Ototoxicity

Introduction

• Definition

– Damage to the cochlea or vestibular apparatus from exposure to a chemical source

• Many sources

– Mercury

– Herbs

– Streptomycin (1944)

• Dihydrostreptomycin (1948)

– Gentamicin (1965)

– Others

Aminoglycosides

– Streptomycin, kanamycin, neomycin, amikacin, gentamicin, tobramycin, sisomycin, netilmicin

– Enter into inner ear by unknown mechanism

• Secreted into the perilymph by spiral ligament or endolymph by stria vascularis

• Diffuse through round window membrane

– Eliminated by kidney

• Cochlear toxicity

– Amikacin, kanamycin, neomycin, netilmicin

• Vestibular toxicity

– Streptomycin, gentamicin, sisomycin

• Can occur simultaneously

– Increase of 10-20 dB in thresholds of one or more frequencies

– Incidence (6-13%), netilmicin lowest

– Risk factors

• Diuretics, renal failure, prolonged treatment, old age, preexisting SNHL

• Infants less affected, once daily dosing

– Outer hair cell loss first in basal turn then to apex

– Inner hair cell loss later

• Cochlear toxicity presentation

– High frequency SNHL first, then lower frequencies to profound loss

– Not reversible

– Damage usually heralded by tinnitus

– Can be familial form of nonsyndromic HL– maternal inheritance

– Associated with mtDNA 1555A to G point mutation in 12S ribosomal RNA gene– causes increased binding to ribosome

Aminoglycosides

• Vestibular toxicity

– Assessment is difficult

– Dynamic posturography can detect

– Pathologically

• Type I hair cells more sensitive

• Cristae ampullaris then utricle and saccule

– Clinically (ambulatory vs. bedridden)

• Ataxic gait, lose balance when turning

• Bobbing oscillopsia

• Prevention

– Pharmacological

– Clinical

• Consider less ototoxic drugs (netilmicin)

• Identify “high-risk” patients

– Audiogram before and weekly after starting

– ENG prior if possible

– History and physical exam daily (Romberg, VA)

– Adjust doses or switch drugs if toxic

Macrolides

• Discovered erythromycin 1952 (McGuire)

• Mintz (1972) first report of ototoxicity

– Reversible 50-55 dB losses in two cases

• Clinically

– Hearing loss with/without tinnitus– 2 days

– All frequencies, recovery after stopping

– Rarely permanent (hepatic)

– Incidence unknown

• Mechanism unknown

• Azithromycin and clarithromycin can cause similar findings in animals

Other antibiotics

• Vancomycin

– Believed to be ototoxic (no data)

• Penicillin, sulfonamides, cephalosporins

– May have topical toxicity in middle ear

• Nucleoside analog reverse transcriptase inhibitors

– Poor study

Loop Diuretics

• Ethacrinic acid, furosemide, bumetaside

• Clinically (6-7%)

– Usually tinnitus, temporary and reversible SNHL, rare vertigo within minutes

– High doses can cause permanent SNHL

– Highest risk– coadministration of aminoglycosides

• Pathologically

– Edema of stria vascularis

– Ionic gradient changes

– Inhibition of adenylate cyclase and G-proteins

Salicylates and NSAIDS

• Most common OTC drugs in US

• Mechanism

– Normal histology (no hair cell loss)

– Decreased blood flow, decreased enzymes

• Clinically

– Tonal, high frequency tinnitus (7-9 kHz)

– Reversible mild to moderate SNHL (usually high frequency)– rarely permanent

Quinine

• Similar clinical findings with aspirin

• Usage up for leg cramps

• Clinically

– High-pitched tinnitus

– Reversible, symmetric SNHL

– Occasional vertigo

• Mechanism

– Decreased perfusion, direct damage to outer hair cells, biochemical alterations

Antineoplastic Agents

• Cisplatin

– Incidence is high (62%-81%)

– Pathologically

• Outer hair cell degeneration

– Clinically

• Bilateral symmetric SNHL, usually high frequency– not reversible, cumulative

• Risks factors– age extremes, cranial irradiation, high dose therapy, high cumulative dose

• Cisplatin

– Prevention

• Probenecid, WR 2721, DDTC, diuretics, calcium supplements– not effective

• L-N-acetyl-cysteine– protective in vitro

Topical Antimicrobials

• Commonly prescribed for otorrhea after tubes and CSOM

• Controversial subject

– Agents may enter middle ear and gain access to membranous labyrinth

– Animal testing reveals irrefutable evidence of severe ototoxicity

• Polymixin B (Brummett)

• Chloramphenicol (Patterson)

• Neomycin (Brummett)

• Gentamicin (Webster)

• Ticarcillin (Jakob)

• Vasocidin (Brown)

• Ciprofloxacin (Lenarz)

• Differences in humans

– Round window is not exposed

– Round window thicker

– Mucosal membrane protective

– Mucosal edema with or without exudates typically present

– Widespread usage with few side effects

• One in ten thousand

• Remains a possibility in humans

• Patient education important

• Prescribe for only necessary duration

• Avoid in healthy ear

• Caution with prexisting vestibular defects

Russell D. Briggs, M.D.

Arun K. Gadre, M.D.