Antibiotics use and misuse and Consequences
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Antibiotics use and misuse and Consequences

Antibiotics use and misuse and Consequences

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Antibiotics use and misuse and Consequences Presentation Transcript

  • 1. ANTIBIOTICSUSE, MISUSE, CONSEQUENCES Dr.T.V.Rao MD
  • 2. WHAT IS A ANTIBIOTIC• Antibiotic (from the Ancient Greek: ἀντί – anti, "against", and βίος – bios, "life") is a substance or compound that kills bacteria or inhibits its growth. Antibiotics belong to the broader group of antimicrobial compounds, used to treat infections caused by microorganisms, including fungi and protozoa.
  • 3. EARLY DEFINITION OF ANTIBIOTIC• The word antibiotic came from the word antibiosis a term coined in 1889 by Louis Pasteurs pupil Paul Vuillemin which means a process by which life could be used to destroy life
  • 4. BEGINNING OF ANTIBIOTICS WITH DISCOVERY OF PENICILLIN• 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
  • 5. FLEMING AND PENICILLIN
  • 6. ANTIBIOTIC/ANTIMICROBIAL AGENT• Antibiotic: Chemical produced by a microorganism that kills or inhibits the growth of another microorganism• Antimicrobial agent: Chemical that kills or inhibits the growth of microorganisms
  • 7. EARLY DEFINITION OF ANTIBIOTIC• The word antibiotic came from the word antibiosis a term coined in 1889 by Louis Pasteurs pupil Paul Vuillemin which means a process by which life could be used to destroy life
  • 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
  • 9. DISCOVERY OF PENICILLIN AWARDED NOBEL PRIZE
  • 10. Brief History of Antibiotics• 1928- Penicillin discovered by Fleming• 1932- Sulfonamide antimicrobial activity discovered {Erlich}•• 1943- Drug companies begin mass production of penicillin• 1948- Cephalosporins precursor sent to Oxford for synthesis• 1952- Erythromycin derived from Streptomyces erythreus• 1956- Vancomycin introduced for penicillin resistant staphylococcus• 1962- Quinolone antibiotics first discovered• 1970s- Linezolid discovered but not pursued• 1980s- Fluorinated Quinolones introduced, making then clinically useful• 2000- Linezolid introduced into clinical practice
  • 11. first description as discoverer Antibiotic natural source anti-infective drugsulfanilamide G.Domagk(prontosil 1932 1941 A.Fleming, Florpenicillin Penicillium notatum Chain Streptomyces griseus S.A.Waksmanstreptomycin 1944cephalosporin Cephalosporium acremonium 1945 G.Brotzubacitracin B.A.Johnson Bacillus subtilis 1945 Streptomyces venezuellae 1947 I.Ehrlichchloramphenicolpolymyxin Bacillus polymyxa 1947 C.G.Ainsworth Streptomyces 1948 B.M.Duggarchlortetracyclin aureofaciens Streptomycesneomycin S.A.Waksman fradiae 1949oxytetracyclin A.C.Finlay Streptomyces rimosus 1950
  • 12. Development of anti-microbials ertapenem tigecyclin daptomicin linezolidThe development telithromicin quinup./dalfop. of anti-infectives … cefepime ciprofloxacin aztreonam norfloxacin imipenem cefotaxime clavulanic ac. cefuroxime gentamicin cefalotina nalidíxico ac. ampicillin methicilin vancomicin rifampin chlortetracyclin streptomycin pencillin G prontosil 1920 1930 1940 1950 1960 1970 1980 1990 2000
  • 13. DEFINITION• Bacteriostatic - Antimicrobial agents that reversibly inhibit growth of bacteria are called as bacteriostatic (Tetracyclines, Chloramphenicol )• Bactericidal – Those with an irreversible lethal action on bacteria are known as bactericidal ( Penicillin, Isoniazid )
  • 14. 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.
