Dr.T.V.

Rao MD

Dr.T.V.Rao MD

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 Tuberculosis
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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; no medications are required: colds, flu, stomach virus
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Development

They dont 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 antibiotic wont work when you really DO need it for a bacterial infection
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of resistance: the

ANTIMICROBIAL AGENT

Any chemical or drug used to treat an infectious disease, either by inhibiting or killing the pathogens in vivo

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The discovery of penicillin has been attributed to Scottish scientist Alexander Fleming in 1928 and the development of penicillin for use as a medicine is attributed to the Australian Nobel Laureate Howard Walter Florey

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Dr.T.V.Rao MD

The term "antibiotic" was coined by Selman Waksman in 1942 to describe any substance produced by a microorganism that is antagonistic to the growth of other microorganisms in high dilution
Dr.T.V.Rao MD

Antimicrobial agents that are produced synthetically but have action similar to that of antibiotics and are defined as chemotherapeuti c agents
Eg Sulphonamides, Quinolones.
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Substances derived from a microorganism or produced synthetically, that destroys or limits the growth of a living organism
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 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 )
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Development of anti-infectives
ertapenem tigecyclin daptomicin The development linezolid of anti-infectives telithromicin

quinup./dalfop.

1920 prontosil

pencillin G

cefepime ciprofloxacin aztreonam norfloxacin imipenem cefotaxime clavulanic ac. cefuroxime gentamicin cefalotina nalidxico ac. ampicillin methicilin vancomicin rifampin chlortetracyclin streptomycin

1930

1940

1950

1960

1970

1980

1990

2000
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Antimicrobial agents are widely employed to cure bacterial diseases Definition of Antibiotic Antibiotics are substances that are derived from a various species of microorganisms and are capable of inhibiting the growth of other microorganism even in small concentrations.

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ANTIBIOTICS Sources
Natural
a.Fungi penicillin, griseofulvin

1.

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

2. Synthetic
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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 become resistant to it

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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

Glycopeptide (vancomycin) cell wall biosynthesis

Aminoglycosides (gentamycin) protein synthesis Macrolides (erythromycin) protein synthesis Quinolones (ciprofloxacin) nucleic acid synthesis Sulfonamides (sulfamethoxazole) folic acid metabolism

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 Is

an antibiotic necessary ? What is the most appropriate antibiotic ? What dose, frequency, route and duration ? Is the treatment effective ?
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 Useful only for the treatment of bacterial infections Not all fevers are due to infection Not all infections are due to bacteria

There is no evidence that antibiotics will prevent secondary bacterial infection in patients with viral infection
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 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 infections as good as parenteral
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 Eliminates

risks of complications associated with intravascular lines Shorter duration of hospital stay Savings in nursing time Savings in overall costs
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Susceptible Bacteria Resistant Bacteria

Resistance Gene Transfer

New Resistant Bacteria

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Decreased entry

Efflux pump Altered target site

Mechanisms of Resistance
Enzymatic degradation

Bypass pathway

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Campaign to Prevent Antimicrobial Resistance in Healthcare Settings

Key Prevention Strategies

Susceptible Pathogen Pathogen Antimicrobial-Resistant Pathogen
Prevent Transmission
Prevent Infection

Antimicrobial Resistance:

Antimicrobial Resistance
Optimize Use

Infection
Effective Diagnosis & Treatment

Antimicrobial Use
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Antibiotic resistance is a consequence 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 their offspring, which will be a fully resistant generation.
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48% of all antibiotics by weight is added to animal 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 pigs from the Netherlands is resistant to vancomycin vs 0% in Sweden. (Sweden bans antibiotic Dr.T.V.Rao MD additives in animal feed)

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Several studies have demonstrated that patterns of antibiotic usage greatly affect the number of resistant organisms which develop. Overuse of broad-spectrum antibiotics, such as second- and thirdgeneration Cephalosporins, generate resistant strains.

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 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.
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RESISTANCE
ACQUISITION OF BACTERIAL RESISTANCE

ACQUIRED RESISTANCE

Species develop ability to resist an antimicrobial drug to which it is as a whole naturally susceptible Two mechanisms: 1. Mutational chromosomal 2. Genetic exchange transformation, transduction, conjugation
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The greatest possibility of evil in selfmedication 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 other until they reach someone who gets a septicemia or a pneumonia which penicillin cannot save. . Sir AlexanderFlemming
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1980s ESBL producing GN bacteria 1990 Vancomycin resistant Enterococci emerged 2000 VISA (intermediate level resistance) 2002-VRSA (high level resistance) 2002- Linezolid resistant enterococci and Staphylococci reported

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Plasmid-Mediated TEM and SHV Enzymes ThirdGeneration Cephalosporins 1965 1970s 1980s

Evolution of b-Lactamase

Ampicillin

1983

1987

2000

1963 TEM-1 Reported in E coli 28 GramS paratyphi Negative Species

TEM-1

ESBL >120 ESBLs ESBL in in Worldwide Europe United States

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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 (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
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Plasmid seem to be ubiquitous in bacteria, May encode genetic information for properties 1 Resistance to Antibiotics 2 Bacteriocins production 3 Enterotoxin production 4 Enhanced pathogen city 5 Reduced Sensitivity to mutagens 6 Degrade complex organic molecules
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Plasmids helps to spread multiple drug resistance Discovered in 1959 Japan Infections caused due to Shigella spread resistance to following Antibiotics Sulphonamides Streptomycin Choramphenicol, Tetracycline

