ANTIBIOTICS USE, MISUSE, consequences

1. ANTIBIOTICS USE, MISUSE, consequences Dr.T.V.Rao MD 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. Dr.T.V.Rao MD

3. Early 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 Dr.T.V.Rao MD

4. Beginning of Antibiotics with Discovery of Penicillin • The discovery of penicillinhas 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

5. Fleming and Penicillin Dr.T.V.Rao MD

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 Dr.T.V.Rao MD

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

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

11. first description as anti-infective drug discoverer Antibiotic natural source sulfanilamide (prontosil G.Domagk 1932 1941 A.Fleming, Florey, Chain penicillin Penicillium notatum S.A.Waksman Streptomyces griseus streptomycin 1944 cephalosporin Cephalosporium acremonium G.Brotzu 1945 bacitracin B.A.Johnson Bacillus subtilis 1945 Streptomyces venezuellae 1947 I.Ehrlich chloramphenicol polymyxin Bacillus polymyxa 1947 C.G.Ainsworth Streptomyces aureofaciens B.M.Duggar 1948 chlortetracyclin Streptomyces fradiae neomycin S.A.Waksman 1949 A.C.Finlay oxytetracyclin Streptomyces rimosus 1950 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-microbials The development of anti-infectives … Dr.T.V.Rao MD

13. Definition • 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 ) Dr.T.V.Rao MD

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. Dr.T.V.Rao MD

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

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 Dr.T.V.Rao MD

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 Dr.T.V.Rao MD

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

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 3rd position of the peptide & the D-alanine in the 4th position of another chain Dr.T.V.Rao MD

20. Inhibition of cell wall synthesis • -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 Dr.T.V.Rao MD

21. 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

22. 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

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

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

25. Penicillinase (b Lactamase) Dr.T.V.Rao MD Figure 20.8

26. Semi synthetic Penicillins • Penicilinase-resistant penicillins • Carbapenem: very broad spectrum • Monobactams: Gram negative • Extended-spectrum penicillins • Penicillins + -lactamase inhibitors Dr.T.V.Rao MD

27. Other Inhibitors of Cell Wall Synthesis • Cephalosporins • 2nd, 3rd, and 4th generations more effective against gram-negatives Dr.T.V.Rao MD Figure 20.9

28. 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

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 Dr.T.V.Rao MD

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. Dr.T.V.Rao MD

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 Cephalosporins. Dr.T.V.Rao MD

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 Dr.T.V.Rao MD

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. Dr.T.V.Rao MD

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 Dr.T.V.Rao MD

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. Dr.T.V.Rao MD

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. Dr.T.V.Rao MD

37. Aminoglycosides • 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 spectinomycins Dr.T.V.Rao MD

38. Dr.T.V.Rao MD

39. Tetracycline'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 Dr.T.V.Rao MD

40. Choramphenicol • Chloramphenicol is bacteriostatic drug • Can produce bone marrow depression • Chloramphenicol interferes with protein synthesis. Dr.T.V.Rao MD

41. 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. Dr.T.V.Rao MD

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43. Other Antimicrobial agents • Lincomycins Clindamycin resembles Macrolides in biting site and antimicrobial activity. Streptogramins Quinpristin / dalfopristin useful in gram positive bacteria Dr.T.V.Rao MD

44. 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 Dr.T.V.Rao MD

45. 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. Dr.T.V.Rao MD

46. 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. Dr.T.V.Rao MD

47. 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. Dr.T.V.Rao MD

48. Emergence of Antibiotic-Resistant Bacteria S aureus Gram-negative rods N. gonorrhoeae Penicillin Ampicillin H. influenzae M. catarrhalis S. pneumoniae Enterococcus sp. 1950 1960 1970 1980 1990 Quinolones 3rd gen Cephalosporins Cohen; Science 1992;257:1050 Dr.T.V.Rao MD

49. Dr.T.V.Rao MD

50. Antibiotic resistance • Antibiotic resistanceis 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 geneis generated, bacteria can then transfer the genetic information in a horizontal fashion (between individuals) by plasmidexchange. Dr.T.V.Rao MD