  • 15. IDEAL ANTIBIOTIC Toxic to microbes, and not to humans Bactericidal rater than bacteriostatic Effective against broad range of bacteria Should not be allergic and hypersensitive reactions Should be active in plasma, and other body fluids Desired levels should be reached rapidly and maintained for adequate period of time. Should not give drug resistance, long shelf life, Cheaper
  • 16. HOW DRUGS ACT• Drugs differ on their capabilities to act at different sites on bacteria.• Some drugs have more than one site of action
  • 17. RESISTANCE AND SUSCEPTIBILITY• Determined by in vitro activity, pharmacologic characteristics, and clinical evaluation.• The minimal inhibitory concentration (MIC) can be comfortably exceeded by doses tolerated by the patient.• Susceptible - implies their MIC is at a concentration attainable in the blood or other body fluid at the recommended dose.• Resistant - MIC is not exceeded by normally attainable levels
  • 18. MAJOR MECHANISMS OF ANTIMICROBIAL DRUGS• 1 Inhibition of cell wall synthesis• 2 Inhibition of cell membrane function• 3 Inhibition of protein synthesis ( inhibition of translation and transcription of genetic material)• 4 Inhibition of nucleic acid synthesis.
  • 19. Inhibition of cell wall synthesisTarget: block peptidoglycan (murein) synthesisPeptidoglycan  Polysaccharide (repeating disaccharides of N- acetyl glucosamine and N-acetylmuramic acid) + cross-linked pentapeptide  Pentapeptide with terminal D-alanyl-D-alanine unit  required for cross-linking  Peptide cross-link formed between the free amine of the amino acid in the 3rd position of the peptide & the D-alanine in the 4th position of another chain
  • 20. Inhibition of cell wall synthesisA. -lactam antibiotics  inhibit transpeptidation reaction (3rd stage) to block peptidoglycan synthesis  involves loss of a D-alanine from the pentapeptide  Steps: a. binding of drug to PBPs b. activation of autolytic enzymes (murein hydrolases) in the cell wall c. degradation of peptidoglycan d. lysis of bacterial cell
  • 21. Inhibition of cell wall synthesisA.-lactam antibiotics Penicillin binding proteins (PBPs)  enzymes responsible for: a. cross-linking (transpeptidase) b. elongation (carboxypeptidase) c. autolysis
  • 22. Inhibition of cell wall synthesis A. -lactam antibiotics Lysis of bacterial cell o Isotonic environment  cell swelling  rupture of bacterial cell o Hypertonic environment – microbes change to protoplasts (gram +) or spheroplasts (gram -) covered by cell membrane  swell and rupture if placed in isotonic environment
  • 23. PENICILLINS AND CEPHALOSPORINS Pencillin and cephalosporins act inhibiting Trans peptidases, the enzyme catalyses the final linking step in synthesis of peptidoglycan. Due to this reason Pencillin in bactericidal for grwoing bacteria since new peptidoglycan is synthesized at that stage only. In nongrwoing cells pencillin is inactive An intact beta – lactum is essential for antibacterial activity of pencillins
  • 24. CLASSIFICATION OF PENCILLINS• Natural Benzyl penicillin Phenoxymethyl penicillin Penicillin v Semi synthetic and pencillase resistant 1 Methicillin 2 Nafcillin 3 Cloxacillin 4 Oxacillin 5 Floxacillin
  • 25. PENICILLINASE (B LACTAMASE) Figure 20.8
  • 26. SEMI SYNTHETIC PENICILLINS• Penicilinase-resistant penicillins • Carbapenem: very broad spectrum • Monobactams: Gram negative• Extended-spectrum penicillins• Penicillins + -lactamase inhibitors
  • 27. OTHER INHIBITORS OF CELL WALL SYNTHESIS• Cephalosporins • 2nd, 3rd, and 4th generations more effective against gram- negatives Figure 20.9
  • 28. EXTENDED SPECTRUM PENCILLINS Aminopencillins - Ampicillin, Amoxycillin Carboxypencillins – Carbencillin, Ticarcillin Ureidopencillin - PiperacillinResistance to penicillin is due to pencillinase commonly called as ßlactamaseThe enzyme opens Betalactum ring hydrolytically and thus converts the antibiotic to inactive pencillonic acid.
