Aminoglycosides

Aminoglycosides (gentamicin, tobramycin, amikacin, streptomycin, kanamycin, neomycin, paromomycin, plazomicin) are bactericidal agents with concentration-dependent killing, a post-antibiotic effect, and synergy with cell wall active drugs. They are cheap, widely available and central to treatment of serious Gram-negative infection, enterococcal and streptococcal endocarditis (synergy), tuberculosis (streptomycin, amikacin) and neonatal sepsis, but they have a narrow therapeutic index.

Mechanism. Irreversible binding to the 30S ribosomal subunit causes misreading and early termination; uptake needs oxygen-dependent energy, so they are inactive against anaerobes and in acidic, abscess environments.

Pharmacokinetics. Polar molecules, not absorbed orally; distribute in extracellular fluid; poor penetration into CSF, bone, lung secretions and abscesses; eliminated unchanged by glomerular filtration (half-life 2 to 3 hours with normal function, days in renal failure). They accumulate in renal cortex and inner ear.

Spectrum. Aerobic Gram-negatives including Pseudomonas aeruginosa (gentamicin, tobramycin, amikacin); Staphylococcus (synergy); enterococci and viridans streptococci (synergy only); Mycobacterium tuberculosis (streptomycin, amikacin). Not active against anaerobes, Streptococcus alone, Stenotrophomonas or Burkholderia.

Resistance. Aminoglycoside-modifying enzymes (amikacin is the most stable), 16S rRNA methyltransferases (pan-aminoglycoside resistance) and efflux.

• Gentamicin: first-line empirical agent for sepsis and endocarditis synergy.
• Tobramycin: more active against Pseudomonas; inhaled formulations for cystic fibrosis.
• Amikacin: active against many gentamicin-resistant organisms; used for non-tuberculous mycobacteria and MDR tuberculosis.
• Streptomycin: tuberculosis, brucellosis, plague, tularaemia; significant vestibular toxicity.
• Plazomicin: complicated urinary infection with resistant Enterobacterales; stable to most enzymes.
• Neomycin and paromomycin: oral, not absorbed; used for gut decontamination, hepatic encephalopathy, and intestinal amoebiasis (paromomycin).

Adult regimens (dose on ideal body weight; adjusted weight in obesity).

• Gentamicin once daily: 5 to 7 mg/kg IV every 24 hours; level taken 6 to 14 hours after the first dose to adjust the interval, and a pre-dose level under 1 mg/L before further doses. Maximum duration for empirical therapy is usually 3 to 5 days.
• Gentamicin synergy in enterococcal or staphylococcal endocarditis: 1 mg/kg IV every 8 hours (peak about 3 to 4 mg/L, trough under 1 mg/L); in streptococcal endocarditis 3 mg/kg once daily for 2 weeks.
• Amikacin: 15 to 20 mg/kg IV once daily (peak 56 to 64 mg/L, trough under 1 mg/L when used once daily).
• Tobramycin: 5 to 7 mg/kg once daily; inhaled 300 mg twice daily for 28 days on and 28 days off.
• Streptomycin: 15 mg/kg IM daily (maximum 1 g), 12 to 15 mg/kg three times weekly in some tuberculosis regimens; reduce in older adults.
• Plazomicin 15 mg/kg IV once daily over 30 minutes for complicated urinary infection.
• Children: gentamicin 5 to 7.5 mg/kg once daily; neonates 4 to 5 mg/kg every 24 to 36 hours by gestation.

Selection. Empirical combination in septic shock when resistant Gram-negatives are likely, usually for the first 48 to 72 hours; endocarditis synergy; urinary sepsis; neonatal sepsis with ampicillin. Avoid as monotherapy for pneumonia and abscess.

Contraindications. Myasthenia gravis; previous aminoglycoside toxicity; mitochondrial 12S rRNA variant (m.1555A>G) with hearing loss; pregnancy where alternatives exist (streptomycin and kanamycin cause foetal deafness).

Serious effects. Nephrotoxicity (non-oliguric acute tubular injury, usually reversible); cochlear and vestibular ototoxicity (often irreversible); neuromuscular blockade; hypomagnesaemia and hypokalaemia. Risk rises with prolonged therapy, older age, dehydration, liver disease and co-prescribed nephrotoxins.

Interactions. Loop diuretics (ototoxicity), vancomycin, amphotericin, cisplatin, ciclosporin and NSAIDs (nephrotoxicity), neuromuscular blockers (prolonged paralysis).

Monitoring. Creatinine at baseline and every 2 to 3 days; drug levels (gentamicin pre-dose under 1 mg/L); audiometry or symptom review for courses over 7 days or high-risk patients; electrolytes.

Special groups. Pregnancy: gentamicin is used only if essential (for example chorioamnionitis). Breastfeeding: acceptable. Renal impairment: lengthen the interval and base dosing on levels; avoid if possible. Obesity: adjusted weight. Region: gentamicin and streptomycin are cheap and widely stocked in East Africa, so level monitoring may be unavailable; limit courses and monitor creatinine.