Dr.T.V.Rao MD ANTIBIOTICS USE, MISUSE, CONSEQUENCES DR.T.V.RAO MD 1

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Transcript of Dr.T.V.Rao MD ANTIBIOTICS USE, MISUSE, CONSEQUENCES DR.T.V.RAO MD 1

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Dr.T.V.Rao MD ANTIBIOTICS USE, MISUSE, CONSEQUENCES DR.T.V.RAO MD 1 Slide 2 WHAT IS A ANTIBIOTIC Antibiotic (from the Ancient Greek: anti, "against", and 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 2 Slide 3 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 3 Slide 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 DR.T.V.RAO MD 4 Slide 5 FLEMING AND PENICILLIN DR.T.V.RAO MD 5 Slide 6 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 6 Slide 7 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 7 Slide 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 8 Slide 9 DISCOVERY OF PENICILLIN AWARDED NOBEL PRIZE DR.T.V.RAO MD 9 Slide 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 DR.T.V.RAO MD 10 Slide 11 Antibioticnatural source first description as anti-infective drug discoverer sulfanilamide (prontosil 1932 1941 G.Domagk penicillin Penicillium notatum A.Fleming, Florey, Chain streptomycin Streptomyces griseus 1944 S.A.Waksman cephalosporinCephalosporium acremonium 1945 G.Brotzu bacitracin Bacillus subtilis 1945 B.A.Johnson chloramphenicol Streptomyces venezuellae 1947I.Ehrlich polymyxinBacillus polymyxa 1947C.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 11 Slide 12 ertapenem tigecyclin daptomicin linezolid telithromicin quinup./dalfop. cefepime ciprofloxacin aztreonam norfloxacin imipenem cefotaxime clavulanic ac. cefuroxime gentamicin cefalotina nalidxico ac. ampicillin methicilin vancomicin rifampin chlortetracyclin streptomycin pencillin G prontosil The development of anti-infectives Development of anti-microbials DR.T.V.RAO MD 12 Slide 13 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 13 Slide 14 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 14 Slide 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 DR.T.V.RAO MD 15 Slide 16 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 16 Slide 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 lev els DR.T.V.RAO MD 17 Slide 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. DR.T.V.RAO MD 18 Slide 19 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 19 Slide 20 Inhibition of cell wall synthesis A.-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 20 Slide 21 Inhibition of cell wall synthesis A.-lactam antibiotics Penicillin binding proteins (PBPs) enzymes responsible for: a. cross-linking (transpeptidase) b. elongation (carboxypeptidase) c. autolysis DR.T.V.RAO MD 21 Slide 22 Inhibition of cell wall synthesis A.-lactam antibiotics Lysis of bacterial cell oIsotonic environment cell swelling rupture of bacterial cell oHypertonic 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 22 Slide 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 DR.T.V.RAO MD 23 Slide 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 DR.T.V.RAO MD 24 Slide 25 PENICILLINASE ( LACTAMASE) Figure 20.8 DR.T.V.RAO MD 25 Slide 26 Penicilinase-resistant penicillins Carbapenem: very broad spectrum Monobactams: Gram negative Extended-spectrum penicillins Penicillins + -lactamase inhibitors SEMI SYNTHETIC PENICILLINS DR.T.V.RAO MD 26 Slide 27 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 27 Slide 28 EXTENDED SPECTRUM PENCILLINS Aminopencillins - Ampicillin, Amoxycillin Carboxypencillins Carbencillin, Ticarcillin Ureidopencillin - Piperacillin Resistance to penicillin is due to pencillinase commonly called as lactamase The enzyme opens Betalactum ring hydrolytically and thus converts the antibiotic to inactive pencillonic acid. DR.T.V.RAO MD 28 Slide 29 Clavulinic acid which is a product of Strept.clavuligerus Acts against the Staphylococcal beta lactamase. 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 29 Slide 30 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 30 Slide 31 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 31 Slide 32 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 32 Slide 33 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 33 Slide 34 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 34 Slide 35 Imip