PharmacologyTier 1Medical Sciences concept

Aminoglycoside toxicity (ototoxic/vestibular, nephrotoxic)

Core concept

	Target	Reversible?	Predicted by
Nephrotoxicity	Proximal tubular cell (megalin-mediated uptake -> lysosomal rupture) -> non-oliguric ATN	Usually yes	Cumulative dose + duration + trough level
Ototoxicity - vestibular	Type I hair cells, crista ampullaris	*Largely irreversible*	Duration, cumulative dose, genetics
Ototoxicity - cochlear	Outer hair cells, basal turn first -> high-frequency loss	*Irreversible*	Duration, cumulative dose, genetics

Gentamicin is predominantly VESTIBULOTOXIC; amikacin and kanamycin are predominantly COCHLEOTOXIC
Mechanism of hair cell death: aminoglycoside-iron complexes -> reactive oxygen species -> apoptosis; accumulation in endolymph with a very long tissue half-life (weeks-months)
- -> damage can progress after the drug is stopped
Neuromuscular blockade - a fourth, rare toxicity: pre-synaptic inhibition of ACh release (dangerous in myasthenia gravis and with anaesthetic agents)

Why bilateral vestibular loss does not look like vertigo

Toxicity is bilateral, symmetrical and gradual
- -> no asymmetry -> no spinning vertigo and no nystagmus
- -> instead: oscillopsia (the visual world bounces with head movement, from loss of the vestibulo-ocular reflex) and imbalance, worse in the dark and on uneven ground
Often noticed only on mobilising after a prolonged admission - and easily misattributed to deconditioning
Bedside test: head impulse test (bilateral catch-up saccades), dynamic visual acuity (>=2 line drop reading a chart while the head is oscillated)

Pharmacokinetics drives dosing

Concentration-dependent killing + post-antibiotic effect -> once-daily (extended-interval) dosing
- Higher peak = better killing; long trough = less tubular and cochlear accumulation (uptake is a saturable, carrier-mediated process)
Small Vd ~0.25 L/kg - distributes into extracellular fluid; dose on adjusted/ideal body weight in obesity
Entirely renally cleared; not metabolised
Monitoring: trough (pre-dose) level is what predicts toxicity; use an AUC/nomogram method where available
- Gentamicin trough should be <1 mg/L on once-daily dosing
Restrict empirical use to 48-72 hours wherever possible - toxicity is duration-driven

Genetics

Mitochondrial 12S rRNA m.1555A>G (MT-RNR1) - maternally inherited
- -> profound, permanent deafness after a single ordinary dose
- Ask about deafness in maternal relatives after aminoglycoside exposure

Risk factors to look for before prescribing: age, pre-existing renal impairment, volume depletion, prolonged course, concurrent vancomycin, loop diuretics, amphotericin, contrast, NSAIDs, ciclosporin, liver disease, sepsis
Baseline and serial: creatinine/eGFR (at least 2-3x weekly), levels, and audiometry + vestibular assessment for courses beyond ~5-7 days
Nephrotoxicity is typically non-oliguric, appears after 5-7 days, with granular casts and a rising creatinine; hypomagnesaemia, hypokalaemia and hypocalcaemia from tubular wasting often precede it
Stop the drug at the first sign of oscillopsia or imbalance - vestibular injury does not recover, although central compensation and vestibular rehabilitation help
Aminoglycosides remain indispensable: synergy in enterococcal endocarditis, serious Gram-negative sepsis, multi-resistant organisms, and single-dose surgical/gonorrhoea regimens where toxicity risk is negligible
Amikacin liposome inhalation for refractory M. avium complex - still causes systemic ototoxicity

Pharmacodynamic indices of antibiotic efficacy (Cmax/MIC for aminoglycosides, vs time>MIC for beta-lactams)
Dose adjustment from clearance changes; age-related pharmacokinetic changes
Drug-induced acute kidney injury; crystal nephropathy (contrast with the tubular mechanism here)
Mitochondrial inheritance and pharmacogenomics
Myasthenia gravis and drugs that unmask neuromuscular weakness
Vestibular assessment - head impulse test, HINTS examination
Therapeutic drug monitoring principles - peak vs trough vs AUC

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