Aminoglycoside Antibiotics
Aminoglycosides provide concentration-dependent bactericidal activity against gram-negative organisms. Their narrow therapeutic index requires therapeutic drug monitoring to balance efficacy against nephrotoxicity and ototoxicity.
## Mechanism of Action
Aminoglycosides (gentamicin, tobramycin, amikacin, streptomycin) bind irreversibly to the 30S ribosomal subunit, causing misreading of mRNA and production of aberrant proteins. These defective proteins insert into the bacterial cell membrane, creating pores that further increase aminoglycoside uptake -- a self-enhancing bactericidal cycle.
This mechanism requires aerobic metabolism for drug uptake (energy-dependent transport), explaining why aminoglycosides are ineffective against anaerobes and have reduced activity in acidic, hypoxic environments like abscesses.
## Pharmacokinetic Properties
Aminoglycosides are highly polar molecules with poor oral absorption (given IV or IM for systemic infections). They distribute primarily in extracellular fluid, penetrate poorly into bone, CSF, and the vitreous, but concentrate in renal cortical tissue and the inner ear endolymph -- explaining their toxicity pattern.
**Concentration-dependent killing:** Bactericidal activity correlates with peak concentration relative to MIC (peak/MIC ratio >8-10 is the target). Higher peaks kill more effectively.
**Post-antibiotic effect (PAE):** Bacterial growth suppression persists for hours after drug levels fall below MIC, particularly against gram-negative rods. This property enables once-daily (extended-interval) dosing.
## Once-Daily vs Traditional Dosing
Extended-interval dosing (e.g., gentamicin 5-7 mg/kg once daily) exploits concentration-dependent killing and PAE while reducing trough exposure and toxicity. A single large dose achieves high peak/MIC ratios for efficacy, then drug levels fall to near zero before the next dose, giving renal cells time to recover.
Traditional divided dosing (e.g., gentamicin 1.5-2 mg/kg every 8 hours) is still used in endocarditis synergy regimens, pregnancy, burns, and dialysis patients.
## Spectrum of Activity
Aminoglycosides are active against aerobic gram-negative bacilli including Pseudomonas aeruginosa, Enterobacteriaceae, and some mycobacteria (streptomycin for TB). They provide synergistic bactericidal activity with beta-lactams against enterococci and staphylococci (the basis for combination therapy in endocarditis).
## Toxicity
**Nephrotoxicity** (5-25%) -- Accumulation in proximal tubular cells causes acute tubular necrosis. Usually reversible. Risk increases with prolonged courses, dehydration, concurrent nephrotoxins (vancomycin, amphotericin B, NSAIDs), and elevated trough levels.
**Ototoxicity** (up to 10%) -- Damage to cochlear hair cells (hearing loss) and vestibular apparatus (vertigo, disequilibrium). Often irreversible. Cochlear toxicity is more common with amikacin; vestibular toxicity with gentamicin.
**Neuromuscular blockade** -- Rare but potentially fatal. Aminoglycosides inhibit presynaptic acetylcholine release. Risk increases in myasthenia gravis patients and with concurrent neuromuscular blockers.
## Therapeutic Drug Monitoring
For traditional dosing: measure peak (30 min post-infusion) and trough (before next dose). For extended-interval dosing: a single random level at 6-14 hours is plotted on a nomogram (Hartford nomogram) to determine if the next dose interval is appropriate. Target trough <1 mcg/mL for gentamicin.
## Key Takeaways
- Once-daily dosing maximizes efficacy and minimizes toxicity for most patients.
- Monitor renal function and drug levels -- nephrotoxicity is usually reversible if caught early.
- Ototoxicity can be permanent -- counsel patients and limit duration of therapy.
- Aminoglycosides require aerobic conditions and are inactive against anaerobes.