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Premium member Presentation Transcript ANTIBIOTICS USE, MISUSE, consequences: Dr.T.V.Rao MD ANTIBIOTICS USE, MISUSE, consequences Dr.T.V.Rao MD 1What is a Antibiotic: 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 . Dr.T.V.Rao MD 2Early definition of Antibiotic: The word antibiotic came from the word antibiosis a term coined in 1889 by Louis Pasteur's pupil Paul Vuillemin which means a process by which life could be used to destroy life Early definition of Antibiotic Dr.T.V.Rao MD 3Beginning of Antibiotics with Discovery of Penicillin: 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 Dr.T.V.Rao MD 4Fleming and Penicillin: Fleming and Penicillin Dr.T.V.Rao MD 5Antibiotic/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 Antibiotic/Antimicrobial agent Dr.T.V.Rao MD 6Early definition of Antibiotic: The word antibiotic came from the word antibiosis a term coined in 1889 by Louis Pasteur's pupil Paul Vuillemin which means a process by which life could be used to destroy life Early definition of Antibiotic Dr.T.V.Rao MD 7Selman 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 8Discovery of Penicillin Awarded Nobel Prize: Discovery of Penicillin Awarded Nobel Prize Dr.T.V.Rao MD 9PowerPoint Presentation: 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 Dr.T.V.Rao MD 10PowerPoint Presentation: Antibiotic natural source first description as anti-infective drug discovere r sulfanilamide (prontosil 1932 1941 G.Domagk penicillin Penicillium notatum A.Fleming, Florey, Chain streptomycin Streptomyces griseus 1944 S.A.Waksman cephalosporin Cephalosporium acremonium 1945 G.Brotzu bacitracin Bacillus subtilis 1945 B.A.Johnson chloramphenicol Streptomyces venezuellae 1947 I.Ehrlich polymyxin Bacillus polymyxa 1947 C.G.Ainsworth chlortetracyclin Streptomyces aureofaciens 1948 B.M.Duggar neomycin Streptomyces fradiae 1949 S.A.Waksman oxytetracyclin Streptomyces rimosus 1950 A.C.Finlay Dr.T.V.Rao MD 11PowerPoint Presentation: 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-microbials Dr.T.V.Rao MD 12Definition: Bacteriostatic - Antimicrobial agents that reversibly inhibit growth of bacteria are called as bacteriostatic (Tetracycline's, Chloramphenicol ) Bactericidal – Those with an irreversible lethal action on bacteria are known as bactericidal ( Penicillin, Isoniazid ) Definition Dr.T.V.Rao MD 13Chemotherapeutic 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 14Ideal Antibiotic: 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 Dr.T.V.Rao MD 15How Drugs Act: Drugs differ on their capabilities to act at different sites on bacteria. Some drugs have more than one site of action How Drugs Act Dr.T.V.Rao MD 16Resistance and Susceptibility : 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 lev els Dr.T.V.Rao MD 17Major mechanisms of antimicrobial drugs: 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. Dr.T.V.Rao MD 18PowerPoint Presentation: Inhibition of cell wall synthesis Target: block peptidoglycan (murein) synthesis Peptidoglycan 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 3 rd position of the peptide & the D-alanine in the 4 th position of another chain Dr.T.V.Rao MD 19PowerPoint Presentation: Inhibition of cell wall synthesis -lactam antibiotics inhibit transpeptidation reaction (3 rd 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 Dr.T.V.Rao MD 20PowerPoint Presentation: Inhibition of cell wall synthesis -lactam antibiotics Penicillin binding proteins (PBPs) enzymes responsible for: a. cross-linking (transpeptidase) b. elongation (carboxypeptidase) c. autolysis Dr.T.V.Rao MD 21PowerPoint Presentation: Inhibition of cell wall synthesis -lactam antibiotics Lysis of bacterial cell Isotonic environment cell swelling rupture of bacterial cell Hypertonic environment – microbes change to protoplasts (gram +) or spheroplasts (gram -) covered by cell membrane swell and rupture if placed in isotonic environment Dr.T.V.Rao MD 22Penicillins and Cephalosporins: 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 Dr.T.V.Rao MD 23Classification of Pencillins: 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 Dr.T.V.Rao MD 24Penicillinase (b Lactamase): Penicillinase ( b Lactamase) Figure 20.8 Dr.T.V.Rao