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Aminoglycosides

  • Discovered in 1940's
  • Derived from soil bacteria
  • Effective against vast majority of Gram negative bacilli

Mechanism of Action

  • Bacteriocidal
  • Multifactorial effect
    • Actively taken up & concentrated by bacteria
    • Bind to Gram negative bacterial cell wall & affect permeability
    • Bind to bacterial Ribosomes & affect protein synthesis

Gentamicin

  • Attaches to specific receptor protein on bacterial 30s ribosome
  • Blocks initiation complex of peptide formation
  • Results in misreading of mRNA & nonfunctional protein production
  • Ribosome break up into fragments
  • Result is cell death

Time Course

  • Concentration-Dependent killing
  • One single bolus dose works better than divided doses in 24 hours

Post-Antibiotic Effect

  • Persistent suppression of bacterial growth
  • After short antimicrobial exposure
  • Continues for 2 hours after exposure
  • Concentration-dependent

Antimicrobial Synergy

  • Synergy between Aminoglycoside (inhibitor of protein synthesis) & cell wall active antimicrobial (Penicillin, Cephalosporin)
  • Against Gram positive cocci

Resistance

  • Due to
    • Lack of receptor on ribosome
      • Result of Chromosomal Mutation
    • Production of drug-destroying enzymes
      • Plasmid-induced
    • Permeability defect
      • Plasmid-induced

Pharmacology

  • Administered IV over 30min or IM
  • Minimal absorption from GIT
  • Large volume of distribution
  • Poorly protein bound & very water soluble
  • Cross membranes poorly
  • Traverse BBB poorly
  • Exception is renal tubular & inner ear cells
  • Enters synovial fluid easily
  • Not metabolized
  • 99% excreted unchanged in kidney

Toxicity

  • Allergies rare
  • Can cause
    • Injury to renal PCT
    • Damage to cochlea & vestibular apparatus
    • Appears to be less with daily dose
    • Idiosyncratic & Dose related

Clinical Indications

  • Aerobic Gram Negative Bacillus
    • Klebsiella
    • Enterobacter
    • Serratia
    • Pseudomonas (Tobramicin)
  • Aerobic Gram Positive cocci
    • S aureus (Methicillin sensitive)
    • S epidermidis
    • S viridans
  • Enterococcus
    • With penicillin or cephalosporin
  • Resistance rare
    • Good for Gram negatives & some Gram positives
  • Anaerobes & Streptococci usually resistant

Dosage

Once daily dose

  • Clinical data not adequate to support unqualified endorsement

Premise

  • Nephrotoxicity & ototoxicity less severe
  • Antibacterial efficacy enhanced with high peak drug concentration

Dosing

  • Dose is 4-5mg/kg (max 7mg/kg) over 60min od
  • Trough levels taken
  • Level at 18 hours to check trough
  • Peak levels not required
  • bd or tds dosing in children

 

 

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