ANTIMICROBIAL AGENTS

1. ANTIMICROBIAL AGENTS

2. ANTIBIOTICS • ANTIMICROBIAL AGENTS • CHEMOTHERAPEUTIC AGENTS

3. ANTIBIOTICS • Natural substances produced by various species of microorganisms bacteria fungi actinomycetes • suppress growth / kill other microorganisms

4. ANTIMICROBIAL AGENTS • Synthetic analogues • ANTIMICROBIAL AGENTS : • includes synthetic as well as naturally obtained drugs that attenuate microorganisms

5. CHEMOTHERAPEUTIC AGENTS • Drugs in this class differ from all others in that they are • Designed to inhibit/kill the infecting organism and have no/minimal effect on the recipient.

6. Classification Of AMA’s

7. Microorganisms of medical impotance fall into four categories • Bacteria • Viruses • Fungi • Parasites

8. Anti-bacterial • Anti-viral • Anti-fungal • Anti-parasitic agents

9. Mechanism of Action • Agents that inhibit synthesis of bacterial cell walls Penicillins & cephalosporins Cycloserine, Vancomycin Bacitracin Azole antifungal agents (clotrimazole, fluconazole, itraconazole)

10. Agents that actdirectly on the cell membranes of the microorganisms Polymixin Polyene antifungal agents (Nystatin, Amphotericin B) Alter cell memb. Permeability, leakage of intracellular comp.

11. Agents that affect the function of 30S or 50S ribosomal subunits to cause a reversible inhibition of protein synthesis • Bacteriostatic drugs Chloramphenicol, Tetracyclines, Erythromycin, Clindamycin, Pristinamycins

12. Agents that bind to 30S ribosomal subunit & alter protein synthesis, which eventually leads to cell death Aminoglycosides

13. Agents that affect bacterial nucleic acid metabolism. Rifamycins which inhibit RNA polymerase Quinolones which inhibit topoisomerases

14. Anti-metabolites including trimethoprim & sulphonamides • Antiviral agents Nucleic acid analogues, Non-nucleoside reverse transcriptase inhibitors, Inhibitors of viral enzymes

16. TYPE OF ACTION Bacteriostatic Agents Bactericidal Agents

17. Bacteriostatic Agents Sulphonamides Tetracyclines Chloramphenicol Erythromycin Ethambutol

18. Bactericidal Agents Penicillins/Cephalosporins/Carbapenems Aminoglycosides Rifampin • Isoniazid • Pyrazinamide

19. Cephalosporins Vancomycin Nalidixic acid Ciprofloxacin Metronidazole & Cotrimoxazole

20. Some primarily static drugs may become cidal at higher concentrations (as attained in the urinary tract) & vice-versa.

21. SPECTRUM Of ACTIVITY Narrow spectrum Broad spectrum

22. SPECTRUM Of ACTIVITY Narrow spectrum Penicillin G Streptomycin Broad spectrum Tetracyclines Chloramphenicol

23. Successful Antimicrobial Therapy • Concentration: site of infection Concentration should inhibit microorganisms simultaneously it should be below the level toxic to human beings. • Host Defences Immunity intact - Bacteriostatic Agents Impaired immunity - Bactericidal Agents

24. Source of antibiotics • Fungi • Bacteria • Actinomycetes.

25. Source of antibiotics • Fungi • Penicillin, Griseofulvin, Cephalosporin • Bacteria • Polymyxin B, Colistin, Bacitracin, Aztreonam. • Actinomycetes. • Aminoglycosides, Macrolides, Tetracyclines, Polyenes, Chloramphenicol

26. Resistance

27. Bacterial resistance to ANTIMICROBIAL AGENTS • 3 general categories Drug does not reach its target Drug is not active Target is altered

28. Drug does not reach its target Porins • Absence/mutation • Reduce drug entry • Reduced effective drug concentration at the target site. Efflux pumps • Transport drugs out of the cell • Resistance to tetracyclines & β-lactam antib

29. Inactivation of Drug • Second general mechanism of drug resistance β-lactam antibiotics - β-lactamase Aminoglycosides - Aminoglycoside modifying enzymes • Variant: failure of bacterial cell to convert an inactive drug to its active metabolite. Resistance to INH in mycobacterium TB

30. Alteration of the Target • Mutation of natural target • Target modification The new target does not bind the drug for native target Resulting in resistance to antibiotic.

31. Components mediating resistance to β –lactam antibiotics in psuedomonas aeruginosa

33. β –lactam antibiotics hydrophilic • Must cross outer membrane barrier of the cell via outer membrane protein (Omp) channel or porins • Mutation/missing/deleted • Drug entry slow or prevented.

34. β - lactamase concentrated between the inner & outer membrane in the periplasmic space • constitutes an enzymatic barrier • Drug destroyed • Effective concentration not achieved

35. Target: PBP penicillin binding protein • Low affinity for drug • Altered

36. Efflux transporter • Mex A, Mex B & Opr F • Pumps the antibiotic across the outer membrane • Reduced intracellular concentration of active drug RESISTANCE

37. Mutations • May occur in • Target protein • Drug transport protein • Protein important for drug activation • Random events • Survival advantage upon re-exposure to the drug

38. Resistance is acquired by horizontal transfer of resistance determinants from a donor cell, often of another bacterial species by • Transduction • Transformation • Conjugation

39. Insatiable need for new antibiotics

40. Emergence of antibiotic resistance in bacterial pathogens both nosocomially & in the community setting is a very serious development that threatens the end of antibiotic era.

41. Responsible approach to the use of antibiotics • That are now available & new agents that might be developed in future • Is essential • If the end of antibiotic era is to be averted.

42. CROSS RESISTANCE

43. CROSS RESISTANCE • Acquisition of resistance to one AMA conferring resistance to another antimicrobial agent to which the organism has not been exposed,is called cross resistance • Seen b/w chemically or mechanistically related drugs.

44. Resistance to one sulphonamide means resistance to all others • Resistance to one tetracyclines means insenstivity to all others • Complete cross resistance

45. Resistance to one aminoglycoside may not extend to others, Gentamycin resistant strains may respond to amikacin. • partial cross resistance

46. Sometimes unrelated drugs show partial cross resistance, e.g. Tetracyclines & Chloramphenicol

47. Prevention DRUG RESISTANCE

48. Prevention DRUG RESISTANCE • Use of AMAs should not be: indiscriminate inadequate undulyprolonged • Use rapidly acting & narrow spectrum (Selective) AMA whenever possible.

49. Prevention DRUG RESISTANCE • Combination AMA • whenever prolonged therapy is undertaken. Tuberculosis, SABE • Infection by organism notorious for developing resistance Staph, E. Coli, M. Tuberculosis must be treated intensively.