MD 25Semi synthetic Penicillins: Penicilinase-resistant penicillins Carbapenem: very broad spectrum Monobactams: Gram negative Extended-spectrum penicillins Penicillins + -lactamase inhibitors Semi synthetic Penicillins Dr.T.V.Rao MD 26Other Inhibitors of Cell Wall Synthesis: Other Inhibitors of Cell Wall Synthesis Cephalosporins 2 nd , 3 rd , and 4 th generations more effective against gram-negatives Figure 20.9 Dr.T.V.Rao MD 27Extended spectrum pencillins: Extended spectrum pencillins Aminopencillins - Ampicillin, Amoxycillin Carboxypencillins – Carbencillin, Ticarcillin Ureidopencillin - Piperacillin Resistance to penicillin is due to pencillinase commonly called as ßlactamase The enzyme opens Betalactum ring hydrolytically and thus converts the antibiotic to inactive pencillonic acid. Dr.T.V.Rao MD 28Inhibitors 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 Inhibitors to Betalactamase Dr.T.V.Rao MD 29Cephalosporins: 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. Cephalosporins Dr.T.V.Rao MD 30Different 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. Different Generations of Cephalosporins Dr.T.V.Rao MD 31Major 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 4 th and 5th generation Cephalosporins are already avail able Major generations of Cephalosporins Dr.T.V.Rao MD 32Basis 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. Basis of generations in Cephalosporins Dr.T.V.Rao MD 33Advantages 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 Advantages with Newer generations Dr.T.V.Rao MD 34Other 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. Other drugs Dr.T.V.Rao MD 35Quinolones: 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. Quinolones Dr.T.V.Rao MD 36Aminoglycosides: Aminoglycosides are group of antibiotics in which amino sugars liked by glycoside bonds Eg Streptomycin, Act at the level of Ribosome's and inhibits protein synthesis Other Aminoglycosides – Gentamycin, neomycins,paromomycins,tobramycins Kanamycins and spectinomyc ins Aminoglycosides Dr.T.V.Rao MD 37PowerPoint Presentation: Dr.T.V.Rao MD 38Tetracycline's: 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 Tetracycline's Dr.T.V.Rao MD 39Choramphenicol: Chloramphenicol is bacteriostatic drug Can produce bone marrow depression Chloramphenicol interferes with protein synthesis. Choramphenicol Dr.T.V.Rao MD 40Macrolides,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. Macrolides,Azalides,Ketolides Dr.T.V.Rao MD 41PowerPoint Presentation: Dr.T.V.Rao MD 42Other Antimicrobial agents: Lincomycins Clindamycin resembles Macrolides in biting site and antimicrobial activity. Streptogramins Quinpristin / dalfopristin useful in gram positive bacteria Other Antimicrobial agents Dr.T.V.Rao MD 43Antibiotics 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 Antibiotics in Anaerobes Dr.T.V.Rao MD 44Metronidazole 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. Metronidazole in Anaerobic Infections Dr.T.V.Rao MD 45Metronidazole 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 infecti ons. Metronidazole in Anaerobic Infections Dr.T.V.Rao MD 46Other 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 . Other Beta-lactams include Dr.T.V.Rao MD 47PowerPoint Presentation: Emergence of Antibiotic-Resistant Bacteria Cohen; Science 1992;257:1050 Gram-negative rods Enterococcus sp . N. gonorrhoeae H. influenzae M. catarrhalis S. pneumoniae 1950 1960 1970 1980 1990 S aureus Penicillin Ampicillin 3 rd gen Cephalosporins Quinolones Dr.T.V.Rao MD 48PowerPoint Presentation: Dr.T.V.Rao MD 49Antibiotic resistance: 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. Dr.T.V.Rao MD 50Antibiotic Pressure and Resistance in Bacteria What is it ? : 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 Dr.T.V.Rao MD 51Antibiotic 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. Antibiotic Pressure and Resistance in Bacteria How does it occur? Dr.T.V.Rao MD 52Resistance and Susceptibility: 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 Dr.T.V.Rao MD 53PowerPoint Presentation: Dr.T.V.Rao MD 54Drug 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. Drug Resistance Dr.T.V.Rao MD 55PowerPoint Presentation: 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 56PowerPoint