

exposure of the organism to the drugDr.T.V.Rao MD

What Is Antimicrobial Stewardship?

• A comination of infection control and antimicrobial management

• Mandatory infection control compliance

• Selection of antimicrobials from each class of drugs that does

the least collateral damage

• Collateral damage issues include

– MRSA

– ESBLs– ESBLs

– C difficile

– Stable derepression

– MBLs and other carbapenemases

– VRE

• Appropriate de-escalation when culture results are available

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

Dr.T.V.Rao MD

IDSA Guidelines – Definition of

Antimicrobial Stewardship

• Antimicrobial stewardship is an activity that

promotes

– The appropriate selection of antimicrobials– 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

Practices Contributing to

Misuse of Antibiotics

< Inappropriate clinical tests

< Failure to use stains/smears

< Failure to use cultures and susceptibility tests

Dr.T.V.Rao MD

Use of antibiotics with no clinical

indication (eg, for viral infections)

Use of broad spectrum antibiotics

Inappropriate Antibiotic Use

Use of broad spectrum antibiotics

when not indicated

Inappropriate choice of empiric

antibiotics

Dr.T.V.Rao MD

Inappropriate dose - ineffective concentration of antibiotics at site of infection

Inappropriate Drug Regimen

Inappropriate route - ineffective concentration of antibiotics at site of infection

Inappropriate durationDr.T.V.Rao MD

Multi Drug resistant pathogens

• If a bacterium carries several resistance

genes, it is called multiresistant or,

informally, a superbug. The term informally, a superbug. The term

antimicrobial resistance is sometimes

use to explicitly encompass organisms

other than 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 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 evaluation Adopt judicious antibioticprescribing practicesImmunize patients

Optimize consultations with other cliniciansUse infection control measuresEducate others about judicious use of antibiotics

Dr.T.V.Rao MD

Antibiotic Pressure and Resistance in Bacteria:

Conclusions

• Bacteria evolve resistance to antibiotics in

response to environmental pressure exerted by

the use of antibiotics.

• Many of these bacteria are significant pathogens. • Many of these bacteria are significant pathogens.

• Our responsibility to our community is to use

antibiotics prudently, for appropriate indications.

Dr.T.V.Rao MD

12 Steps to Prevent Antimicrobial Resistance

12 Break the chain11 Isolate the pathogen

Prevent Transmission

Use Antimicrobials Wisely

Campaign to Prevent Antimicrobial Resistance in Healthcare Settings

11 Isolate the pathogen10 Stop treatment when cured

9 Know when to say “no” to vanco8 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

Use Antimicrobials Wisely

Diagnose & Treat Effectively

Prevent Infections

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 � 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 overusing AntibioticsAre we overusing AntibioticsAre we overusing AntibioticsAre we overusing Antibiotics

Dr.T.V.Rao MD

Choose the Appropriate

Antibiotic

Think before

prescribing

Are we using Are we using

Right drug

for the Right

bug ?

Dr.T.V.Rao MD

The e-programme created by Dr.T.V.Rao MD for

teaching the Medical Graduates in the teaching the Medical Graduates in the

Developing world.

Email

doctortvrao@gmail.com

Dr.T.V.Rao MD