OTOTOXICITY

MS ENT University Pattern — 10 Marks

DEFINITION

OTOTOXIC DRUGS - CLASSIFICATION

AMINOGLYCOSIDES (Most Important Class)

Relative Cochleotoxicity vs Vestibulotoxicity

SGT KAN - Streptomycin, Gentamicin, Tobramycin, Kanamycin, Amikacin, Neomycin

• Streptomycin, Gentamicin - predominantly vestibulotoxic
• Neomycin, Amikacin, Kanamycin - predominantly cochleotoxic

Mechanism of Aminoglycoside Ototoxicity

1. Aminoglycosides (AGs) bind to a phospholipid - phosphatidylinositol - on the hair cell membrane
2. AGs chelate iron, which generates free radicals (reactive oxygen species)
3. Free radicals cause oxidative damage to hair cells
4. Damage begins at the inner row of outer hair cells (OHCs) at the basal turn of the cochlea
5. Progresses in a basal-to-apical direction - explaining why high-frequency SNHL appears first
6. Histopathology shows OHC loss and stria vascularis damage
7. Drug levels concentrate and persist in endolymph, even after serum levels normalize - this explains delayed/progressive toxicity

Genetic Predisposition

• A1555G mutation in mitochondrial 12S rRNA gene imparts extreme susceptibility to aminoglycoside ototoxicity
• This mutation causes the 12S rRNA to structurally resemble the bacterial ribosomal binding site
• More common in certain Chinese and other Asian populations
• Screening for A1555G before initiating AG therapy can reduce ototoxicity risk

CISPLATIN AND PLATINUM-BASED AGENTS

• Cisplatin is the most ototoxic of the platinum compounds
• Causes high-frequency SNHL (4-8 kHz initially, progressing to lower frequencies)
• SNHL seen in >50% of patients; tinnitus in 7%
• Audiometric changes detectable in up to 75% in some studies
• Effect is dose-dependent but with significant inter-individual variation (suggesting polymorphism in metabolic pathways)
• Onset is variable: some patients develop severe loss after a single dose; others develop symptoms months after the last dose
• Risk factors:
  • Renal failure (reduced drug clearance)
  • Concomitant ototoxic drugs (especially loop diuretics, AGs)
  • Concurrent radiotherapy (synergistic effect)
  • Children (especially at high risk - consequences for speech and language development)

LOOP DIURETICS

• Furosemide (~6% usage) and ethacrynic acid (~1%) are the main agents
• Work by blocking the Na⁺-K⁺-2Cl⁻ symporter in the ascending loop of Henle
• Ototoxic effect is via blocking the H⁺/K⁺ ATPase in the stria vascularis → electrolyte imbalance in endolymph → reduced endocochlear potential
• Effects are typically transient
• Toxicity can be minimized by slow IV infusion rather than bolus administration
• Synergistic ototoxicity when combined with aminoglycosides or vancomycin (significant risk)

SALICYLATES

• Doses > 2.7 g/day of aspirin needed to produce ototoxic effects
• Cause reversible hearing loss and tinnitus
• Mechanism: interference with outer hair cell electromotility (prestin inhibition) and cochlear blood flow
• Effects resolve once drug is cleared renally

QUININE / CHLOROQUINE

• Antimalarial agents
• Cochleotoxic via reversible vasculitis and ischemia of the inner ear
• Degenerative changes in the organ of Corti and stria vascularis
• Transplacental transmission: neonates born to mothers taking these drugs can have bilateral SNHL even when the mother's hearing is normal

MONITORING AND ASSESSMENT

Audiological Monitoring Protocol

1. Baseline audiogram before initiating ototoxic therapy (pre-treatment)
2. Serial audiograms during and after treatment
3. Ultra-high frequency audiometry (above 8 kHz) - detects subclinical damage before speech frequencies are affected
4. Distortion product OAEs (DPOAEs) - more sensitive than conventional audiometry, useful in children under 5 years

American Speech-Language-Hearing Association (ASHA) Criteria for Ototoxicity Monitoring:

• 20 dB shift at any single frequency

• 10 dB shift at two or more contiguous frequencies

• Loss of a previously measurable response

RISK FACTORS FOR OTOTOXICITY

• Renal impairment (reduced drug clearance)
• High cumulative dose
• Prolonged duration of therapy
• Peak and trough serum levels above therapeutic target
• Concurrent use of two or more ototoxic drugs
• Pre-existing hearing loss
• Dehydration
• Advanced age or extreme youth (children especially vulnerable)
• Bacteremia (increases cochlear drug uptake)
• Genetic susceptibility (A1555G mitochondrial mutation for AGs)
• Concurrent radiotherapy (for cisplatin)
• Presence of tympanic membrane perforation (topical AGs)

PREVENTION OF OTOTOXICITY

1. Use ototoxic drugs only when indicated - avoid unnecessary/prolonged use
2. Monitor serum drug levels - measure peak and trough levels of AGs (note: not an absolute guarantee against vestibular toxicity)
3. Audiological monitoring as above (baseline + serial audiograms, ultra-HF audiometry)
4. Dose reduction or cessation when early changes detected
5. Avoid synergistic combinations (e.g., aminoglycoside + furosemide + vancomycin)
6. Slow IV infusion for loop diuretics (avoid bolus)
7. Renal function monitoring - especially with AGs and cisplatin
8. Genetic screening for A1555G mutation before AG therapy
9. Sodium thiosulphate - trialed as a chemoprotective agent against cisplatin ototoxicity (efficacy not yet established due to lack of consensus on assessment criteria)
10. Intratympanic dexamethasone - investigated as protective agent for cisplatin-induced ototoxicity

CLINICAL FEATURES

MANAGEMENT

1. Identify and stop the offending drug as soon as ototoxicity is suspected
2. Serial audiograms to monitor progression or recovery
3. Hearing rehabilitation: hearing aids for significant SNHL
4. Cochlear implantation for severe-to-profound bilateral SNHL
5. Vestibular rehabilitation physiotherapy for vestibulotoxic damage
6. Patient counseling especially regarding children and speech development implications
7. Damage from AGs and cisplatin is typically irreversible; loop diuretic and salicylate effects are usually reversible on stopping the drug

KEY POINTS FOR EXAM

• Aminoglycosides damage OHCs from base to apex - high frequencies first
• SGT KAN mnemonic for AG toxicity (S/G/T = vestibulotoxic; K/A/N = cochleotoxic)
• Cisplatin + radiotherapy = synergistic ototoxicity
• Topical AG drops are safe with intact TM; dangerous with perforation
• Intratympanic gentamicin is deliberately used for chemical labyrinthectomy in Meniere's disease
• Ototoxicity monitoring with serial audiograms and DPOAEs is standard of care
• Genetic test: A1555G mitochondrial mutation = extreme AG sensitivity
• Furosemide + aminoglycoside + vancomycin = dangerous synergistic combination

• K. J. Lee's Essential Otolaryngology, 11th ed., pp. 226-227
• Scott-Brown's Otorhinolaryngology Head & Neck Surgery, Vol. 1
• Cummings Otolaryngology Head and Neck Surgery, 7th ed.
• Shambaugh Surgery of the Ear