  • 29. INHIBITORS TO BETALACTAMASE• Clavulinic acid which is a product of Strept.clavuligerus• Acts against the Staphylococcal beta ßlactamase.• And plasmid mediated Betalactamase of Gram negative bacteria.• Salbactum – this is a semisyntetic sulfone derivative with weak antibacterial activity
  • 30. CEPHALOSPORINS• Like penicillin acts similar• Products of the molds of genus Cephalosporium except cefoxilin• Divided into 4 generation of Cephalosporins depending on the spectrum of activity.
  • 31. DIFFERENT GENERATIONS OF CEPHALOSPORINS• Cephalosporins are grouped into "generations" based on their spectrum of antimicrobial activity. The first Cephalosporins were designated first generation while later, more extended spectrum Cephalosporins were classified as second generation Cephalosporin s.
  • 32. MAJOR GENERATIONS OF CEPHALOSPORINS Cephalosporins are divided into 3 generations: 1st generation: Cephelexin, cefadroxil, cephradine 2nd generation: Cefuroxime, cefaclor 3rd generation: cefotaxime, Ceftazidime, cefixime - these give the best CNS penetration 4th and 5th generation Cephalosporins are already available
  • 33. BASIS OF GENERATIONS IN CEPHALOSPORINS• Cephalosporins are grouped into "generations" based on their spectrum of antimicrobial activity. The first cephalosporins were designated first generation while later, more extended spectrum cephalosporins were classified as second generation cephalosporins.
  • 34. ADVANTAGES WITH NEWER GENERATIONS• Each newer generation of cephalosporins has significantly greater gram- negative antimicrobial properties than the preceding generation, in most cases with decreased activity against gram- positive organisms. Fourth generation cephalosporins, however, have true broad spectrum activity
  • 35. OTHER DRUGS• Imipenem: a carbapenem with a broader spectrum of activity against Gram positive and negative aerobes and anaerobes. Needs to be given with cilastatin to prevent inactivation by the kidney.
  • 36. QUINOLONES• Quinolones are the first wholly synthetic antimicrobials. The commonly used Quinolones.• Act on the DNA gyrase which prevents DNA polymerase from proceeding at the replication fork and consequently stopping synthesis.
  • 37. AMINOGLYCOSIDES• Aminoglycosides are group of antibiotics in which amino sugars liked by glycoside bonds• Eg Streptomycin,• Act at the level of Ribosomes and inhibits protein synthesis• Other Aminoglycosides – Gentamycin, neomycins,paromomycins,tobra mycins Kanamycins and spectinomycins
  • 38. TETRACYCLINES• Broad spectrum antibiotic produced by Streptomyces species• 1. Oxytetracycle, chlortetracycle and tetracycline• Tetracyclnes are bacteriostatic drugs inhibits rapidly multiplying organisms• Resistance develops slowly and attributed to alterations in cell membrane permeability to enzymatic inactivation of the drug
  • 39. CHORAMPHENICOL• Chloramphenicol is bacteriostatic drug• Can produce bone marrow depression• Chloramphenicol interferes with protein synthesis.
  • 40. MACROLIDES,AZALIDES,KETOLIDES• Contain macro cyclic lactone ring Erythromycin. Is popularly used drug• Other drugs Roxithromycin,Azithromycin• Inhibits the protein synthesis.• Used as alternative to pencillin allergy patients.
  • 41. OTHER ANTIMICROBIAL AGENTS• Lincomycins Clindamycin resembles Macrolides in biting site and antimicrobial activity.Streptogramins Quinpristin / dalfopristin useful in gram positive bacteria
  • 42. ANTIBIOTICS IN ANAEROBES• Major anaerobes – Anaerobic cocci, clostridia and Bactericides are susceptible to Benzyl pencillin• Bact.fragilis as well as many other anaerobes are treatable with Erythromycin,Lincomycin, tetracycline and Chloramphenicol• Clindamycin is effective against many strains of Bacteroides
  • 43. METRONIDAZOLE IN ANAEROBIC INFECTIONS• Since the discovery of Metronidazole in 1973 since then it was identified as leading agent anaerobes.• But also useful in treating parasitic infections Trichomonas, Amoebiasis and other protozoan infections.
