Antimicrobial

• Chemotherapy


  The use of drugs to treat a disease
• Antimicrobial drugs


  Interfere with the growth of microbes within a host

  
• Antibiotic


  A substance produced by a microbe that, in small amounts, inhibits another microbe

  
• Selective toxicity


  A drug that kills harmful microbes without damaging the host
• Types of antimicrobial drugs

  • Semisynthetics
  • Synthetics
• Semisynthetics


  Chemically altered antibiotics that are more effective, longer lasting, or easier to administer than naturally occurring ones

  
• Synthetics


  Antimicrobials that are completely synthesized in a lab
• Spectrum of action

  • Narrow-spectrum: effective against G+ cells
  • Broad-spectrum: effective against G+ and G- cells
• Broad-spectrum antimicrobials may allow for secondary or superinfections to develop and killing of normal flora reduces microbial antagonism

  
• Tests to assess antimicrobial effectiveness

  • Diffusion susceptibility test
  • Minimum inhibitory concentration test
  • Minimum bactericidal concentration test

  
• Routes of administration

  • Topical application
  • Oral
  • Intramuscular
  • Intravenous
• Must know how antimicrobial agent will be distributed to infected tissues

  
• Safety and side effects

  • Toxicity
  • Allergies
  • Disruption of normal microbiota

  
• Therapeutic index


  The ratio of the dose of a drug that can be tolerated to the drug's effective dose
• Ideal antimicrobial agent should be readily available, inexpensive, chemically stable, easily administered, nontoxic and nonallergenic, and selectively toxic against a wide range of pathogens
• Mechanisms of action of antimicrobial drugs

  • Inhibition of cell wall synthesis
  • Inhibition of protein synthesis
  • Disruption of cytoplasmic membranes
  • Inhibition of nucleic acid synthesis
  • Inhibition of metabolic pathways
  • Prevention of virus attachment and entry

  
• Inhibition of cell wall synthesis


  • Antibiotics prevent the synthesis of intact peptidoglycan, the cell wall is greatly weakened and undergoes lysis, only actively growing cells are affected

  
• Beta-lactam antibiotics


  • Carbapenems
  • Monobactam
  • Cephalosporins
• Polypeptide antibiotics


  • Bacitracin blocks transport of NAG and NAM from cytoplasm, effective against gram-positives
  • Vancomycin interferes with particular bridges that link NAM subunits in many gram-positive bacteria

  
• Antimycobacterial antibiotics


  • Disrupt mycolic acid formation in mycobacterial species

  
• Inhibition of protein synthesis


  • Chloramphenicol
  • Aminoglycosides
  • Tetracyclines
  • Macrolides
  • Oxazolidinones
• Chloramphenicol


  • Broad spectrum, binds 50S subunit, inhibits peptide bond formation
• Aminoglycosides


  • Broad spectrum, changes shape of the 30S subunit
• Tetracyclines


  • Broad spectrum, interferes with tRNA attachment
• Macrolides


  • Gram-positives, binds 50S, prevents translocation
• Oxazolidinones


  • Linezolid: gram-positives, binds 50S subunit, prevents formation of 70S ribosome, against many resistant pathogens
• Disruption of cytoplasmic membranes

  • Azoles and allylamines inhibit ergosterol synthesis
  • Polymyxin disrupts cytoplasmic membranes of gram-negative bacteria
  • Pyrazinamide only disrupts transport across the cytoplasmic membrane of Mycobacterium tuberculosis

  
• Inhibition of nucleic acid synthesis

  • Rifamycin: inhibits RNA synthesis
  • Quinolones and fluoroquinolones: inhibit DNA gyrase
  • Flucytocine: cytosine analog interferes with RNA synthesis
  • Pentamidine isethionate: may bind DNA
• Drugs that inhibit nucleic acid synthesis often affect both eukaryotic and prokaryotic cells and are not normally used to treat infections, but used primarily in research and perhaps to slow cancer cell replication
• Inhibition of metabolic pathways


  • Antimetabolic agents can be effective when pathogen and host metabolic processes differ
  • Antiviral agents can target unique aspects of viral metabolism
  • Sulfonamides (sulfa drugs) inhibit folic acid synthesis

  
• Prevention of virus attachment and entry


  • Attachment antagonists block viral attachment or receptor proteins
• Antifungal drugs


  • Inhibition of ergosterol synthesis
  • Inhibition of cell wall synthesis
  • Damage plasma membranes

  
• Anti-viral drugs

  • Amantadine - blocks entry or uncoating of the virus
  • Guanine analogs - inhibit DNA and RNA synthesis
  • Thymine analogs - inhibit DNA synthesis

  
• Antiprotozoan drugs

  • Chloroquine: inhibits DNA synthesis
  • Diiodohydroxyquin: unknown mode of action
  • Metronidazole: damages DNA
  • Nitazoxanide: interferes with metabolism of anaerobes
• Antihelminthic drugs

  • Niclosamide: prevents ATP generation
  • Praziquantel: alters membrane permeability
  • Mebendazole: inhibits nutrient absorption
  • Ivermectin: paralyzes worms

  
• Tests to guide chemotherapy

  • Kirby-Bauer test
  • Minimum inhibitory concentration (MIC) test
  • Minimum bactericidal concentration (MBC) test
• Kirby-Bauer test


  • Bacterial culture is inoculated on agar, filter paper disks impregnated with chemotherapeutic agents are overlaid
• MIC test


  • The E Test: A plastic-coated strip contains a gradient of antibiotic concentrations, and the minimal inhibitory concentration is read from a scale printed on the strip
• MBC test


  • The microorganism is grown in liquid media containing different concentrations of a chemotherapeutic agent, the lowest concentration that kills bacteria is the minimal bactericidal concentration

  
• Mechanisms of antibiotic resistance

  • Produce enzyme that destroys or deactivates drug
  • Slow or prevent entry of drug into the cell
  • Alter target of drug so it binds less effectively
  • Alter their own metabolic chemistry
  • Pump antimicrobial drug out of the cell before it can act
  • Bacteria in biofilms can resist antimicrobials