Antibiotics, Misuse of Antibiotics

ANTIBIOTICS Use, Misuse and Consequences : 

ANTIBIOTICS Use, Misuse and Consequences Dr.T.V.Rao MD Dr.T.V.Rao MD 1

Diseases Caused by Viruses and Bacteria Differentiate Before a Decision: 

Diseases Caused by Viruses and Bacteria Differentiate Before a Decision 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 Dr.T.V.Rao MD 2

Bacterial diseases are very common Health problems: 

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 Bacterial diseases are very common Health problems Dr.T.V.Rao MD 3

Problems With Improper Use of Antibiotics: 

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 DO need it for a bacterial infection Problems With Improper Use of Antibiotics Dr.T.V.Rao MD 4

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ANTIMICROBIAL AGENT Any chemical or drug used to treat an infectious disease, either by inhibiting or killing the pathogens in vi vo Dr.T.V.Rao MD 5

Beginning of Antibiotics with Discovery of Pencillin: 

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 penicillin for use as a medicine is attributed to the Australian Nobel Laureate Howard Walter Florey Dr.T.V.Rao MD 6

Discovery of Pencillin Awarded Nobel Prize: 

Discovery of Pencillin Awarded Nobel Prize Dr.T.V.Rao MD 7

Selman Waksman: 

Selman Waksman 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 8

Chemotherapeutic Agents: 

Antimicrobial agents – that are produced synthetically but have action similar to that of antibiotics and are defined as chemotherapeutic agents Eg Sulphonamides, Quinolones. Chemotherapeutic Agents Dr.T.V.Rao MD 9

ANTIBIOTICS : 

Substances derived from a microorganism or produced synthetically, that destroys or limits the growth of a living organism ANTIBIOTICS Dr.T.V.Rao MD 10

Definition: 

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 ) Definition Dr.T.V.Rao MD 11

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ertapenem tigecyclin daptomicin linezolid telithromicin quinup./dalfop. cefepime ciprofloxacin aztreonam norfloxacin imipenem cefotaxime clavulanic ac. cefuroxime gentamicin cefalotina nalidíxico ac. ampicillin methicilin vancomicin rifampin chlortetracyclin streptomycin pencillin G prontosil The development of anti-infectives … Development of anti-infectives Dr.T.V.Rao MD 12

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 of microorganisms and are capable of inhibiting the growth of other microorganism even in small concentrations. Uses of Antimicrobial Agents Dr.T.V.Rao MD 13

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ANTIBIOTICS – Sources Natural Fungi – penicillin, griseofulvin Bacteria – Bacillus sp. (polymixin, bacitracin) ; Actinomycetes (tetracycline, chloramphenicol, streptomycin) Synthetic Dr.T.V.Rao MD 14

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ANTIMICROBIAL AGENT Ideal Qualities: kill or inhibit the growth of pathogens cause no damage to the host cause no allergic reaction to the host stable when stored in solid or liquid form remain in specific tissues in the body long enough to be effective kill the pathogens before they mutate and become resistant to it Dr.T.V.Rao MD 15

Basic Classes of Antibiotics : 

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 –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

Prescribing an antibiotic: 

Is an antibiotic necessary ? What is the most appropriate antibiotic ? What dose, frequency, route and duration ? Is the treatment effective ? Prescribing an antibiotic Dr.T.V.Rao MD 17

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 There is no evidence that antibiotics will prevent secondary bacterial infection in patients with viral infection Is an antibiotic necessary ? Dr.T.V.Rao MD 18

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 infections as good as parenteral Choice of regimen Dr.T.V.Rao MD 19

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 Advantages of oral treatment Dr.T.V.Rao MD 20

Emergence of Antimicrobial Resistance: 

New Resistant Bacteria Mutations XX Emergence of Antimicrobial Resistance Susceptible Bacteria Resistant Bacteria Resistance Gene Transfer Dr.T.V.Rao MD 21