  • 44. METRONIDAZOLE IN ANAEROBIC INFECTIONS• Since the discovery of Metronidazole in 1973 since then it was identified as leading agent anaerobes.• But also useful in treating parasitic infections Trichomonas, Amoebiasis and other protozoan infections.
  • 45. OTHER BETA-LACTAMS INCLUDE• Other beta-lactams include:• Aztreonam: a monocytic beta-lactam, with an antibacterial spectrum which is active only against Gram negative aerobes, including Pseudomonas aeruginosa, Neisseria meningitidis and N. gonorrhoea.
  • 46. Emergence of Antibiotic-Resistant Bacteria S aureus Gram-negative rods N. gonorrhoeaeP Aen m p H. influenzaei ici c i M. catarrhalisl lli l i S. pneumoniaen n Enterococcus sp. 1950 1960 1970 1980 1990 Quinolones 3rd gen Cohen; Science 1992;257:1050 Cephalosporins
  • 47. ANTIBIOTIC RESISTANCE Antibiotic resistance is the ability of a micro organism to withstand the effects of antibiotics. It is a specific type of drug resistance. Antibiotic resistance evolves naturally via natural selection acting upon random mutation, but it can also be engineered by applying an evolutionary stress on a population. Once such a gene is generated, bacteria can then transfer the genetic information in a horizontal fashion (between individuals) by plasmid exchange.
  • 48. ANTIBIOTIC PRESSURE AND RESISTANCE IN BACTERIA WHAT IS IT ?• ”Selection pressure of antibiotics has led to the emergence of antibiotic-resistant bacteria.” • Antibiotics can effect bacteria unrelated to the targeted infectious agent; these may be “normal” flora, leading to the emergence of resistant mutants inhabiting the same environment. Baquero et al., International Report 1996;23:819
  • 49. ANTIBIOTIC PRESSURE AND RESISTANCE IN BACTERIA HOW DOES IT OCCUR?• All antibiotics do NOT kill bacteria in the same way.• Various classes of antibiotics work on different aspects of bacterial replication.
  • 50. RESISTANCE AND SUSCEPTIBILITY• Determined by in vitro activity, pharmacologic characteristics, and clinical evaluation.• The minimal inhibitory concentration (MIC) can be comfortably exceeded by doses tolerated by the patient.• Susceptible - implies their MIC is at a concentration attainable in the blood or other body fluid at the recommended dose.• Resistant - MIC is not exceeded by normally attainable levels
  • 51. DRUG RESISTANCE• In spite discovery of several antibiotics several microorganisms attained resistance.• The major factor contributing to persistence of infectious disease has been the tremendous capacity of microorganisms for circumventing the action of inhibitory drugs.• The drug resistance continues to be a threat for usefulness of the chemotherapeutic agents.
  • 52. RESISTANCE ORIGIN OF DRUG RESISTANCENON-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)
  • 53. DNA gyrase DNA-directed RNA polymerase Quinolones Cell wall synthesis Rifampin ß-lactams & Glycopeptide (Vancomycin) DNA THFA mRNATrimethoprim Protein Ribosomes synthesisFolic acid inhibitionsynthesis DHFA 50 50 50 Macrolides & 30 30 30 LincomycinsSulfonamides PABA Protein synthesis Protein synthesis inhibition mistranslation Tetracyclines Aminoglycosides Cohen. Science 1992; 257:1064
  • 54. 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.
  • 55. 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
  • 56. 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
  • 57. 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
  • 58. ANTIBIOTIC RESISTANCE Antibiotic resistance is a specific type of drug resistance when a microorganism has the ability of withstanding the effects of antibiotics. Antibiotic resistance evolves via natural selection acting upon random mutation, but it can also be engineered by applying an evolutionary stress on a population. Once such a gene is generated, bacteria can then transfer the genetic information in a horizontal fashion (between individuals) by conjugation, transduction, or transformation.
