Aminoglycosides Pharmacology
Aminoglycosides cause irreversible mistranslation of bacterial proteins and have concentration-dependent bactericidal activity, but require monitoring for nephrotoxicity and ototoxicity.
## Overview
Aminoglycosides are polycationic antibiotics that irreversibly inhibit bacterial protein synthesis. They display concentration-dependent bactericidal activity with a prolonged post-antibiotic effect, and are primarily used against aerobic gram-negative bacteria and synergistically against gram-positive organisms. Nephrotoxicity and ototoxicity require careful therapeutic drug monitoring.
## Mechanism of Action
Aminoglycosides enter bacteria via oxygen-dependent active transport (requiring the proton motive force), which explains their lack of activity against strict anaerobes. Inside the bacterial ribosome, they bind the 30S subunit (16S rRNA, decoding A-site), causing misreading of mRNA codons and synthesis of aberrant proteins. These misread proteins insert into the bacterial membrane, causing increased permeability and enhanced aminoglycoside uptake (self-potentiating mechanism), leading to cell death.
## Spectrum and Clinical Uses
Primary gram-negative activity: Pseudomonas aeruginosa, Enterobacteriaceae, Acinetobacter. Used as synergistic combination partners for gram-positive infections (enterococcal endocarditis: ampicillin/vancomycin + gentamicin; streptococcal endocarditis: penicillin + gentamicin — though high-level aminoglycoside resistance testing is essential before synergy can be assumed).
**Individual agents**:
- **Gentamicin/tobramycin**: Broad gram-negative coverage; tobramycin preferred for Pseudomonas
- **Amikacin**: Resistant to most aminoglycoside-modifying enzymes; reserved for MDR organisms
- **Streptomycin**: Used for tuberculosis, tularemia, plague, brucellosis
- **Neomycin**: Oral (not absorbed); bowel decontamination, hepatic encephalopathy
## Pharmacokinetics and Dosing
Poor oral bioavailability; IV or IM administration. Volume of distribution ~0.25 L/kg. Renal elimination unchanged. Concentration-dependent killing → once-daily (extended-interval) dosing (e.g., 5-7 mg/kg/day gentamicin) maximizes Cmax/MIC while reducing renal accumulation time.
## Toxicities
**Nephrotoxicity**: Aminoglycosides accumulate in proximal tubular cells. Acute tubular necrosis (typically reversible) occurs in 10-25% with conventional dosing. Risk factors: prolonged courses, elevated troughs, concurrent nephrotoxins, hypovolemia. Once-daily dosing reduces nephrotoxicity vs. multiple-daily dosing.
**Ototoxicity**: Irreversible cochlear (hearing loss) and vestibular damage from inner ear hair cell death. Cochlear toxicity: high-frequency hearing loss (audiometric screening). Vestibular: ataxia, oscillopsia.
**Neuromuscular blockade**: Rare; calcium gluconate reverses.
## Key Takeaways
- Aminoglycosides are concentration-dependent; once-daily dosing optimizes Cmax/MIC and reduces nephrotoxicity
- Active transport requires oxygen; ineffective against anaerobes
- Nephrotoxicity is usually reversible; ototoxicity is often permanent
- Amikacin resists most aminoglycoside-modifying enzymes; reserved for MDR gram-negatives