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Antibiotics

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Antibiotics

Antibiotics

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  • 1. Antibiotics: Protein Synthesis, Nucleic Acid Synthesis and Metabolism www.freelivedoctor.com
  • 2. Principles and Definitions
    • Selectivity
      • Selectivty   toxicity 
    • Therapeutic index
      • Toxic dose/ Effective dose
    • Categories of antibiotics
      • Bacteriostatic
        • Duration of treatment sufficient for host defenses
      • Bactericidal
        • Usually antibiotic of choice
    www.freelivedoctor.com
  • 3. Principles and Definitions
    • Selectivity
    • Therapeutic index
    • Categories of antibiotics
      • Use of bacteriostatic vs bactericidal antibiotic
        • Therapeutic index better for bacteriostatic antibiotic
        • Resistance to bactericidal antibiotic
        • Protein toxin mediates disease – use bacteriostatic protein synthesis inhibitor
    www.freelivedoctor.com
  • 4. Principles and Definitions
    • Antibiotic susceptibility testing (in vitro)
      • Minimum inhibitory concentration (MIC)
        • Lowest concentration that results in inhibition of visible growth
      • Minimum bactericidal concentration (MBC)
        • Lowest concentration that kills 99.9% of the original inoculum
    www.freelivedoctor.com
  • 5. Antibiotic Susceptibility Testing www.freelivedoctor.com 8 4 0 2 1 Tetracycline (  g/ml) MIC = 2  g/ml Determination of MIC Chl Amp Ery Str Tet Disk Diffusion Test
  • 6. Zone Diameter Standards for Disk Diffusion Tests www.freelivedoctor.com
  • 7. Principles and Definitions
    • Combination therapy
      • Prevent emergence of resistant strains
      • Temporary treatment until diagnosis is made
      • Antibiotic synergism
        • Penicillins and aminoglycosides
        • CAUTION: Antibiotic antagonism
          • Penicillins and bacteriostatic antibiotics
    • Antibiotics vs chemotherapeutic agents vs antimicrobials
    www.freelivedoctor.com
  • 8. Antibiotics that Inhibit Protein Synthesis www.freelivedoctor.com
  • 9. Review of Initiation of Protein Synthesis www.freelivedoctor.com 30S 1 3 2 GTP 1 2 3 GTP Initiation Factors mRNA 3 1 2 GTP 30S Initiation Complex f-met-tRNA Spectinomycin Aminoglycosides 1 2 GDP + Pi 50S 70S Initiation Complex A P
  • 10. Review of Elongation of Protein Synthesis www.freelivedoctor.com GTP A P Tu GTP Tu GDP Ts Ts Tu + GDP Ts Pi P A Tetracycline A P Erythromycin Fusidic Acid Chloramphenicol G GTP G GDP + Pi G GDP A P + GTP
  • 11. Protein Synthesis Microbe Library -American Society for Microbiology www.microbelibrary.org www.freelivedoctor.com
  • 12. Survey of Antibiotics www.freelivedoctor.com
  • 13. Protein Synthesis Inhibitors
    • Mostly bacteriostatic
    • Selectivity due to differences in prokaryotic and eukaryotic ribosomes
    • Some toxicity - eukaryotic 70S ribosomes
    www.freelivedoctor.com
  • 14. Antimicrobials that Bind to the 30S Ribosomal Subunit www.freelivedoctor.com
  • 15. Aminoglycosides (bactericidal) streptomycin , kanamycin, gentamicin, tobramycin, amikacin, netilmicin, neomycin (topical)
    • Mode of action - The aminoglycosides irreversibly bind to the 16S ribosomal RNA and freeze the 30S initiation complex (30S-mRNA-tRNA) so that no further initiation can occur. They also slow down protein synthesis that has already initiated and induce misreading of the mRNA. By binding to the 16 S r-RNA the aminoglycosides increase the affinity of the A site for t-RNA regardless of the anticodon specificity. May also destabilize bacterial membranes.
    www.freelivedoctor.com
  • 16. www.freelivedoctor.com Microbe Library American Society for Microbiology www.microbelibrary.org
  • 17. Aminoglycosides (bactericidal) streptomycin , kanamycin, gentamicin, tobramycin, amikacin, netilmicin, neomycin (topical)
    • Spectrum of Activity -Many gram-negative and some gram-positive bacteria; Not useful for anaerobic (oxygen required for uptake of antibiotic) or intracellular bacteria .