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Mechanisms of Resistance Enzymatic degradation Decreased entry Efflux pump Altered target site Bypass pathway Dr.T.V.Rao MD 22

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Antimicrobial Resistance: Key Prevention Strategies Optimize Use Prevent Transmission Prevent Infection Effective Diagnosis & Treatment Pathogen Antimicrobial-Resistant Pathogen Antimicrobial Resistance Antimicrobial Use Infection Campaign to Prevent Antimicrobial Resistance in Healthcare Settings Susceptible Pathogen Dr.T.V.Rao MD 23

Emerging Resistance: 

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. Emerging Resistance Dr.T.V.Rao MD 24

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ANTIMICROBIAL RESISTANCE: The role of animal feed antibiotic additives: 

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 additives in animal feed) ANTIMICROBIAL RESISTANCE : The role of animal feed antibiotic additives Dr.T.V.Rao MD 28

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-spectrum antibiotics, such as second- and third-generation Cephalosporins, generate resistant strains. Irrational Use of Third Generation Cephalosporins Dr.T.V.Rao MD 29

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. Origin of Drug Resistant Strains Dr.T.V.Rao MD 30

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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: Mutational – chromosomal Genetic exchange – transformation, transduction, conjugation Dr.T.V.Rao MD 31

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 other until they reach someone who gets a septicemia or a pneumonia which penicillin cannot save. . Sir Ale xanderFlemming Self Medication Dr.T.V.Rao MD 32

Historical aspects : 

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 Historical aspects Dr.T.V.Rao MD 33

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Evolution of b-Lactamase Plasmid-Mediated TEM and SHV Enzymes Ampicillin Third-Generation Cephalosporins 1963 1965 TEM-1 E coli S paratyphi 1970s TEM-1 Reported in 28 Gram- Negative Species 1980s 1983 ESBL in United States 1987 ESBL in Europe 2000 >120 ESBLs Worldwide Dr.T.V.Rao MD 34

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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 (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 difficult for the antibiotic to get into the cell 5.Actively remove the antibiotic from the cell Dr.T.V.Rao MD 35

Plasmids : 

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 T.V.Rao MD Plasmids Dr.T.V.Rao MD 36

Resistance Transfer Factor RTF: 

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 Resistance Transfer Factor RTF Dr.T.V.Rao MD 37

RTF: 

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 38

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, Microorganisms Animals Laboratory Manipulations are called as Genetic Engineering Transposons and R factor Dr.T.V.Rao MD 39

Plasmid Mediated Drug resistance: 

Sulphonamides --- Reduce permeability Erythromycin ---- Modification of ribosome's Tetracyclnes ----- Reduced permeability Chloramphenicol ---- Acetylation of drug Streptomycin ----- Adenylation of drug Pencillin ----- Hydrolysis of lactum ring Plasmid Mediated Drug resistance Dr.T.V.Rao MD 40

Clinical Significance of Antibiotic Resistance: 

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 Clinical Significance of Antibiotic Resistance Dr.T.V.Rao MD 41

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RESISTANCE ACQUIRED RESISTANCE – EXAMPLES: Resistance (R) plasmids Transmitted by conjugation mecA gene Codes for a PBP with low affinity for -lactam antibiotics Methicillin-resistant S. aureus Dr.T.V.Rao MD 42

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RESISTANCE ORIGIN OF DRUG RESISTANCE NON-GENETIC Metabolically inactive organisms may be phenotypically resistant to drugs – M. tuberculosis Loss of specific target structure for a drug for several generations 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 43

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RESISTANCE GENETIC Chromosomal Occurs at a frequency of 10 -12 to 10 -7 2 0 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 Dr.T.V.Rao MD 44

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RESISTANCE GENETIC 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 Dr.T.V.Rao MD 45

Development of Resistance in Gram Positive Pathogens: 

