Pharm 101: Gentamicin

Class

Aminoglycoside antibiotic

Pharmacodynamics

• Passive diffusion into cell via porin channels across outer membrane, then oxygen-dependent active transport into cytoplasm
  • Active transport is enhanced by cell wall active drugs such as penicillin and vancomycin (synergistic effect)
  • Low ECF pH and anaerobic conditions inhibit transport by reducing gradient
• Binds to 30S subunit of ribosomal proteins and irreversibly inhibits protein synthesis (bactericidal) by:
  • Interfering with initiation complex of peptide formation
  • Inducing misreading of mRNA thus producing non-functional protein
  • Causing break up of polysomes into non-functional monosomes
• Exhibits concentration-dependent killing and a post-antibiotic effect
• Mechanisms of aminoglycoside resistance:
  • Transferase enzyme that inactivates drug
  • Impaired entry of drug into cell
  • Alteration/deletion of 30S ribosomal subunit receptor protein

Pharmacokinetics

• IV, IM, topical administration
• Absorption:
  • Well absorbed
• Distribution:
  • Small volume of distribution
  • 10% plasma protein bound
  • Doesn’t reach CNS and eye readily
• Metabolism:
  • Not metabolised
• Elimination:
  • Renal excretion. Glomerular filtration
  • Half-life 2-3 hours in normal renal function, 24-48 hours in significant renal impairment

Antimicrobial activity

• Aerobic gram negative bacteria:
  • E Coli
  • Pseuodomonas, Enterobacter
  • Proteus, Klebsiella, Serratia
• Gram positive bacteria: (with beta lactams or vancomycin)
  • Staph
  • Strep
• No activity against anaerobes

Adverse effects

• Reversible nephrotoxicity
  • Acute tubular necrosis
• Irreversible ototoxicity
  • 1-5% receiving gentamicin for more than 5 days
  • Mainly vestibular dysfunction, although loss of hearing can also occur
• Neuromuscular blockade in high doses

Precautions/contraindications

• Administration with loop diuretics potentiates nephrotoxicity

Benefits of once daily dosing

• Just as effective, and probably less toxic, than multiple smaller doses
• Concentration-dependent killing: kills increased number of bacteria at more rapid rate at higher concentration
• Post-antibiotic effect: effects last longer than detectable serum level
• Reduced toxicity: decreased time above toxic threshold concentration
• Practical advantages:
  • Less nursing time
  • OPD therapy possible
  • Drug level not required unless > 3 day therapy

References

• Katzung BG. Basic and Clinical Pharmacology. 14e. 2018