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. Ototoxicity Ototoxicity is defined as the tendency of certain therapeutic agents to cause functional impairment and cellular degeneration of the inner ear and of the eighth cranial nerve. Ototoxicity may be reversible or irreversible. Ototoxicity is differentiated from neurotoxicity where the site of action is central to the eighth cranial nerve. The aminoglycosides are a class of broad-spectrum antibiotics capable of producing profound, irreversible sensorineural hearing loss (SNHL). Morphologic studies demonstrate that the inner row of outer hair cells (OHCs) of the basal turn of the cochlea are affected first, followed by the other two rows of OHCs and the inner hair cells. Prospective studies demonstrate an incidence ranging from 4% to 24%. Clinically, patients frequently develop symptoms following the cessation of therapy. SNHL is primarily high frequency and may be unilateral. Risk factors for aminoglycoside ototoxicity include: therapy lasting more than seven days, elevated serum levels, prior exposure to aminoglycosides, noise exposure, high daily dose, and use in neonates. Loop diuretics, including furosemide and ethacrynic acid, are capable of producing SNHL which is frequently reversible. The site of action is thought to be the stria vascularis, with inhibition of potassium chloride co-transport. Risk factors include renal insufficiency, use in neonates, intravenous administration, and co-administration with aminoglycosides. Cis-platinum is a relatively new cytoreductive agent used to treat a variety of malignancies. The mechanism of ototoxic action is uncertain; however, it produces a loss of OHCs in the basal turn of the cochlea in a fashion similar to the aminoglycosides. Morphological changes have not been noted in the vestibular organs. Clinical studies demonstrate an irreversible ototoxicity incidence ranging from 9% to 91%, depending on the criteria used and the cumulative dose. Symptoms are frequently present at the onset of measurable hearing loss. Risk factors for ototoxicity include renal insufficiency, intravenous bolus, co-administration with aminoglycosides, and increased cumulative doses. An audiogram should be obtained at the onset of therapy, before each successive dose, and with the onset of symptoms. Salycilates have been used for more than 100 years and have long been known to produce reversible hearing loss associated with tinnitus. The mechanism of action is thought to involve vasoconstriction of capillaries in the stria vascularis. Symptoms typically resolve within 24 hours following cessation of therapy; however, cases of irreversible SNHL and tinnitus have been reported. Following a single dose in sensitive individuals or, more typically, after a prolonged course, the antimalarial agent quinine can produce the symptom complex of hearing loss, tinnitus, vertigo, nausea, and vomiting (cinchonism). Symptoms resolve following cessation of therapy. However, several cases of irreversible SNHL and tinnitus have been reported. Monitoring for ototoxicity should be individualized to the drug and to the patient. The early symptoms seen with some drugs, such as the salycilates and quinine, obviate the need for formal monitoring. The profound, irreversible effects seen with drugs such as the aminoglycosides and cis-platinum require much more formal monitoring. Case Presentation A 64-year-old man was initially referred to the Otolaryngology service for evaluation prior to initiation of aminoglycoside therapy. He had no prior otologic history, including surgery, noise exposure, or ototoxic drugs. Past medical history was significant for a right total knee replacement seven months prior to consultation. His postoperative course was complicated by wound dehiscence and osteomyelitis. He underwent removal of the hardware and debridement. Cultures grew Serratia marcescens. The Infectious Disease service was consulted and a six-week course of gentamycin was initiated. A baseline audiogram was obtained which demonstrated a mild sensitivity loss on the right with normal sensitivity on the left to 1 kHz, at which point he had a severe sensorineural loss. An audiogram performed eight days later