Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature.

Aminoglycoside ototoxicity is associated with the total daily dose, duration of treatment, previous treatment with aminoglycosides, and renal disease. The ototoxicity has a delayed onset (months to years later). Aminoglycosides enter the fluids of the inner ear via the bloodstream or via the round window with topical application. The drug is cleared more slowly from perilymph and endolymph than from serum, hence the once-daily dosing theory to reduce ototoxicity. A review of 29 clinical trials (Barclay et al, 1994) found that if the same total daily dose of drug is given with a once-daily regimen as opposed to the traditional 2-4 doses/day, the efficacy of antibiotic activity was the same, but there tended to be less ototoxicity.

Symptoms of aminoglycoside ototoxicity include irreversible high-frequency sensorineural hearing loss, decreased otoacoustic emissions, and disequilibrium. With further toxicity, this can lead to complete deafness and/or oscillopsia. Studies of the organ of corti reveal widespread loss of outer hair cells. Potential mechanisms of toxicity include:

1. Aminoglycosides binding to the cell membrane and blocking transmembrane signaling systems.
2. Inhibition of the enzyme, ornithine decarboxylase, leading to decreased polyamine synthesis (Henley, 1994).
3. An unknown drug metabolite may be responsible for the ototoxicity. (Schacht, 1993).

Briefly stated, topical antimicrobials (particularly Cortisporin) are severely ototoxic in guinea pigs (Barlow et al, 1994). However, there is no evidence for toxicity of topical agents in humans. There has never been a controlled study that demonstrates hearing loss, and there has never even been a case report of hearing loss after treatment with a topical antimicrobial.

Salicylates and NSAID's cause reversible tinnitus and hearing loss. Also decreased otoacoustic emissions have been noted. Theories of salicylate ototoxicity include:

1. Vasoconstriction of vessels in stria vascularis, leading to decreased cochlear blood flow (Didier et al, 1993).
2. Reversible ultrastructural changes in outer hair cells that correlate with decreased electromotility (Dieler et al, 1991).

In summary, aminoglycosides cause permanent structural damage to hair cells, and lead to permanent hearing loss and disequilibrium. Salicylates cause reversible changes in hair cells or the cochlea, and lead to reversible symptoms.

A 41-year-old female presented with complaints of high-pitched ringing in her ears for one week. She stated the sound was worse in quiet environments, and was particularly noticeable when trying to fall asleep. She had no complaints of hearing loss, aural fullness, unsteadiness, or vertiginous symptoms. She had no history of ear infections or ear surgery. Family history was negative. There was no history of autoimmune disease, skin rashes, or arthritis. The patient denied use of diuretics, intravenous antibiotics, or chemotherapy medications. She did state that she had been taking 3 aspirin tablets 3 to 4 times per day for stress headaches recently.

Physical examination, including complete neuro-otologic exam, was unremarkable. A preliminary diagnosis of salicylate ototoxicity was made, and discontinuing the use of aspirin was recommended to see if her tinnitus resolved. In addition, a neurology appointment was made for evaluation of her headaches. After one week the patient returned for follow-up and stated that her tinnitus, as well as her headache, had resolved. She had no further complaints and was discharged from clinic.

Aran JM. Current perspectives on inner ear toxicity. Otolaryngol Head Neck Surg 1995;112:133-144.

Aran JM, Hiel H, Hayashida T, et al. Noise, aminoglycosides, and diuretics. In: Dancer A, Henderson D, Salvi RJ, Hamemik RP, eds. Noise Induced Hearing Loss. Philadelphia: B.C. Decker, 1991:188-195.

Barclay ML, Begg EJ. Aminoglycoside toxicity and relation to dose regimen. Adverse Drug Reactions & Toxicological Reviews 1994;13:207-234.

Barclay ML, Begg EJ, Hickling KG. What is the evidence for once-daily aminoglycoside therapy? Clin Pharmacokinetics 1994;27:32-48.

Barlow DW, Duckert LG, Kreig CS, Gates GA. Ototoxicity of topical otomicrobial agents. Acta Otolaryngol 1994;115:231-235.

Barlow DW, Duckert LG, Kreig CS, Gates GA. Ototoxicity of topical otomicrobial agents. Acta Oto-Laryngologica 1995;115:231-235.

Brown AM, Williams DM, Gaskill SA. The effect of aspirin on cochlear mechanical tuning. J Acoust Soc Am 1993;93:3298-3307.

Brownlee RE, Hulka GF, Prazma J, Pillsbury HC, 3d. Ciprofloxacin. Use as a topical otic preparation. Arch Otolaryngol Head Neck Surg 1992;118:392-396.

Didier A, Miller JM, Nuttall AL. The vascular component of sodium salicylate ototoxicity in the guinea pig. Hear Res 1993;69:199-206.

Dieler R, Shehata-Dieler WE, Brownell WE. Concomitant salicylate-induced alterations of outer hair cell subsurface cisternae and electromotility. J Neurocytol 1991;20:637-653.

