1. Batterjee Medical College

2. Dr. Manal El Said Department Head of Microbiology Antimicrobial Drugs: Mechanism of Action

3. Batterjee Medical College Antimicrobial Drugs: Resistance Four main mechanisms of antibiotic resistance are: (1) enzymatic degradation of drug (2) modification of drug's target (3) reduced permeability of drug (4) active export of drug. Most drug resistance is result of genetic change in organism, caused either by chromosomal mutation or acquisition of plasmid or transposon.

4. Batterjee Medical College Antimicrobial Drugs: Major Mechanisms of Bacterial Resistance

5. Batterjee Medical College Antimicrobial Drugs: Major Mechanisms of Bacterial Resistance

6. Batterjee Medical College Bacterial resistance to antibiotics—producing an enzyme to destroy or inactivate the antibiotic. This animation can be found at The Grapes of Staph: Doc Kaiser's Microbiology Website, http://student.ccbcmd.edu/~gkaiser/goshp.html. Antimicrobial Drugs: Resistance: Specific Mechanisms of Resistance

7. Batterjee Medical College Antimicrobial Drugs: Resistance: Specific Mechanisms of Resistance Bacterial resistance to antibiotics—producing an altered enzyme to which the antibiotic no longer binds. This animation can be found at The Grapes of Staph: Doc Kaiser's Microbiology Website, http://student.ccbcmd.edu/~gkaiser/goshp.html.

8. Batterjee Medical College Bacterial resistance to antibiotics—producing an altered ribosomal subunit to which the antibiotic no longer binds. This animation can be found at The Grapes of Staph: Doc Kaiser's Microbiology Website, http://student.ccbcmd.edu/~gkaiser/goshp.html. Antimicrobial Drugs: Resistance: Specific Mechanisms of Resistance

9. Batterjee Medical College Antimicrobial Drugs: Resistance: Specific Mechanisms of Resistance A bacterium producing altered porins that block passage of the antibiotic through the outer membrane of a gram-negative bacterium.

10. Batterjee Medical College A bacterium producing an altered transport (carrier) protein that prevents transport of the antibiotic through the cytoplasmic membrane. Antimicrobial Drugs: Resistance: Specific Mechanisms of Resistance

11. Batterjee Medical College A bacterium producing transporter molecules that pump the antibiotic out of the bacterium. Antimicrobial Drugs: Resistance: Specific Mechanisms of Resistance

12. Batterjee Medical College A bacterium producing greater amounts of the limited enzyme being tied up or inactivated by the antimicrobial agent. Although some enzyme is tied up by the drug, there is still enzyme available to react with its substrate and produce end products. Antimicrobial Drugs: Resistance: Specific Mechanisms of Resistance

13. Batterjee Medical College Antimicrobial Drugs: Resistance: Genetic Basis of Resistance Chromosomal mutations typically: -Change target of drug so that drug does not bind -Change membrane so that drug does not penetrate well into cell. Chromosomal mutations occur at low frequency (perhaps 1 in 10 million organisms). It often affect only one drug or one family of drugs.

14. Batterjee Medical College Plasmids cause drug resistance by encoding enzymes that degrade or modify drugs. Plasmid-mediated resistance occurs at higher frequency, often affecting multiple drugs or families of drugs. Resistance plasmids (R plasmids, R factors) carry two sets of genes: - One set encodes enzymes that degrade or modify drugs - Other encodes proteins that mediate conjugation Antimicrobial Drugs: Resistance: Genetic Basis of Resistance

15. Batterjee Medical College Transposons are small pieces of DNA that move: - from one site on bacterial chromosome to another or, - from bacterial chromosome to plasmid DNA. Transposons often carry drug resistance genes. Many R plasmids carry one or more transposons. Antimicrobial Drugs: Resistance: Genetic Basis of Resistance

16. Batterjee Medical College Antimicrobial Drugs: Resistance: Genetic Basis of Resistance

17. Batterjee Medical College Antimicrobial Drugs: Resistance: Specific Mechanisms of Resistance Resistance to penicillins & cephalosporins is mediated by three main mechanisms: (1) degradation by β-lactamases (most important) (2) mutations in genes for penicillin-binding proteins (3) reduced permeability.

18. Batterjee Medical College Antimicrobial Drugs: Resistance: Specific Mechanisms of Resistance

19. Batterjee Medical College Resistance to vancomycin is caused by change in D- alanyl-D-alanine part of peptide in peptidoglycan to D- alanine-D-lactate, resulting in inability of vancomycin to bind. Antimicrobial Drugs: Resistance: Specific Mechanisms of Resistance

20. Batterjee Medical College Resistance to aminoglycosides is mediated by three main mechanisms: (1)modification of drug by phosphorylating, adenylylating, & acetylating enzymes (2)mutations in genes encoding one of 30S ribosomal proteins (3)reduced permeability. Antimicrobial Drugs: Resistance: Specific Mechanisms of Resistance

21. Batterjee Medical College Resistance to tetracyclines is caused by either - reduced permeability - active export of drug from bacterium. Antimicrobial Drugs: Resistance: Specific Mechanisms of Resistance