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Shigella + E.coli excreted in the stool resistant to several drugs in vivo and vitro Plasmid mediated transmitted by Conjugation Episomes spread the resistance
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R forms may have evolved as a collection of Transposons Each carrying Genes that confers resistance to one or several Antibiotics Seen in Plasmids, Microorganisms Animals Laboratory Manipulations are called as Genetic Engineering

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Sulphonamides --- Reduce permeability Erythromycin ---- Modification of ribosome's Tetracyclnes ----- Reduced permeability Chloramphenicol ---- Acetylation of drug Streptomycin ----- Adenylation of drug Pencillin ----- Hydrolysis of lactum ring

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 Therapeutic

failures and relapse Facilitates spread in the hospital under antibiotic pressure Need to use more costly and toxic agents The emergence of untreatable pathogens
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RESISTANCE
ACQUIRED RESISTANCE EXAMPLES:

1. Resistance (R) plasmids Transmitted by conjugation

2. mecA gene
Codes for a PBP with low affinity for -lactam antibiotics Methicillin-resistant S. aureus
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RESISTANCE
ORIGIN OF DRUG RESISTANCE NON-GENETIC

1. Metabolically inactive organisms may be phenotypically resistant to drugs M. tuberculosis 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)
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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 to mutation in gene that codes for either: a. drug target

b. transport system in the membrane that controls drug uptake

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RESISTANCE
GENETIC 2. Extrachromosomal a. Plasmid-mediated

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

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Pathogens Resistant to Antibiotics (%)

100 90 80 70 60 50 40 30 20 10 1975

MRSA = methicillin-resistant Staphylococcus aureus VRE = vancomycin-resistant enterococci GISA = glycopeptide-intermediate S aureus VRSA = vancomycin-resistant S aureus MRSA1

VRE2 GISA3
1980 1985 1990

VRSA4
2002

Year

1995

1996

2000

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.
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Practices Contributing to Misuse of Antibiotics

<
Inappropriate specimen selection and
collection

<
< <

Inappropriate clinical tests

Failure to use stains/smears Failure to use cultures and susceptibility tests
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RESISTANCE
LIMITATION OF DRUG RESISTANCE

1. Maintain sufficiently high levels of the drug in the tissues inhibit original population 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 drug
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What Is Antimicrobial Stewardship?

A combination 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 C difficile Stable derepression MBLs and other carbapenemases VRE Appropriate de-escalation when culture results are available Dr.T.V.Rao MD

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IDSA Guidelines Definition 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
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 The primary goal of antimicrobial stewardship is to

The Primary Goal of Antimicrobial Stewardship

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

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 The primary goal of antimicrobial stewardship is to

The Primary Goal of Antimicrobial Stewardship

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

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Practices Contributing to Misuse of Antibiotics

<
Inappropriate specimen selection and
collection

<
< <

Inappropriate clinical tests

Failure to use stains/smears Failure to use cultures and susceptibility tests
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Inappropriate Antibiotic Use

Use of antibiotics with no clinical indication (eg, for viral infections) Use of broad spectrum antibiotics when not indicated Inappropriate choice of empiric antibiotics
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Inappropriate Drug Regimen

Inappropriate dose - ineffective concentration of antibiotics at site of infection Inappropriate route - ineffective concentration of antibiotics at site of infection
Inappropriate duration

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 If

a bacterium carries several resistance genes, it is called multiresistant or, informally, a superbug. The term antimicrobial resistance is sometimes use to explicitly encompass organisms other than bacteria
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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

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Fischbach MA and Walsh CT Science 2009

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Patients

Other clinicians

Optimize patient evaluation Adopt judicious antibiotic prescribing practices Immunize patients

Optimize consultations with other clinicians Use infection control measures Educate others about judicious use of antibiotics
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Bacteria evolve resistance to antibiotics in response to environmental pressure exerted by the use of antibiotics. Many of these bacteria are significant pathogens. Our responsibility to our community is to use antibiotics prudently, for appropriate indications.

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Campaign to Prevent Antimicrobial Resistance in Healthcare Settings

12 Steps to Prevent Antimicrobial Resistance

Prevent Transmission
12 Break the chain 11 Isolate the pathogen Use Antimicrobials Wisely 10 Stop treatment when cured 9 Know when to say no to vanco 8 Treat infection, not colonization 7 Treat infection, not contamination Diagnose & Treat 6 Use local data Effectively 5 Practice antimicrobial control 4 Access the experts 3 Target the pathogen Prevent Infections 2 Get the catheters out 1 Vaccinate
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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
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Surveillance
Prevention and Control Research Product Development
Health Care Financing Administration Department of Agriculture Agency for Health Care Research and Department of Quality Defense

Environmental Protection Agency Department of Veterans Affairs Health Resources and Services Administration Dr.T.V.Rao MD

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Think before prescribing Are we using Right drug for the Right bug ?

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 Created

by Dr.T.V.Rao MD for Medical Professionals in the Developing World Email doctortvrao@gmail.com

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