Presentation: Folic acid synthesis ß -lactams & Glycopeptide ( Vancomycin) 50 50 50 30 30 30 DNA mRNA Ribosomes PABA DHFA THFA Cell wall synthesis DNA gyrase Quinolones Protein synthesis inhibition Protein synthesis inhibition Tetracycline's Protein synthesis mistranslation Macrolides & Lincomycins Cohen. Science 1992; 257:1064 DNA-directed RNA polymerase Rifampin Aminoglycosides Sulfonamides Trimethoprim Dr.T.V.Rao MD 57Origin 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 58PowerPoint Presentation: 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 59PowerPoint Presentation: 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 60PowerPoint Presentation: 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 61Antibiotic resistance: 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. Dr.T.V.Rao MD 62Plasmids : 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 Dr.T.V.Rao MD 63Resistance Transfer Factor RTF: 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 Dr.T.V.Rao MD 64RTF: 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 65Transposons and R factor: 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 66Multi 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 67Biochemical mechanisms of Drug resistance: Resistance arises due to Biochemical changes Increased synthesis of drug antagonist Decreased permeability to drug Increased destruction of inhibitor Biochemical mechanisms of Drug resistance Dr.T.V.Rao MD 68Differentiation of Mutation and transferable drug resistance: Mutation Usually one drug Low degree of resistance Increasing dose can benefit Prevented by combination of drugs Low virulence of bacteria Transferable Multiple drugs High degree of resistance Increasing dose do not benefit Can not be prevented by combination of drugs High virulence of bacteria Differentiation of Mutation and transferable drug resistance Dr.T.V.Rao MD 69Plasmid Mediated Drug resistance: 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 70Antibiotics 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 Antibiotics resistance and plasmids Dr.T.V.Rao MD 71Antibiotic 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 Antibiotic Resistance Threat to Humans and Animals Dr.T.V.Rao MD 72Between 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 73Extended-Spectrum β-Lactamases: 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 Dr.T.V.Rao MD 74Carbapenemases: 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 Dr.T.V.Rao MD 75K. 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 K. pneumonia carbapenemases ) Dr.T.V.Rao MD 76K.pneumoniae carbapenemase-producing bacteria : Nordmann P et al. LID 2009 K.pneumoniae carbapenemase-producing bacteria Dr.T.V.Rao MD 77PowerPoint Presentation: 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 Dr.T.V.Rao MD 78PowerPoint Presentation: 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 79PowerPoint Presentation: 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 80Physicians Can Impact Patients : Optimize patient evaluation Adopt judicious antibiotic prescribing practices Immunize patients Physicians Can Impact Patients Dr.T.V.Rao MD 81Physicians Can Impact Other clinicians : Optimize consultations with other clinicians Use infection control measures Educate others about judicious use of antibiotics Physicians Can Impact Other clinicians Dr.T.V.Rao MD 82Antibiotic Pressure and Resistance in Bacteria: Conclusions: 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. Dr.T.V.Rao MD 83Are we overusing Antibiotics: Are we overusing Antibiotics Dr.T.V.Rao MD 84Dedicated handwashing has many solutions to prevent spread of drug resistant strains: Dedicated handwashing has many solutions to prevent spread of drug resistant strains Dr.T.V.Rao MD 85PowerPoint Presentation: Programme created by Dr.T.V.Rao MD for Medical Professionals in the Developing World Email doctortvrao@gmail.com Dr.T.V.Rao MD 86 You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.
