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Antimicrobial drugs corrected1 300409


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Antimicrobial drugs corrected1 300409

  2. 2. MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS Mechanism of action include:  Inhibition of cell wall synthesis  Inhibition of protein synthesis  Inhibition of nucleic acid synthesis  Inhibition of metabolic pathways  Interference with cell membrane integrity
  3. 3. MECHANISMS OF ACTION OFANTIBACTERIAL DRUGS Inhibition of Cell wall synthesis  Bacteria cell wall unique in construction  Contains peptidoglycan  Antimicrobials that interfere with the synthesis of cell wall do not interfere with eukaryotic cell  Due to the lack of cell wall in animal cells and differences in cell wall in plant cells  These drugs have very high therapeutic index  Low toxicity with high effectiveness  Antimicrobials of this class include  β lactam drugs  Vancomycin  Bacitracin
  4. 4. MECHANISMS OF ACTION OFANTIBACTERIAL DRUGS  Penicillins and cephalosporins  Part of group of drugs called β –lactams  Have shared chemical structure called β-lactam ring  Competitively inhibits function of penicillin- binding proteins  Inhibits peptide bridge formation between glycan molecules  This causes the cell wall to develop weak points at the growth sites and become fragile.
  5. 5. MECHANISMS OF ACTION OFANTIBACTERIAL DRUGS The weakness in the cell wall causes the cell to lyze.
  6. 6. MECHANISMS OF ACTIONOF ANTIBACTERIAL DRUGS The weakness in the cell wall causes the cell to lyze. Penicillins and cephalosporins are considered bactericidal. Penicillins are more effective against Gram+ bacteria. This is because Gram + bacteria have penicillin binding proteins on their walls.
  7. 7. MECHANISMS OF ACTIONOF ANTIBACTERIAL DRUGS The cephalosporins  Chemical structures make them resistant to inactivation by certain β-lactamases  Tend to have low affinity to penicillin-binding proteins of Gram + bacteria, therefore, are most effective against Gram – bacteria.  Chemically modified to produce family of related compounds  First, second, third and fourth generation cephalosporins
  8. 8. MECHANISMS OF ACTIONOF ANTIBACTERIAL DRUGS Vancomycin  Inhibits formation of glycan chains  Inhibits formation of peptidoglycans and cell wall construction  Does not cross lipid membrane of Gram -  Gram - organisms innately resistant  Important in treating infections caused by penicillin resistant Gram + organisms  Must be given intravenously due to poor absorption from intestinal tract  Acquired resistance most often due to alterations in side chain of NAM molecule  Prevents binding of vancomycin to NAM component of glycan
  9. 9. MECHANISMS OF ACTIONOF ANTIBACTERIAL DRUGS Bacitracin  Interferes with transport of peptidoglycan precursors across cytoplasmic membrane  Toxicity limits use to topical applications  Common ingredient in non-prescription first- aid ointments
  10. 10. MECHANISMS OF ACTIONOF ANTIBACTERIAL DRUGS Inhibition of protein synthesis  Structure of prokaryotic ribosome acts as target for many antimicrobials of this class  Differences in prokaryotic and eukaryotic ribosomes responsible for selective toxicity  Drugs of this class include  Aminoglycosides  Tetracyclins  Macrolids  Chloramphenicol
  11. 11. MECHANISMS OF ACTIONOF ANTIBACTERIAL DRUGS Aminoglycosides  Irreversibly binds to 30S ribosomal subunit  Causes distortion and malfunction of ribosome  Blocks initiation translation  Causes misreading of mRNA  Not effective against anaerobes, enterococci and streptococci  Often used in synergistic combination with β-lactam drugs  Allows aminoglycosides to enter cells that are often resistant
  12. 12. MECHANISMS OF ACTION OFANTIBACTERIAL DRUGS  Examples of aminoglycosides include  Gentamicin, streptomycin and tobramycin  Side effects with extended use include  Otto toxicity  Nephrotoxicity
  13. 13. MECHANISMS OF ACTIONOF ANTIBACTERIAL DRUGS Tetracyclins  Reversibly bind 30S ribosomal subunit  Blocks attachment of tRNA to ribosome  Prevents continuation of protein synthesis  Effective against certain Gram + and Gram -  Newer tetracyclines such as doxycycline have longer half-life  Allows for less frequent dosing
  14. 14. MECHANISMS OF ACTION OFANTIBACTERIAL DRUGS  Resistance due to decreased accumulation by bacterial cells  Can cause discoloration of teeth if taken as young child
  15. 15. MECHANISMS OF ACTION OFANTIBACTERIAL DRUGS Macrolids  Reversibly binds to 50S ribosome  Prevents continuation of protein synthesis  Effective against variety of Gram + organisms and those responsible for atypical pneumonia  Often drug of choice for patients allergic to penicillin  Macrolids include  Erythromycin, clarithromycin and azithromycin
  16. 16. MECHANISMS OF ACTION OFANTIBACTERIAL DRUGS  Resistance can occur via modification of RNA target  Other mechanisms of resistance include production of enzyme that chemically modifies drug as well as alterations that result in decreased uptake of drug