    • Resistance - Common
    • Synergy - The aminoglycosides synergize with  -lactam antibiotics. The  -lactams inhibit cell wall synthesis and thereby increase the permeability of the aminoglycosides.
    www.freelivedoctor.com
  • 18. Tetracyclines (bacteriostatic) tetracycline , minocycline and doxycycline
    • Mode of action - The tetracyclines reversibly bind to the 30S ribosome and inhibit binding of aminoacyl-t-RNA to the acceptor site on the 70S ribosome.
    • Spectrum of activity - Broad spectrum; Useful against intracellular bacteria
    • Resistance - Common
    • Adverse effects - Destruction of normal intestinal flora resulting in increased secondary infections; staining and impairment of the structure of bone and teeth.
    www.freelivedoctor.com
  • 19. Spectinomycin (bacteriostatic)
    • Mode of action - Spectinomycin reversibly interferes with m-RNA interaction with the 30S ribosome. It is structurally similar to the aminoglycosides but does not cause misreading of mRNA.
    • Spectrum of activity - Used in the treatment of penicillin-resistant Neisseria gonorrhoeae
    • Resistance - Rare in Neisseria gonorrhoeae
    www.freelivedoctor.com
  • 20. Antimicrobials that Bind to the 50S Ribosomal Subunit www.freelivedoctor.com
  • 21. Chloramphenicol , Lincomycin, Clindamycin (bacteriostatic)
    • Mode of action - These antimicrobials bind to the 50S ribosome and inhibit peptidyl transferase activity.
    • Spectrum of activity - Chloramphenicol - Broad range; Lincomycin and clindamycin - Restricted range
    • Resistance - Common
    • Adverse effects - Chloramphenicol is toxic (bone marrow suppression) but is used in the treatment of bacterial meningitis.
    www.freelivedoctor.com
  • 22. Macrolides (bacteriostatic) erythromycin , clarithromycin, azithromycin, spiramycin
    • Mode of action - The macrolides inhibit translocation.
    • Spectrum of activity - Gram-positive bacteria, Mycoplasma, Legionella
    • Resistance - Common
    www.freelivedoctor.com
  • 23. www.freelivedoctor.com Microbe Library American Society for Microbiology www.microbelibrary.org
  • 24. Antimicrobials that Interfere with Elongation Factors Selectivity due to differences in prokaryotic and eukaryotic elongation factors www.freelivedoctor.com
  • 25. Fusidic acid (bacteriostatic)
    • Mode of action - Fusidic acid binds to elongation factor G (EF-G) and inhibits release of EF-G from the EF-G/GDP complex.
    • Spectrum of activity - Gram-positive cocci
    www.freelivedoctor.com
  • 26. Inhibitors of Nucleic Acid Synthesis www.freelivedoctor.com
  • 27. Inhibitors of RNA Synthesis Selectivity due to differences between prokaryotic and eukaryotic RNA polymerase www.freelivedoctor.com
  • 28. Rifampin , Rifamycin, Rifampicin, Rifabutin (bactericidal)
    • Mode of action - These antimicrobials bind to DNA-dependent RNA polymerase and inhibit initiation of mRNA synthesis.
    • Spectrum of activity - Broad spectrum but is used most commonly in the treatment of tuberculosis
    • Resistance - Common
    • Combination therapy - Since resistance is common, rifampin is usually used in combination therapy.
    www.freelivedoctor.com
  • 29. Inhibitors of DNA Synthesis Selectivity due to differences between prokaryotic and eukaryotic enzymes www.freelivedoctor.com
  • 30. Quinolones (bactericidal) nalidixic acid , ciprofloxacin , ofloxacin, norfloxacin, levofloxacin, lomefloxacin, sparfloxacin
    • Mode of action - These antimicrobials bind to the A subunit of DNA gyrase (topoisomerase) and prevent supercoiling of DNA, thereby inhibiting DNA synthesis.
