Ototoxicity Russell D. Briggs, M.D. Faculty Advisor: Arun K. Gadre, M.D. The University of Texas Medical Branch Department of Otolaryngology Grand Rounds Presentation November 7, 2001
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
Aminoglycosides Cochlear toxicity Amikacin, kanamycin, neomycin, netilmicin Vestibular toxicity Streptomycin, gentamicin, sisomycin Can occur simultaneously
Aminoglycosides Cochlear toxicity 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
Aminoglycosides Cochlear toxicity Outer hair cell loss first in basal turn then to apex Inner hair cell loss later
Aminoglycosides
Aminoglycosides Cochlear toxicity presentation High frequency SNHL first, then lower frequencies to profound loss Not reversible Damage usually heralded by tinnitus
Aminoglycosides Cochlear toxicity 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
Aminoglycosides
Aminoglycosides 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
Macrolides 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
Loop Diuretics 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
Salicylates and NSAIDs
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
Antineoplastic Drugs
Antineoplastic Drugs 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
Topical Antimicrobials Polymixin B (Brummett) Chloramphenicol (Patterson) Neomycin (Brummett) Gentamicin (Webster) Ticarcillin (Jakob) Vasocidin (Brown) Ciprofloxacin (Lenarz)
Topical Antimicrobials 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
Topical Antimicrobials Remains a possibility in humans Patient education important Prescribe for only necessary duration Avoid in healthy ear Caution with prexisting vestibular defects
Case Presentation 68 yowf presents to clinic with complaint of ringing in my ears
Case Presentation 68 yowf presents to clinic with complaint of ringing in my ears Described as high pitched in both ears, onset was 5 days prior and worsening, not able to sleep
Case Presentation 68 yowf presents to clinic with complaint of ringing in my ears Described as high pitched in both ears, onset was 5 days prior and worsening, not able to sleep Long history of mild hearing loss, now worsening also Denies vertigo or dysequilibrium
Case Presentation Has prior history of significant noise exposure (worked in factory) No recent or prior antibiotic use No prior otologic history except mild HL
Case Presentation PMH: HTN (controlled with medications), CRI ( no change - creatinine 2.0) PSH: none
Case Presentation PMH: HTN (controlled with medications), CRI ( no change - creatinine 2.0), arthritis, back pain PSH: none Medications: clonidine tid, lasix bid, vitamins qd, aspirin qid, ibuprofen prn
Case Presentation PMH: HTN (controlled with medications), CRI ( no change - creatinine 2.0), arthritis, back pain PSH: none Medications: clonidine tid, lasix bid, vitamins qd, aspirin qid, ibuprofen prn SH/FH: noncontributory
Case Presentation PMH: HTN (controlled with medications), CRI ( no change - creatinine 2.0), arthritis, back pain PSH: none Medications: clonidine tid, vitamins qd, aspirin qid, ibuprofen prn SH/FH: noncontributory ROS: leg swelling worsening, DOE, anterior neck pain, arthritis worsening
Case Presentation PE: H/N normal except?left TVC paresis on IDL, tender nodules on pinna Neurologic exam normal Remainder exam normal except decreased ROM fingers, tender proximal joints
Case Presentation Labs: CBC normal, Cr=3.5, remainder nl
Case Presentation Labs: CBC normal, Cr=3.5, remainder nl Rheumatoid factor positive
Case Presentation Labs: CBC normal, Cr=3.5, remainder nl Rheumatoid factor positive
Case Presentation Labs: CBC normal, Cr=3.5, remainder nl Rheumatoid factor positive Salicylate level 20
Case Presentation Labs: CBC normal, Cr=3.5, remainder nl Rheumatoid factor positive Salicylate level 20