Antibiotic use and misuse and conseqeunces doctorrao Download Post to : URL : Related Presentations : Share Add to Flag Embed Email Send to Blogs and Networks Add to Channel Uploaded from authorPOINT lite Insert YouTube videos in PowerPont slides with aS Desktop Copy embed code: (To copy code, click on the text box) Embed: URL: Thumbnail: WordPress Embed Customize Embed The presentation is successfully added In Your Favorites. Views: 98 Category: Education License: All Rights Reserved Like it (0) Dislike it (0) Added: December 30, 2011 This Presentation is Public Favorites: 0 Presentation Description Antibiotic use and misuse and conseqeunces Comments Posting comment... Premium member Presentation Transcript ANTIBIOTICS USE, MISUSE, consequences: Dr.T.V.Rao MD ANTIBIOTICS USE, MISUSE, consequences Dr.T.V.Rao MD 1What is a Antibiotic: 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 . Dr.T.V.Rao MD 2Early definition of Antibiotic: The word antibiotic came from the word antibiosis a term coined in 1889 by Louis Pasteur's pupil Paul Vuillemin which means a process by which life could be used to destroy life Early definition of Antibiotic Dr.T.V.Rao MD 3Beginning of Antibiotics with Discovery of Penicillin: 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 Dr.T.V.Rao MD 4Fleming and Penicillin: Fleming and Penicillin Dr.T.V.Rao MD 5Antibiotic/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 Antibiotic/Antimicrobial agent Dr.T.V.Rao MD 6Early definition of Antibiotic: The word antibiotic came from the word antibiosis a term coined in 1889 by Louis Pasteur's pupil Paul Vuillemin which means a process by which life could be used to destroy life Early definition of Antibiotic Dr.T.V.Rao MD 7Selman 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 8Discovery of Penicillin Awarded Nobel Prize: Discovery of Penicillin Awarded Nobel Prize Dr.T.V.Rao MD 9PowerPoint Presentation: 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 Dr.T.V.Rao MD 10PowerPoint Presentation: Antibiotic natural source first description as anti-infective drug discovere r sulfanilamide (prontosil 1932 1941 G.Domagk penicillin Penicillium notatum A.Fleming, Florey, Chain streptomycin Streptomyces griseus 1944 S.A.Waksman cephalosporin Cephalosporium acremonium 1945 G.Brotzu bacitracin Bacillus subtilis 1945 B.A.Johnson chloramphenicol Streptomyces venezuellae 1947 I.Ehrlich polymyxin Bacillus polymyxa 1947 C.G.Ainsworth chlortetracyclin Streptomyces aureofaciens 1948 B.M.Duggar neomycin Streptomyces fradiae 1949 S.A.Waksman oxytetracyclin Streptomyces rimosus 1950 A.C.Finlay Dr.T.V.Rao MD 11PowerPoint Presentation: 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-microbials Dr.T.V.Rao MD 12Definition: Bacteriostatic - Antimicrobial agents that reversibly inhibit growth of bacteria are called as bacteriostatic (Tetracycline's, Chloramphenicol ) Bactericidal – Those with an irreversible lethal action on bacteria are known as bactericidal ( Penicillin, Isoniazid ) Definition Dr.T.V.Rao MD 13Chemotherapeutic 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 14Ideal Antibiotic: 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 Dr.T.V.Rao MD 15How Drugs Act: Drugs differ on their capabilities to act at different sites on bacteria. Some drugs have more than one site of action How Drugs Act Dr.T.V.Rao MD 16Resistance and Susceptibility : 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 lev els Dr.T.V.Rao MD 17Major mechanisms of antimicrobial drugs: 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. Dr.T.V.Rao MD 18PowerPoint Presentation: Inhibition of cell wall synthesis Target: block peptidoglycan (murein) synthesis Peptidoglycan 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 3 rd position of the peptide & the D-alanine in the 4 th position of another chain Dr.T.V.Rao MD 19PowerPoint Presentation: Inhibition of cell wall synthesis -lactam antibiotics inhibit transpeptidation reaction (3 rd 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 Dr.T.V.Rao MD 20PowerPoint Presentation: Inhibition of cell wall synthesis -lactam antibiotics Penicillin binding proteins (PBPs) enzymes responsible for: a. cross-linking (transpeptidase) b. elongation (carboxypeptidase) c. autolysis Dr.T.V.Rao MD 21PowerPoint Presentation: Inhibition of cell wall synthesis -lactam antibiotics Lysis of bacterial cell Isotonic environment cell swelling rupture of bacterial cell Hypertonic environment – microbes change to protoplasts (gram +) or spheroplasts (gram -) covered by cell membrane swell