Development of Resistance in Gram Positive Pathogens 1 Smith TL et al. N Engl J Med. 1999;340:493-501. 2 Martone WJ. Infect Control Hosp Epidemiol . 1998;19:539-545. 3 Hiramatsu K et al. J Antimicrob Chemother . 1997;40:135-136. 4 CDC. MMWR Morb Mortal Wkly Rep . 2002;51:565-567. 1975 1995 1990 1985 1980 Pathogens Resistant to Antibiotics (%) 100 90 80 70 60 50 40 30 20 10 1996 2000 MRSA = methicillin-resistant Staphylococcus aureus VRE = vancomycin-resistant enterococci GISA = glycopeptide-intermediate S aureus VRSA = vancomycin-resistant S aureus MRSA 1 VRE 2 GISA 3 Year 2002 VRSA 4 Dr.T.V.Rao MD 46

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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

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RESISTANCE LIMITATION OF DRUG RESISTANCE Maintain sufficiently high levels of the drug in the tissues  inhibit original population and first-step mutants. Simultaneous administration of two drugs that do not give cross-resistance  delay emergence of mutants resistant to the drug (e.g. INH + Rifampicin) Limit the use of a valuable drug  avoid exposure of the organism to the drug Dr.T.V.Rao MD 48

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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 Dellit TH, et al. Clin Infect Dis. 2007;44:159-177 . Dr.T.V.Rao MD 49

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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 Dr.T.V.Rao MD 50

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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 51

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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 52

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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

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Use of antibiotics with no clinical indication (eg, for viral infections) Use of broad spectrum antibiotics when not indicated Inappropriate choice of empiric antibiotics Inappropriate Antibiotic Use Dr.T.V.Rao MD 54

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Inappropriate dose - ineffective concentration of antibiotics at site of infection Inappropriate route - ineffective concentration of antibiotics at site of infection Inappropriate duration Inappropriate Drug Regimen Dr.T.V.Rao MD 55

Multi Drug resistant pathogens: 

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 Multi Drug resistant pathogens Dr.T.V.Rao MD 56

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 locati on Antibiotic Resistance Threat to Humans and Animals Dr.T.V.Rao MD 57

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Between 1962 and 2000, no major classes of antibiotics were introduced : 

Between 1962 and 2000, no major classes of antibiotics were introduced Fischbach MA and Walsh CT Science 2009 Dr.T.V.Rao MD 59

Physicians Can Impact: 

Physicians Can Impact Other clinicians Patients 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 Dr.T.V.Rao MD 60

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. Our responsibility to our community is to use antibiotics prudently, for appropriate indications. Antibiotic Pressure and Resistance in Bacteria: Conclusions Dr.T.V.Rao MD 61

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12 Steps to Prevent Antimicrobial Resistance 12 Break the chain 11 Isolate the pathogen 10 Stop treatment when cured 9 Know when to say “no” to vanco 8 Treat infection, not colonization 7 Treat infection, not contamination 6 Use local data 5 Practice antimicrobial control 4 Access the experts 3 Target the pathogen 2 Get the catheters out 1 Vaccinate Prevent Transmission Use Antimicrobials Wisely Diagnose & Treat Effectively Prevent Infections Campaign to Prevent Antimicrobial Resistance in Healthcare Settings Dr.T.V.Rao MD 62

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 Conclusions Dr.T.V.Rao MD 63

Are we Overusing Antibiotics: 

Are we Overusing Antibiotics Dr.T.V.Rao MD 64

Organizations - Curb Unwarranted Antibiotics: 

Organizations - Curb Unwarranted Antibiotics Surveillance Prevention and Control Research Product Development Agency for Health Care Research and Quality Department of Defense Environmental Protection Agency Health Care Financing Administration Health Resources and Services Administration Department of Agriculture Department of Veterans Affairs Dr.T.V.Rao MD 65

Choose the Appropriate Antibiotic: 

Choose the Appropriate Antibiotic Think before prescribing Are we using Right drug for the Right bug ? Dr.T.V.Rao MD 66

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Created by Dr.T.V.Rao MD for Medical Professionals in the Developing World Email doctortvrao@gmail.com Dr.T.V.Rao MD 67