Dieler R, Shehata-Dieler WE, Richter CP, Klinke R. Effects of endolymphatic and perilymphatic application of salicylate in the pigeon. II: Fine structure of auditory hair cells. Hear Res 1994;74:85-98.

Duckert LG, Rubel EW. Morphological correlates of functional recovery in the chicken inner ear after gentamycin treatment. J Comp Neurol 1993;331:75-96.

Ernst A, Reuter G, Zimmermann U, Zenner HP. Acute gentamicin ototoxicity in cochlear outer hair cells of the guinea pig. Brain Res 1994;636:153-156.

Fitzgerald JJ, Robertson D, Johnstone BM. Effects of intra-cochlear perfusion of salicylates on cochlear microphonic and other auditory responses in the guinea pig. Hear Res 1993;67:147-156.

Forge A, Li L, Corwin JT, Nevill G. Ultrastructural evidence for hair cell regeneration in the mammalian inner ear. Science 1993;259:1616-1619.

Garetz SL, Altschuler RA, Schacht J. Attenuation of gentamicin ototoxicity by glutathione in the guinea pig in vivo. Hear Res 1994;77:81-87.

Garetz SL, Rhee DJ, Schacht J. Sulfhydryl compounds and antioxidants inhibit cytotoxicity to outer hair cells of a gentamicin metabolite in vitro. Hear Res 1994;77:75-80.

Hawkins JE. Drug Ototoxicity. In: Anonymous Handbook of Sensory Physiology, 1st ed. Berlin: Springer-Verlag, 1976:707-739.

Henley CH. Kanamycin depletes cochlear polyamines in the developing rat. Otolaryngol Head Neck Surg 1994;110:103-109.

Henley CM, Rybak LP. Developmental ototoxicity. Otolaryngologic Clin North Am 1993;26:857-871.

Henley CM, Rybak LP. Ototoxicity in developing mammals. Brain Res 1995;20:68-90.

Hiel H, Erre JP, Aurousseau C, Bouali R, Dulon D, Aran JM. Gentamicin uptake by cochlear hair cells precedes hearing impairment during chronic treatment. Audiology 1993;32:78-87.

Hotz MA, Harris FP, Probst R. Otoacoustic emissions: an approach for monitoring aminoglycoside-induced ototoxicity. Laryngoscope 1994;104:1130-1134.

Hutchin T, Cortopassi G. Proposed molecular and cellular mechanism for aminoglycoside ototoxicity. Antimicrobial Agents & Chemotherapy 1994;38:2517-2520.

Hyde GE, Rubel EW. Mitochondrial role in hair cell survival after injury. Otolaryngol Head Neck Surg 1995;113:530-540.

Jung TT, Miller SK, Rozehnal S, Woo HY, Park YM, Baer W. Effect of round window membrane application of salicylate and indomethacin on hearing and levels of arachidonic acid metabolites in perilymph. Acta Otolaryngol Suppl 1992;493:81-87.

Jung TT, Rhee CK, Lee CS, Park YS, Choi DC. Ototoxicity of salicylate, nonsteroidal antiinflammatory drugs, and quinine. Otolaryngologic Clin North Am 1993;26:791-810.

Matz GJ. Aminoglycoside cochlear ototoxicity. Otolaryngol Clin North Am 1993;26:705-712.

Meiteles LZ, Raphael Y. Scar formation in the vestibular sensory epithelium after aminoglycoside toxicity. Hear Res 1994;79:26-38.

Mukhopadhyay S, Baer S, Blanshard J, Coleman M, Carswell F. Assessment of potential ototoxicity following high-dose nebulized tobramycin in patients with cystic fibrosis. J Antimicrob Chemother 1993;31:429-436.

Pollice PA, Brownell WE. Characterization of the outer hair cell's lateral wall membranes. Hear Res 1993;70:187-196.

Schacht J. Biochemical basis of aminoglycoside ototoxicity. Otolaryngol Clin North Am 1993;26:845-856.

Schuknecht HF. Pathology of the Ear,2nd ed. Philadelphia: Lea & Febiger, 1993.

Shehata-Dieler WE, Richter CP, Dieler R, Klinke R. Effects of endolymphatic and perilymphatic application of salicylate in the pigeon. I: Single fiber activity and cochlear potentials. Hear Res 1994;74:77-84.

Spongr VP, Boettcher FA, Saunders SS, Salvi RJ. Effects of noise and salicylate on hair cell loss in the chinchilla cochlea. Arch Otolaryngol Head Neck Surg 1992;118:157-164.

Tunstall MJ, Gale JE, Ashmore JF. Action of salicylate on membrane capacitance of outer hair cells from the guinea-pig cochlea. J Physiol 1995;485:739-752.

Warchol ME, Lambert PR, Goldstein BJ, Forge A, Corwin JT. Regenerative proliferation in inner ear sensory epithelia from adult guinea pigs and humans. Science 1993;259:1619-1622.

Weisleder P, Rubel EW. Hair cell regeneration after streptomycin toxicity in the avian vestibular epithelium. J Comp Neurol 1993;331:97-110.

Wersall J. Ototoxic antibiotics: a review. Acta Otolaryngol Suppl 1995;519:26-29.

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