and rupture if placed in isotonic environment Dr.T.V.Rao MD 22Penicillins and Cephalosporins: 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 Dr.T.V.Rao MD 23Classification of Pencillins: 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 Dr.T.V.Rao MD 24Penicillinase (b Lactamase): Penicillinase ( b Lactamase) Figure 20.8 Dr.T.V.Rao MD 25Semi synthetic Penicillins: Penicilinase-resistant penicillins Carbapenem: very broad spectrum Monobactams: Gram negative Extended-spectrum penicillins Penicillins + -lactamase inhibitors Semi synthetic Penicillins Dr.T.V.Rao MD 26Other Inhibitors of Cell Wall Synthesis: Other Inhibitors of Cell Wall Synthesis Cephalosporins 2 nd , 3 rd , and 4 th generations more effective against gram-negatives Figure 20.9 Dr.T.V.Rao MD 27Extended spectrum pencillins: Extended spectrum pencillins Aminopencillins - Ampicillin, Amoxycillin Carboxypencillins – Carbencillin, Ticarcillin Ureidopencillin - Piperacillin Resistance to penicillin is due to pencillinase commonly called as ßlactamase The enzyme opens Betalactum ring hydrolytically and thus converts the antibiotic to inactive pencillonic acid. Dr.T.V.Rao MD 28Inhibitors 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 Inhibitors to Betalactamase Dr.T.V.Rao MD 29Cephalosporins: 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. Cephalosporins Dr.T.V.Rao MD 30Different 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. Different Generations of Cephalosporins Dr.T.V.Rao MD 31Major 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 4 th and 5th generation Cephalosporins are already avail able Major generations of Cephalosporins Dr.T.V.Rao MD 32Basis 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. Basis of generations in Cephalosporins Dr.T.V.Rao MD 33Advantages 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 Advantages with Newer generations Dr.T.V.Rao MD 34Other 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. Other drugs Dr.T.V.Rao MD 35Quinolones: 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. Quinolones Dr.T.V.Rao MD 36Aminoglycosides: Aminoglycosides are group of antibiotics in which amino sugars liked by glycoside bonds Eg Streptomycin, Act at the level of Ribosome's and inhibits protein synthesis Other Aminoglycosides – Gentamycin, neomycins,paromomycins,tobramycins Kanamycins and spectinomyc ins Aminoglycosides Dr.T.V.Rao MD 37PowerPoint Presentation: Dr.T.V.Rao MD 38Tetracycline's: 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 Tetracycline's Dr.T.V.Rao MD 39Choramphenicol: Chloramphenicol is bacteriostatic drug Can produce bone marrow depression Chloramphenicol interferes with protein synthesis. Choramphenicol Dr.T.V.Rao MD 40Macrolides,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. Macrolides,Azalides,Ketolides Dr.T.V.Rao MD 41PowerPoint Presentation: Dr.T.V.Rao MD 42Other Antimicrobial agents: Lincomycins Clindamycin resembles Macrolides in biting site and antimicrobial activity. Streptogramins Quinpristin / dalfopristin useful in gram positive bacteria Other Antimicrobial agents Dr.T.V.Rao MD 43Antibiotics 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 Antibiotics in Anaerobes Dr.T.V.Rao MD 44Metronidazole 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. Metronidazole in Anaerobic Infections Dr.T.V.Rao MD 45Metronidazole 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 infecti ons. Metronidazole in Anaerobic Infections Dr.T.V.Rao MD 46Other 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 . Other Beta-lactams include Dr.T.V.Rao MD 47PowerPoint Presentation: Emergence of Antibiotic-Resistant Bacteria Cohen; Science 1992;257:1050 Gram-negative rods Enterococcus sp . N. gonorrhoeae H. influenzae M. catarrhalis S. pneumoniae 1950 1960 1970 1980 1990 S aureus Penicillin Ampicillin 3 rd gen Cephalosporins Quinolones Dr.T.V.Rao MD 48PowerPoint Presentation: Dr.T.V.Rao MD 49Antibiotic resistance: 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. Dr.T.V.Rao MD 50Antibiotic Pressure and Resistance in Bacteria What is it ? : 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 Dr.T.V.Rao MD 51Antibiotic 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. Antibiotic Pressure and Resistance in Bacteria How does it occur? Dr.T.V.Rao