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Antibiotics
 

Antibiotics

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Antibiotics

Antibiotics

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    Antibiotics Antibiotics Presentation Transcript

    • Antibiotics: Protein Synthesis, Nucleic Acid Synthesis and Metabolism www.freelivedoctor.com
    • 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
    • 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
    • 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
    • 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
    • Zone Diameter Standards for Disk Diffusion Tests www.freelivedoctor.com
    • 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
    • Antibiotics that Inhibit Protein Synthesis www.freelivedoctor.com
    • 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
    • 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
    • Protein Synthesis Microbe Library -American Society for Microbiology www.microbelibrary.org www.freelivedoctor.com
    • Survey of Antibiotics www.freelivedoctor.com
    • Protein Synthesis Inhibitors
      • Mostly bacteriostatic
      • Selectivity due to differences in prokaryotic and eukaryotic ribosomes
      • Some toxicity - eukaryotic 70S ribosomes
      www.freelivedoctor.com
    • Antimicrobials that Bind to the 30S Ribosomal Subunit www.freelivedoctor.com
    • 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
    • www.freelivedoctor.com Microbe Library American Society for Microbiology www.microbelibrary.org
    • 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
    • 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
    • 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
    • Antimicrobials that Bind to the 50S Ribosomal Subunit www.freelivedoctor.com
    • 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
    • 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
    • www.freelivedoctor.com Microbe Library American Society for Microbiology www.microbelibrary.org
    • Antimicrobials that Interfere with Elongation Factors Selectivity due to differences in prokaryotic and eukaryotic elongation factors www.freelivedoctor.com
    • 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
    • Inhibitors of Nucleic Acid Synthesis www.freelivedoctor.com
    • Inhibitors of RNA Synthesis Selectivity due to differences between prokaryotic and eukaryotic RNA polymerase www.freelivedoctor.com
    • 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
    • Inhibitors of DNA Synthesis Selectivity due to differences between prokaryotic and eukaryotic enzymes www.freelivedoctor.com
    • 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
    • Antimetabolite Antimicrobials www.freelivedoctor.com
    • 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
    • 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
    • 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
    • Anti-Mycobacterial Antibiotics www.freelivedoctor.com
    • Para-aminosalicylic acid (PSA) (bacteriostatic)
      • Mode of action - Similar to sulfonamides
      • Spectrum of activity - Specific for Mycobacterium tuberculosis
      www.freelivedoctor.com
    • Dapsone (bacteriostatic)
      • Mode of action - Similar to sulfonamides
      • Spectrum of activity - Used in treatment of leprosy ( Mycobacterium leprae )
      www.freelivedoctor.com
    • 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
    • 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
    • Antimicrobial Drug Resistance Mechanisms
      • Altered permeability
        • Altered influx
          • Gram negative bacteria
      www.freelivedoctor.com
    • www.freelivedoctor.com Microbe Library American Society for Microbiology www.microbelibrary.org
    • Antimicrobial Drug Resistance Mechanisms
      • Altered permeability
        • Altered efflux
          • tetracycline
      www.freelivedoctor.com Microbe Library American Society for Microbiology www.microbelibrary.org
    • Antimicrobial Drug Resistance Mechanisms
      • Inactivation
        •  -lactamase
        • Chloramphenicol acetyl transferase
      www.freelivedoctor.com Microbe Library American Society for Microbiology www.microbelibrary.org
    • 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
    • Antimicrobial Drug Resistance Mechanisms
      • Replacement of a sensitive pathway
        • Acquisition of a resistant enzyme (sulfonamides, trimethoprim)
      www.freelivedoctor.com