    • Spectrum of activity - Gram-positive cocci and urinary tract infections
    • Resistance - Common for nalidixic acid; developing for ciprofloxacin
    www.freelivedoctor.com
  • 31. Antimetabolite Antimicrobials www.freelivedoctor.com
  • 32. Inhibitors of Folic Acid Synthesis
    • Basis of Selectivity
    • Review of Folic Acid Metabolism
    www.freelivedoctor.com p-aminobenzoic acid + Pteridine Dihydropteroic acid Dihydrofolic acid Tetrahydrofolic acid Pteridine synthetase Dihydrofolate synthetase Dihydrofolate reductase Thymidine Purines Methionine Trimethoprim Sulfonamides
  • 33. Sulfonamides , Sulfones (bacteriostatic)
    • Mode of action - These antimicrobials are analogues of para-aminobenzoic acid and competitively inhibit formation of dihydropteroic acid.
    • Spectrum of activity - Broad range activity against gram-positive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections.
    • Resistance - Common
    • Combination therapy - The sulfonamides are used in combination with trimethoprim; this combination blocks two distinct steps in folic acid metabolism and prevents the emergence of resistant strains.
    www.freelivedoctor.com
  • 34. Trimethoprim , Methotrexate, Pyrimethamine (bacteriostatic)
    • Mode of action - These antimicrobials binds to dihydrofolate reductase and inhibit formation of tetrahydrofolic acid.
    • Spectrum of activity - Broad range activity against gram-positive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections.
    • Resistance - Common
    • Combination therapy - These antimicrobials are used in combination with the sulfonamides; this combination blocks two distinct steps in folic acid metabolism and prevents the emergence of resistant strains.
    www.freelivedoctor.com
  • 35. Anti-Mycobacterial Antibiotics www.freelivedoctor.com
  • 36. Para-aminosalicylic acid (PSA) (bacteriostatic)
    • Mode of action - Similar to sulfonamides
    • Spectrum of activity - Specific for Mycobacterium tuberculosis
    www.freelivedoctor.com
  • 37. Dapsone (bacteriostatic)
    • Mode of action - Similar to sulfonamides
    • Spectrum of activity - Used in treatment of leprosy ( Mycobacterium leprae )
    www.freelivedoctor.com
  • 38. Isoniazid (INH) (bacteriostatic )
    • Mode of action - Isoniazid inhibits synthesis of mycolic acids.
    • Spectrum of activity - Used in treatment of tuberculosis
    • Resistance - Has developed
    www.freelivedoctor.com
  • 39. Antimicrobial Drug Resistance Principles and Definitions
    • Clinical resistance vs actual resistance
    • Resistance can arise by mutation or by gene transfer ( e.g. acquisition of a plasmid)
    • Resistance provides a selective advantage
    • Resistance can result from single or multiple steps
    • Cross resistance vs multiple resistance
      • Cross resistance -- Single mechanism-- closely related antibiotics
      • Multiple resistance -- Multiple mechanisms -- unrelated antibiotics
    www.freelivedoctor.com
  • 40. Antimicrobial Drug Resistance Mechanisms
    • Altered permeability
      • Altered influx
        • Gram negative bacteria
    www.freelivedoctor.com
  • 41. www.freelivedoctor.com Microbe Library American Society for Microbiology www.microbelibrary.org
  • 42. Antimicrobial Drug Resistance Mechanisms
    • Altered permeability
      • Altered efflux
        • tetracycline
    www.freelivedoctor.com Microbe Library American Society for Microbiology www.microbelibrary.org
  • 43. Antimicrobial Drug Resistance Mechanisms
    • Inactivation
      •  -lactamase
      • Chloramphenicol acetyl transferase
    www.freelivedoctor.com Microbe Library American Society for Microbiology www.microbelibrary.org
  • 44. Antimicrobial Drug Resistance Mechanisms
    • Altered target site
      • Penicillin binding proteins (penicillins)
      • RNA polymerase (rifampin)
      • 30S ribosome (streptomycin)
    www.freelivedoctor.com Microbe Library American Society for Microbiology www.microbelibrary.org
  • 45. Antimicrobial Drug Resistance Mechanisms
    • Replacement of a sensitive pathway
      • Acquisition of a resistant enzyme (sulfonamides, trimethoprim)
    www.freelivedoctor.com

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