Current Pharmaceutical Design, 2007, 13, 119-126 119 1381-6128/07 $50.00+.00 © 2007 Bentham Science Publishers Ltd. Aminoglycoside-Induced Ototoxicity Erol Selimoglu * Inonu University, Department of Otorhinolaryngology, Malatya, Turkey Abstract: It has long been known that the major irreversible toxicity of aminoglycosides is ototoxicity. Among them, streptomycin and gentamicin are primarily vestibulotoxic, whereas amikacin, neomycin, dihydrosterptomycin, and ka- namicin are primarily cochleotoxic. Cochlear damage can produce permanent hearing loss, and damage to the vestibular apparatus results in dizziness, ataxia, and/or nystagmus. Aminoglycosides appear to generate free radicals within the inner ear, with subsequent permanent damage to sensory cells and neurons, resulting in permanent hearing loss. Two mutations in the mitochondrial 12S ribosomal RNA gene have been previously reported to predispose carriers to aminoglycoside- induced ototoxicity. As aminoglycosides are indispensable agents both in the treatment of infections and Meniere’s dis- ease, a great effort has been made to develop strategies to prevent aminoglycoside ototoxicity. Anti-free radical agents, such as salicylate, have been shown to attenuate the ototoxic effects of aminoglycosides. In this paper, incidence, predis- position, mechanism, and prevention of aminoglycoside-induced ototoxicity is discussed in the light of literature data. Key Words: Aminoglycosides, ototoxicity. INTRODUCTION Ototoxicity refers to medication-caused auditory and/or vestibular system dysfunction those results in hearing loss or disequilibrium [1]. Aminoglycoside antibiotics are the first ototoxic agents to highlight the problem of drug-induced hearing and vestibular loss [2]. It has long been known that the major irreversible toxicity of aminoglycosides is ototox- icity [3,4]. This finding first came to light shortly after the discovery of streptomycin [3]. Aminoglycosides have vari- able cochleotoxicity and vestibulotoxicity [2]. Among them, streptomycin and gentamicin are primarily vestibulotoxic, whereas amikacin, neomycin, dihydrosterptomycin, and ka- namicin are primarily cochleotoxic [2]. Less is known re- garding netilmicin ototoxicity but its ototoxic potential ap- pears to be low [2]. Cochlear damage can produce permanent hearing loss, and damage to the vestibular apparatus results in dizziness, ataxia, and/or nystagmus [5]. Because it is pos- sible to physiologically compensate for vestibular damage, cochleotoxicity is generally considered to be a far more seri- ous problem [5]. In humans, the ototoxic effect of these drugs is reported as a sensorineural hearing loss, which is permanent because the hair cells in the cochlea do not regen- erate [6]. Although beneficial effects of aminoglycosides in Meniere's disease (MD) made these antibiotics popular again, the relative ototoxicities of the aminoglycosides to the cochlea is important in making a choice between them [7]. In this paper, incidence, predisposition, mechanism, and pre- vention of aminoglycoside-induced ototoxicity is discussed in the light of literature data. *Address correspondence to this author at the Inonu University, Department of Otorhinolaryngology, 44315, Malatya, Turkey; Tel: 00 90 422 3410660- 4601; Fax: 00 90 422 3410128; E-mail: erolselimoglu@hotmail.com INCIDENCE OF AMINOGLYCOSIDE-INDUCED OTOTOXICITY In a nationwide survey of 2235 otolaryngologists, it was reported that 94% of respondents used ototopicals in the presence of post-tympanostomy tube otorrhea, 84% used them in the presence of a draining perforation, and 75% used them with intraoperative packing [8]. Only 3.4% of the re- spondents reported irreversible inner ear damage caused by an ototopical drug [3,8]. In another report, the incidence of topical aminoglycoside toxicity was noted as only 1 in 10,000 [9]. However, in many of these earlier studies, oto- toxicity was considered as hearing loss; vestibular symptoms and other complications were often not taken into account because they were either unrecognized or unreported [3]. Bath et al. [10] reported a large series of 29 patients with true, unmitigated ototoxicity caused by commercially avail- able aminoglycoside-containing drops applied topically to the ear, in which 9 developed ataxia, 7 never returned to work, and 5 were confined to a wheelchair [10]. In the study of Black et al. [11] vestibular and auditory function test re- sults of patients at least 1 year after discontinuation of gen- tamicin were investigated. It was reported that all subjects had vestibular function test results consistent with permanent gentamicin ototoxicity [11]. All complained of disequilib- rium, 32 out of 33 described oscillopsia, and 23 had tinnitus. All 33 subjects had complained of symptoms consistent with ototoxicity within 1 to 3 weeks of initiation of gentamicin therapy; however, gentamicin vestibulotoxicity was not rec- ognized before hospital discharge in 32 of 33 subjects [11]. In a MEDLINE search of the published literature from 1966 to the 2004, a total of 54 cases of gentamicin vestibular toxicity and, in 24 of these patients, cochlear toxicity was also documented [12]. In the same study, 11 cases of co-