Mod 5 DOC CHE

• Antimicrobial agents


  Natural or synthetic substance that kills (bactericidal) or inhibits (bacteriostatic) growth of microorganisms
• Types of antimicrobial agents

  • Antibacterial/antibiotic
  • Antiviral
  • Antifungal
  • Antiparasitic

  
• The bactericidal and bacteriostatic nature of an antimicrobial may vary depending on the concentration of the agent used and the bacterial species targeted

  
• Classification of antibiotics

  • Natural drugs
  • Semi-synthetic drugs
  • Synthetic drugs

  
• Natural drugs

  Produced by bacteria or fungi
• Semi-synthetic drugs

  Modified natural drugs with added chemical groups
• Semi-synthetic drugs

  • ampicillin (pen + amino grp), carbenicillin (pen+carboxy grp), and methicillin
• Synthetic drugs

  Chemically-produced drugs
• Synthetic drugs


  • sulfonamides, trimethoprim, chloramphenicol, isoniazid, ciprofloxacin, and dapsone
• Steps for an antimicrobial agent to successfully inhibit or kill an infecting microorganism

  1. The agent must be in an active form

  2. The antibiotic must be able to achieve sufficient levels or concentrations at the site of infection

  3. Direct interactions between the antibacterial agent and the bacterial cell

  4. Binding to a specific target occurs

  5. Adequate binding of the target results in disruption of cellular processes

  
• Chemotherapeutic criteria for antibacterial agents

  • Narrow-spectrum antibiotics
  • Extended-spectrum antibiotics
  • Broad-spectrum antibiotics

  
• Narrow-spectrum antibiotics


  Acting only on a single or a limited group of microorganisms

  
• Narrow-spectrum antibiotics

  • Isoniazid is active against mycobacteria

  
• Extended-spectrum antibiotics

  Effective against gram-pos and also against a significant number of gram neg
• Extended-spectrum antibiotics

  • Ampicillin is effective against gram-positive and some gram negative bacteria
• Broad-spectrum antibiotics


  Affect a wide variety of microbial species

  
• Broad-spectrum antibiotics


  • tetracycline and chloramphenicol
• Processes or structures targeted by antibacterial agents

  • Cell wall (peptidoglycan) synthesis
  • Cell membrane
  • Protein synthesis
  • Metabolic pathways
  • DNA and RNA synthesis

  
• Antimicrobial Susceptibility Testing (AST)


  Also known as Antimicrobial Sensitivity Testing, in vitro tests procedures used to produce antimicrobial susceptibility profiles and detect resistance to therapeutic agents
• Classification of antibacterial agents by their sites of action

  • Inhibitors of cell wall synthesis
  • Inhibitors of protein synthesis
  • Inhibitors of nucleic acid (DNA/RNA) function or synthesis
  • Inhibitors of cell membrane function
  • Inhibitors of metabolism
• Purpose of Antimicrobial Susceptibility Testing

  • To determine whether the bacterial isolate is capable of expressing resistance to the antimicrobial agents selected for treatment

  
• Inhibitors of cell wall synthesis (Beta-Lactams)

  Bind enzymes involved in peptidoglycan production (i.e., penicillin-binding proteins PBPs) - transpeptidases and transglycosylases. Binding to these PBPs halts cell wall synthesis, leading to death caused by faulty cell wall synthesis, autolysis and death of the cell.
• Standardization of Antimicrobial Susceptibility Testing

  1. Optimizes bacterial growth conditions so that inhibition of growth can be attributed to the antimicrobial agent

  2. Optimizes conditions for maintaining antimicrobial integrity and activity

  3. Maintains reproducibility and consistency in the resistance profile of an organism, regardless of the microbiology laboratory performing the test

  
• Standardized components of antimicrobial susceptibility testing

  • Bacterial inoculum size
  • Growth medium (typically a Mueller-Hinton base)
  • pH
  • Cation concentration
  • Blood and serum supplements
  • Thymidine content
  • Incubation atmosphere
  • Incubation temperature
  • Incubation duration
  • Antimicrobial concentrations

  
• Beta-Lactams are effective against both gram-pos and gram-neg bacteria, but bacteria can exhibit resistance by producing beta-lactamase
• In vitro susceptibility testing provides valuable data that are used in conjunction with other diagnostic information to guide patient therapeutic options
• Beta-lactamase inhibitors

  Given with a beta-lactam antibiotic to provide effective treatment. Have structural similarity with the B-lactam antibiotics and function as substrate of B-lactamase, thus reducing harm on the B-lactam antibiotic.
• Beta-lactamase inhibitors

  • Clavulanic acid, Sulbactam, Tazobactam
• Dilution Tests


  Involves challenging the organism of interest with antimicrobial agents in a liquid environment

  
• Beta-lactam combinations

  Comprised of a beta-lactam with antimicrobial activity, a beta-lactam without activity that is capable of binding and inhibiting beta-lactamases, and beta-lactam combinations
• Categories of Dilution Tests

  • Macrodilution (test tubes, total broth: 1mL or greater)
  • Microdilution (microtiter trays, total broth: 0.05 to 0.1 mL)

  
• Beta-lactam combinations are only effective against organisms that produce beta-lactamases that are bound by the inhibitor, and have little effect on resistance that is mediated by altered PBPs
• Minimum Inhibitory Concentration (MIC)


  Lowest concentration of antibiotic that inhibits growth, as detected visually or with an automated or semiautomated method, expressed in ug/mL

  
• Glycopeptides


  Bind to precursors of cell wall synthesis, e.g. Vancomycin, bacitracin, teicoplanin, daptomycin.
• Minimum Bactericidal Concentration (MBC)


  Lowest concentration of antibiotic that kills 99.9% of bacteria

  
• Vancomycin is used to treat Methicillin-resistant Staph. aureus (MRSA)
• Macrodilution is rarely used in most clinical laboratories, and subsequent comments regarding broth dilution focus on the microdilution approach

  
• Inhibitors of protein synthesis

  Bind to the 23S ribosomal RNA (rRNA) on the bacterial 50S ribosomal subunit, blocking translocation and inhibiting the addition of amino acids to the growing peptide chain by reversibly binding to the 50S ribosomal subunit, preventing peptide chain elongation.

  
• Broth-Macrodilution Test


  Challenging the organism of interest with antimicrobial agents in a liquid environment using test tubes

  
• ABELARDO B. AGUILAR: 'A Filipino scientist who was "supposed to be" the discoverer of a powerful macrolide antibiotic, erythromycin, which was isolated by Eli Lilly and Company from soil samples he sent them.'