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Antibiotics, Misuse of antibiotics

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  1. ANTIBIOTICS Use, Misuse andConsequences Dr.T.V.Rao MD Dr.T.V.Rao MD

  2. Diseases Caused by Viruses and BacteriaDifferentiate 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

  3. 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 Dr.T.V.Rao MD

  4. 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 ofresistance: the antibiotic won’t work when you really DO need it for a bacterial infection Dr.T.V.Rao MD

  5. 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

  6. 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

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

  8. 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

  9. 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. Dr.T.V.Rao MD

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

  11. 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 ) Dr.T.V.Rao MD

  12. 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 Development of anti-infectives The development of anti-infectives … Dr.T.V.Rao MD

  13. 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. Dr.T.V.Rao MD

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

  15. 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

  16. 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

  17. 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

  18. 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 Dr.T.V.Rao MD

  19. 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 Dr.T.V.Rao MD

  20. 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

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

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

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

  24. 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. Dr.T.V.Rao MD

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  28. 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) Dr.T.V.Rao MD

  29. 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. Dr.T.V.Rao MD

  30. 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

  31. 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

  32. 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 AlexanderFlemming Dr.T.V.Rao MD

  33. 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 Dr.T.V.Rao MD

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

  35. 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

  36. 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 Dr.T.V.Rao MD

  37. Resistance Transfer FactorRTF • 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 Dr.T.V.Rao MD

  38. 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

  39. 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 Dr.T.V.Rao MD

  40. 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 Dr.T.V.Rao MD

  41. 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 Dr.T.V.Rao MD

  42. 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

  43. 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

  44. RESISTANCE GENETIC • 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 Dr.T.V.Rao MD

  45. 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

  46. 100 90 80 70 60 50 40 30 20 10 MRSA = methicillin-resistant Staphylococcus aureus VRE = vancomycin-resistant enterococci GISA = glycopeptide-intermediate S aureus VRSA = vancomycin-resistant S aureus Pathogens Resistant to Antibiotics (%) MRSA1 VRE2 VRSA4 GISA3 1975 1980 1985 1990 1995 2000 1996 2002 Year Development of Resistance in Gram Positive Pathogens 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. Dr.T.V.Rao MD

  47. 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 Dr.T.V.Rao MD

  48. 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

  49. 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

  50. 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