Amikacin for Tuberculosis

Amikacin is a semisynthetic aminoglycoside given by injection for rifampicin-resistant tuberculosis, mainly where bedaquiline-based oral regimens cannot be used or when resistance leaves few options. Ototoxicity (often irreversible) and nephrotoxicity limit its use, and oral regimens have largely replaced it.

Class. Aminoglycoside; injectable second-line antituberculosis drug.

Mechanism. Binds the 30S ribosomal subunit and causes mistranslation and protein synthesis inhibition. Resistance arises through rrs (A1401G) and eis promoter mutations; cross-resistance with kanamycin is common.

Pharmacokinetics. Not absorbed orally. Intramuscular peak at about 1 hour, intravenous peak at the end of infusion. Half life 2 to 3 hours in normal renal function. Extracellular distribution, poor cerebrospinal fluid penetration. Excreted unchanged by glomerular filtration.

Rifampicin-resistant tuberculosis with limited oral options (adults). - 15 mg/kg (range 15 to 20) intramuscularly or intravenously once daily; maximum 1000 mg daily. - Duration: usually up to 6 months or as the regimen directs, then stop. - Loading dose: none. Maintenance dose: 15 mg/kg daily; some programmes give three times weekly after culture conversion. - Older adults over 59 years: 10 mg/kg daily, maximum 750 mg.

Children. 15 to 20 mg/kg daily; maximum 1000 mg daily.

Dosing weight. Use ideal body weight in obesity, or adjusted weight with levels.

Therapeutic drug monitoring. Peak 35 to 45 mg/L (1 hour after intramuscular dose or 30 minutes after infusion) and trough under 5 mg/L, where available.

Contraindications. Pregnancy (foetal ototoxicity, boxed-warning-level), myasthenia gravis, hypersensitivity to aminoglycosides and pre-existing hearing loss where alternatives exist.

Serious adverse effects. Irreversible cochlear and vestibular ototoxicity, nephrotoxicity, neuromuscular blockade and respiratory depression, and hypokalaemia, hypomagnesaemia and hypocalcaemia.

Common adverse effects. Pain at injection site, tinnitus, and mild kidney function changes.

Interactions. Loop diuretics and cisplatin increase ototoxicity; NSAIDs, ciclosporin, tenofovir disoproxil fumarate, amphotericin B and vancomycin increase nephrotoxicity; neuromuscular blockers prolong paralysis.

Common prescribing errors. Continuing past the intended duration, no baseline audiometry, dosing on actual body weight in obesity, full dose in kidney failure, and use in pregnancy.

Special groups. - Pregnancy: avoid; risk of congenital deafness. - Breastfeeding: poorly absorbed by the infant; acceptable if essential. - Children: audiometry is difficult but essential. - Older adults: reduce dose to 10 mg/kg and monitor kidney function. - Kidney impairment: with CrCl under 30 mL/min, give 12 to 15 mg/kg two or three times weekly, adjusted to levels; after dialysis. - Liver impairment: no adjustment.

Formulations. Injection 250 mg/mL (500 mg and 1 g vials).

Administration. Deep intramuscular injection, or intravenous in 100 to 200 mL of 0.9% sodium chloride over 30 to 60 minutes.

Baseline. Audiometry, creatinine, potassium, magnesium, calcium, vestibular assessment.

Monitoring. Creatinine and electrolytes at baseline and weekly in the first month, then monthly; audiometry monthly; ask about hearing, tinnitus and balance at every visit.

Stopping thresholds. Stop for new hearing loss, vestibular symptoms, a rise in creatinine of over 50% from baseline, or persistent electrolyte wasting.

Referral and escalation. Audiology for any hearing change; nephrology for kidney injury; manage within a drug-resistant tuberculosis programme.