  • 59. 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
  • 60. 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
  • 61. 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
  • 62. 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 AnimalsLaboratory Manipulations are called as Genetic Engineering
  • 63. 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
  • 64. BIOCHEMICAL MECHANISMS OF DRUG RESISTANCE• Resistance arises due to Biochemical changes Increased synthesis of drug antagonist Decreased permeability to drug Increased destruction of inhibitor
  • 65. DIFFERENTIATION OF MUTATION AND TRANSFERABLE DRUG RESISTANCE Mutation Transferable• Usually one drug • Multiple drugs• Low degree of resistance • High degree of resistance• Increasing dose can • Increasing dose do not benefit benefit• Prevented by • Can not be prevented by combination of drugs combination of drugs• Low virulence of bacteria • High virulence of bacteria
  • 66. PLASMID MEDIATED DRUG RESISTANCESulphonamides --- Reduce permeabilityErythromycin ---- Modification of ribosomesTetracyclnes ----- Reduced permeabilityChloramphenicol ---- Acetylation of drugStreptomycin ----- Adenylation of drugPencillin ----- Hydrolysis of lactum ring
  • 67. ANTIBIOTICS RESISTANCE AND PLASMIDS• Many antibiotic resistance genes reside on plasmids facilitating their transfer. If a bacterium carries several resistance genes, it is called multiresistant or, informally, a superbug. The term antimicrobial resistance is sometimes used to explicitly encompass organisms other than bacteria
  • 68. 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
  • 69. BETWEEN 1962 AND 2000, NO MAJOR CLASSES OF ANTIBIOTICS WERE INTRODUCED Fischbach MA and Walsh CT Science 2009
  • 70. EXTENDED-SPECTRUM Β-LACTAMASES• β-lactamases capable of conferring bacterial resistance to • the penicillins • first-, second-, and third-generation cephalosporins • aztreonam • (but not the cephamycins or carbapenems)• These enzymes are derived from group 2b β-lactamases (TEM-1, TEM-2, and SHV-1) • differ from their progenitors by as few as one AA
  • 71. CARBAPENEMASES• Ability to hydrolyze penicillins, cephalosporins, monobactams, and carbapenems• Resilient against inhibition by all commercially viable ß- lactamase inhibitors • Subgroup 2df: OXA (23 and 48) carbapenemases • Subgroup 2f : serine carbapenemases from molecular class A: GES and KPC • Subgroup 3b contains a smaller group of MBLs that preferentially hydrolyze carbapenems • IMP and VIM enzymes that have appeared globally, most frequently in non-fermentative bacteria but also in Enterobacteriaceae
  • 72. K. PNEUMONIA CARBAPENEMASES )• KPCs are the most prevalent of this group of enzymes, found mostly on transferable plasmids in K. pneumonia• Substrate hydrolysis spectrum includes cephalosporins and carbapenems
  • 73. K.PNEUMONIAE CARBAPENEMASE-PRODUCING BACTERIA Nordmann P et al. LID 2009
  • 74. Antibiotic resistance  “Antibiotic resistance continues to plague antimicrobial chemotherapy of infectious diseases” Keith. Poole. J Antimicrob Chemother 2005; 56: 20-51 “Evolution of bacteria towards resistance… …is unavoidable because it represents a particular aspect of the general evolution of bacteria that is unstoppable” Patrice Courvalin. Emerg Infect Dis 2005; 11: 1507-6“Antibiotic resistance has resulted in a continuous need for new therapeutic alternatives” Carl Erik Nord. Clin Microbiol Infect 2004;10 (Supp 4) “There is a need to re-invigorate antimicrobial development, which has been downgraded by major pharmaceutical houses” David Livermore. Lancet Infect Dis 2005; 5:450-59
  • 75. 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
  • 76. 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
  • 77. PHYSICIANS CAN IMPACT PATIENTS• Optimize patient evaluation• Adopt judicious antibiotic• prescribing practices• Immunize patients
  • 78. PHYSICIANS CAN IMPACT OTHER CLINICIANS • Optimize consultations with other clinicians • Use infection control measures • Educate others about judicious use of antibiotics
  • 79. 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.
  • 80. ARE WE OVERUSING ANTIBIOTICS
  • 81. DEDICATED HANDWASHING HAS MANY SOLUTIONS TO PREVENT SPREAD OF DRUG RESISTANT STRAINS
  • 82. • Programme created by Dr.T.V.Rao MD for Medical Professionals in the Developing World • Email • doctortvrao@gmail.com