22. Batterjee Medical College Resistance to erythromycins is caused by plasmid-encoded enzyme that methylates 23S ribosomal RNA, thereby blocking binding of the drug. Antimicrobial Drugs: Resistance: Specific Mechanisms of Resistance

23. Batterjee Medical College Resistance to sulfonamides is due to plasmid-encoded enzymes that actively export drug from bacterium. Antimicrobial Drugs: Resistance: Specific Mechanisms of Resistance

24. Batterjee Medical College Resistance to quinolones is caused by mutations in gene encoding bacterial DNA gyrase. Antimicrobial Drugs: Resistance: Specific Mechanisms of Resistance

25. Batterjee Medical College Resistance to rifampin is caused by mutations in gene encoding bacterial RNA polymerase. Antimicrobial Drugs: Resistance: Specific Mechanisms of Resistance

26. Batterjee Medical College Resistance to isoniazid is due to loss of bacterial peroxidase (catalase) that activates isoniazid to metabolite that inhibits mycolic acid synthesis. Antimicrobial Drugs: Resistance: Specific Mechanisms of Resistance

27. Batterjee Medical College Drugs may not reach bacteria located in center of abscess Certain drugs, such as penicillins, will not affect bacteria that are not growing. Presence of foreign bodies makes successful antibiotic treatment more difficult. Antimicrobial Drugs: Nongenetic Basis of Resistance

28. Batterjee Medical College The minimal inhibitory concentration (MIC) It is lowest concentration of drug that inhibits growth of bacteria isolated from patient (it is not known whether inhibited bacteria have been killed or just have stopped growing). The minimal bactericidal concentration (MBC) It is lowest concentration of drug that kills bacteria isolated from patient. Antimicrobial Drugs: Antibiotic Sensitivity Testing

29. Batterjee Medical College Two or more antibiotics are used to: - treat life-threatening infections before cause has been identified, - prevent emergence of resistant bacteria during prolonged treatment regimens - achieve synergistic (augmented) effect. Antimicrobial Drugs: Use of Antibiotic Combinations

30. Batterjee Medical College Synergistic effect is one in which effect of two drugs given together is much greater than sum of effect of two drugs given individually. Example of synergy is marked killing effect of combination of penicillin & aminoglycoside on enterococci compared to minor effect of either drug given alone. Antimicrobial Drugs: Use of Antibiotic Combinations

31. Batterjee Medical College Antimicrobial Drugs: Use of Antibiotic Combinations

32. Batterjee Medical College Immunity to certain bacterial diseases can be induced by: Immunization with bacterial antigens (active immunity) Administration of preformed antibodies (passive immunity). Bacterial Vaccines

33. Batterjee Medical College Active immunity can be achieved by vaccines consisting of: (1)bacterial capsular polysaccharides, toxoids, whole bacteria (either killed or live, attenuated) (2)purified proteins isolated from bacteria. Active Immunity

34. Batterjee Medical College Vaccines containing capsular polysaccharide as immunogen are directed against : Streptococcus pneumoniae Haemophilus influenzae Neisseria meningitidis Salmonella typhi. Active Immunity Capsular polysaccharide is conjugated to carrier protein to enhance antibody response.

35. Batterjee Medical College Two vaccines contain toxoids as immunogen: - Diphtheria - Tetanus. Toxoid is inactivated toxin that has lost its ability to cause disease but has retained its immunogenicity. Active Immunity

36. Batterjee Medical College Two vaccines contain purified bacterial proteins as immunogen: Acellular pertussis vaccine: combination with diphtheria & tetanus toxoids It is recommended for all children. Anthrax vaccine: contains purified proteins It is recommended only for individuals who are likely to be exposed to organism. Active Immunity

37. Batterjee Medical College Active Immunity BCG vaccine against tuberculosis contains live, attenuated Mycobacterium bovis & is used in countries where the disease is endemic. One of vaccines against typhoid fever contains live, attenuated Sal. typhi. Vaccines against cholera, plague, typhus, & Q fever contain whole killed bacteria. These vaccines are used only to protect those likely to be exposed.

38. Batterjee Medical College Passive Immunity Antitoxins for prevention & treatment of : - Tetanus - Botulism - Diphtheria. These three diseases are caused by exotoxins. Antitoxins (antibodies against exotoxins) bind to exotoxins & prevent their toxic effects, i.e., they neutralize toxins.

39. Batterjee Medical College This involves providing both immediate (but short-term) protection in form of antibodies & long-term protection in form of active immunization. Example of use of passive-active immunity is prevention of tetanus in unimmunized person who has sustained contaminated wound. Both tetanus antitoxin & tetanus toxoid should be given. They should be given at different sites so that antibodies in antitoxin do not neutralize toxoid. Passive–Active Immunity

40. Batterjee Medical College Recommended Immunization Schedule

41. Batterjee Medical College Recommended Immunization Schedule

42. Batterjee Medical College Recommended Immunization Schedule