demonstrated no change in sensitivity; however, the PB performance dropped from 95% to 76% on the right, and from 70% to 28% on the left. The patient denied symptoms of hearing loss, tinnitus, or vertigo at that time. However, he noticed progressive difficulty understanding speech during the next several days. On physical examination, the tympanic membranes were clear and there was no evidence of nystagmus. The dose of gentamycin was decreased and serum levels were monitored closely. He completed five weeks of therapy prior to discontinuation due to elevation of his blood urea nitrogen and creatinine. Serial audiograms performed weekly during the course of therapy, as well as those performed during the following five years, have failed to demonstrate any changes in sensitivity or speech understanding. Bibliography Bernard PA. Freedom from ototoxicity in aminoglycoside treated neonates: a mistaken notion. Laryngoscope 1981;91:1985-1994. 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Randomized, controlled trial of the comparative efficacy, auditory toxicity, and nephrotoxicity of tobramycin and netilmicin. Lancet 1983;1:1123-1126. Lerner SA, Matz GH, Hawkins JE Jr. Aminoglycoside ototoxicity. Boston: Little, Brown, 1981. Lerner SA, Seligshon R, Matz GH. Comparative clinical studies of ototoxicity and nephrotoxicity of amikacin and gentamicin. Am J Med 1977;62:919-923. Lim DJ. Effects of noise and ototoxic drugs at the cellular level in the cochlea: a review. Am J Otolaryngol 1986;7:117-119. Marot M, Uziel A, Romand R. Ototoxicity of kanamycin in developing rats: relationship with the onset of auditory function. Hear Res 1990;2:111-113. Meyerhoff WL, Morizono T, Wright CG, Shaddock LC, Shea DA, Sikora MA. Tympanostomy tubes and otic drops. Laryngoscope 1983;93:1022-1027. New HC, Bendush CL. Ototoxicity of tobramycin: a clinical overview. J Inf Dis 1976;134(Suppl):5206-5218. Paloheimo JA, Thalmann R. Influence of "loop" diuretics upon Na-K-ATPase and adenylate cyclase of the stria vascularis. Arch Otorhinolaryngol 1977;217:347-359. Pujol R. Periods of sensitivity to antibiotic treatment. Acta Otolaryngol 1986;249:29-33. Reddel RR, Kefford RF, Grant JM, Coates AS, Fox RM, Tattersall MH. Ototoxicity in patients receiving cis-platin: importance of dose and method of drug administration. Cancer Treat Rep 1982;66:19-23. Rybak LP. Cis-platinum associated hearing loss. J Laryngol Otol 1981;95:745-747. Rybak LP. Drug ototoxicity. Ann Rev Pharmacol Toxicol 1986;26:79-99. Rybak LP. Pathophysiology of furosemide ototoxicity. J Otolaryngol 1982;11:127-133. Rybak LP, Whitworth C, Scott V, Weberg A. Ototoxicity of furosemide drug development. Laryngoscope 1991;101:1167-1174. Schacht J. Molecular mechanisms of drug-induced hearing loss. Hear Res 1986;22:297-304. Silverstein J, Bernstein J, Davies DG. Salicylate ototoxicity: a biochemical and electrophysiological study. Ann Otol Rhinol Laryngol 1967;76:118-128. Smith BM, Myers MG. The penetration of gentamicin and neomycin into perilymph across the round window membrane. Head Neck Surg 1979;87:888-891. Strauss M, Towfighi J, Lord S, Lipton A, Brown HA. Cis-platinum ototoxicity: clinical experience and temporal bone histopathology. Laryngoscope 1983;93:1554-1559. Stupp H, Kupper K, Lagler F et al. Inner ear concentration and ototoxicity of different antibiotics in local and systemic application. Audiology 1973;12:350-363. Tange RA, Dreschler WA, van der Hulst RJAM. The importance of high-tone audiometry in monitoring for ototoxicity. Arch Otorhinolaryngol 1985;242:77-81. Toone EC Jr, Hayden GD, Ellmann HM. Ototoxicity of chloroquine. Arthritis Rheum 1965;8:475-476. Weatherly RA, Owens JJ, Catlin FI, Mahoney DH. Cis-platinum ototoxicity in children. Laryngoscope 1991;101:917-924. Wright CG, Meyerhoff WL. Ototoxicity of otic drops applied to the middle ear in the chinchilla. Am J Otolaryngol 1984;5:166-176. Wright DB, Schaefer SD. Inner ear histopathology in patients treated with cis-platinum. Laryngoscope 1982;92:1408-1413. Grand Rounds Archive | Department Home page BCM Public | BCM Intranet | Privacy Notices | Contact BCM | BCM Site Map | ©2001-2006 Baylor College of Medicine
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