  17. 17. MECHANISMS OF ACTIONOF ANTIBACTERIAL DRUGS Chloramphenicol  Binds to 50S ribosomal subunit  Prevents peptide bonds from forming and blocking proteins synthesis  Effective against a wide variety of organisms  Generally used as drug of last resort for life- threatening infections  Rare but lethal side effect is aplastic anemia
  18. 18. MECHANISMS OF ACTIONOF ANTIBACTERIAL DRUGS Inhibition of nucleic acid synthesis  These include  Fluoroquinolones  Rifamycins
  19. 19. MECHANISMS OF ACTIONOF ANTIBACTERIAL DRUGS Fluoroquinolones  Inhibit action of topoisomerase DNA gyrase  Topoisomerase maintains supercoiling of DNA  Effective against Gram + and Gram -  Examples include  Ciprofloxacin and ofloxacin  Resistance due to alteration of DNA gyrase
  20. 20. MECHANISMS OF ACTIONOF ANTIBACTERIAL DRUGS Rifamycins  Block prokaryotic RNA polymerase  Block initiation of transcription  Rifampin most widely used rifamycins  Effective against many Gram + and some Gram - as well as members of genus Mycobacterium  Primarily used to treat tuberculosis and Hansen’s disease as well as preventing meningitis after exposure to N. meningitidis  Resistance due to mutation coding RNA polymerase  Resistance develops rapidly
  21. 21. MECHANISMS OF ACTIONOF ANTIBACTERIAL DRUGS Inhibition of metabolic pathways  Relatively few  Most useful are folate inhibitors  Mode of actions to inhibit the production of folic acid  Antimicrobials in this class include  Sulfonamides  Trimethoprim
  22. 22. MECHANISMS OF ACTIONOF ANTIBACTERIAL DRUGS Sulfonamides  Group of related compounds  Collectively called sulfa drugs  Inhibit growth of Gram + and Gram - organisms  Through competitive inhibition of enzyme that aids in production of folic acid  Structurally similar to para-aminobenzoic acid  Substrate in folic acid pathway  Human cells lack specific enzyme in folic acid pathway  Basis for selective toxicity  Resistance due to plasmid  Plasmid codes for enzyme that has lower affinity to drug
  23. 23. MECHANISMS OF ACTIONOF ANTIBACTERIAL DRUGS Trimethoprim  Inhibits folic acid production  Interferes with activity of enzyme following enzyme inhibited by sulfonamides  Often used synergistically with sulfonamide  Most common mechanism of resistance is plasmid encoded alternative enzyme  Genes encoding resistant to sulfonamide and trimethoprim are often carried on same plasmid
  24. 24. MECHANISMS OF ACTIONOF ANTIBACTERIAL DRUGS Interference with cell membrane integrity  Few damage cell membrane  Polymixn B most common  Common ingredient in first-aid skin ointments  Binds membrane of Gram - cells  Alters permeability  Leads to leakage of cell and cell death  Also bind eukaryotic cells but to lesser extent  Limits use to topical application
  25. 25. RESISTANCE TOANTIMICROBIAL DRUGS Mechanisms of resistance  Drug inactivating enzymes  Some organisms produce enzymes that chemically modify drug  Penicillinase breaks β-lactam ring of penicillin antibiotics  Alteration of target molecule  Minor structural changes in antibiotic target can prevent binding  Changes in ribosomal RNA prevent macrolids from binding to ribosomal subunits
  26. 26. SUSCEPTIBILITY OF BACTERIALTO ANTIMICROBIAL DRUG  Mechanisms of resistance  Decreased uptake of the drug  Alterations in porin proteins decrease permeability of cells  Prevents certain drugs from entering  Increased elimination of the drug  Some organisms produce efflux pumps  Increases overall capacity of organism to eliminate drug  Enables organism to resist higher concentrations of drug  Tetracycline resistance
  27. 27. ANTIMICROBIALSUSCEPTIBILITY TESTING Probably the most widely used testing method is the disk- diffusion method, also known as the Kirby- Bauer test.
  28. 28. SUSCEPTIBILITY OF BACTERIALTO ANTIMICROBIAL DRUG Conventional disc diffusion method  Kirby-Bauer disc diffusion routinely used to qualitatively determine susceptibility  Standard concentration of  Clear zone of inhibition strain uniformly spread of around disc reflects standard media susceptibility  Discs impregnated with specific concentration of  Based on size of zone antibiotic placed on plate organism can be and incubated described as susceptible or resistant
  29. 29. EFFECTS OFCOMBINATIONS OF DRUGSSometimes the chemotherapeutic effects of two drugs given simultaneously is greater than the effect of either given alone. This is called synergism. For example, penicillin and streptomycin in the treatment of bacterial endocarditis. Damage to bacterial cell walls by penicillin makes it easier for streptomycin to enter.
  30. 30. EFFECTS OFCOMBINATIONS OF DRUGS Other combinations of drugs can be antagonistic. For example, the simultaneous use of penicillin and tetracycline is often less effective than when wither drugs is used alone. By stopping the growth of the bacteria, the bacteriostatic drug tetracycline interferes with the action of penicillin, which requires bacterial growth.
  31. 31. EFFECTS OFCOMBINATIONS OF DRUGS Combinations of antimicrobial drugs should be used only for: 1. To prevent or minimize the emergence of resistant strains. 2. To take advantage of the synergistic effect. 3. To lessen the toxicity of individual drugs.