MD 52Resistance and Susceptibility: 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 Dr.T.V.Rao MD 53PowerPoint Presentation: Dr.T.V.Rao MD 54Drug 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. Drug Resistance Dr.T.V.Rao MD 55PowerPoint Presentation: 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 56PowerPoint Presentation: Folic acid synthesis ß -lactams & Glycopeptide ( Vancomycin) 50 50 50 30 30 30 DNA mRNA Ribosomes PABA DHFA THFA Cell wall synthesis DNA gyrase Quinolones Protein synthesis inhibition Protein synthesis inhibition Tetracycline's Protein synthesis mistranslation Macrolides & Lincomycins Cohen. Science 1992; 257:1064 DNA-directed RNA polymerase Rifampin Aminoglycosides Sulfonamides Trimethoprim Dr.T.V.Rao MD 57Origin 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 58PowerPoint Presentation: 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 59PowerPoint Presentation: 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 60PowerPoint Presentation: 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 61Antibiotic resistance: 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. Dr.T.V.Rao MD 62Plasmids : 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 Dr.T.V.Rao MD 63Resistance Transfer Factor RTF: 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 Dr.T.V.Rao MD 64RTF: 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 65Transposons and R factor: 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 66Multi 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 67Biochemical mechanisms of Drug resistance: Resistance arises due to Biochemical changes Increased synthesis of drug antagonist Decreased permeability to drug Increased destruction of inhibitor Biochemical mechanisms of Drug resistance Dr.T.V.Rao MD 68Differentiation of Mutation and transferable drug resistance: Mutation Usually one drug Low degree of resistance Increasing dose can benefit Prevented by combination of drugs Low virulence of bacteria Transferable Multiple drugs High degree of resistance Increasing dose do not benefit Can not be prevented by combination of drugs High virulence of bacteria Differentiation of Mutation and transferable drug resistance Dr.T.V.Rao MD 69Plasmid Mediated Drug resistance: 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 70Antibiotics 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 Antibiotics resistance and plasmids Dr.T.V.Rao MD 71Antibiotic 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 Antibiotic Resistance Threat to Humans and Animals Dr.T.V.Rao MD 72Between 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 73Extended-Spectrum β-Lactamases: 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 Dr.T.V.Rao MD 74Carbapenemases: 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 Dr.T.V.Rao MD 75K. 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 K. pneumonia carbapenemases ) Dr.T.V.Rao MD 76K.pneumoniae carbapenemase-producing bacteria : Nordmann P et al. LID 2009 K.pneumoniae carbapenemase-producing bacteria Dr.T.V.Rao MD 77PowerPoint Presentation: 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 Dr.T.V.Rao MD 78PowerPoint Presentation: 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 79PowerPoint Presentation: 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 80Physicians Can Impact Patients : Optimize patient evaluation Adopt judicious antibiotic prescribing practices Immunize patients Physicians Can Impact Patients Dr.T.V.Rao MD 81Physicians Can Impact Other clinicians : Optimize consultations with other clinicians Use infection control measures Educate others about judicious use of antibiotics Physicians Can Impact Other clinicians Dr.T.V.Rao MD 82Antibiotic Pressure and Resistance in Bacteria: Conclusions: 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. Dr.T.V.Rao MD 83Are we overusing Antibiotics: Are we overusing Antibiotics Dr.T.V.Rao MD 84Dedicated handwashing has many solutions to prevent spread of drug resistant strains: Dedicated handwashing has many solutions to prevent spread of drug resistant strains Dr.T.V.Rao MD 85PowerPoint Presentation: Programme created by Dr.T.V.Rao MD for Medical Professionals in the Developing World Email doctortvrao@gmail.com Dr.T.V.Rao MD 86