Middle ear instillation of gentamicin and streptomycin in chinchillas: morphologic appraisal of selective ototoxicity.

OBJECTIVE: To determine selective cochlear and vestibular ototoxicity of two aminoglycoside antibiotics (gentamicin and streptomycin) in the chinchilla model. Middle ear application of these agents mirrors the clinical practice of chemical vestibular ablation used in Meniere's disease. BACKGROUND: Middle ear instillation of gentamicin or streptomycin has become a popular form of vestibular ablative treatment for disabling Meniere's disease. The vestibular selectivity of these two drugs applied in this fashion has clinical support but is not fully established in humans. Our understanding in this regard has largely been limited to animal models exposed to systemic infusion of aminoglycosides. METHOD: Ten chinchillas underwent left middle ear instillation of one of three agents using variable dosing schedules: gentamicin (n = 6), streptomycin (n = 2), and saline (n = 2) as control. Animals were sacrificed for temporal bone studies using scanning electron microscopy. Morphologic changes in the cochlear and vestibular neuroepithelia were identified. RESULTS: Widespread cochlear and vestibular neuroepithelial injuries were observed with both gentamicin and streptomycin. Contralateral ototoxicity was variable and not related to the total dose of drug delivered. The effect of these two aminoglycosides on the dark cells of the vestibular system appeared negligible. CONCLUSION: We were unable to confirm the selective damage of vestibular end-organ in the chinchilla by either gentamicin or streptomycin, a phenomenon that is generally perceived to occur in humans. Chinchillas, like other small mammals, may not be an ideal model for the study of human ototoxicity.     

水杨酸钠中耳灌注对庆大霉素耳毒性的防护作用

目的 观察水杨酸钠经中耳局部灌注给药对庆大霉素耳毒性的防护作用。方法 24只健康杂色豚鼠均接受圆窗置管术，然后随机分成3组：Ⅰ组为生理盐水对照组；Ⅱ组为庆大霉素组，腹腔注射庆大霉素，经听泡灌注生理盐水；Ⅲ组为庆大霉素加水杨酸钠组，腹腔注射庆大霉素，经听泡灌注水杨酸钠。观察各组给药前后听性脑干反应阈的变化和给药后4周毛细胞损失情况。结果 听泡置管术后ABR反应阈无明显改变；给药后2周和4周，庆大霉素组ABR反应阈较庆大霉素加水杨酸组显著增高（P〈0．01），对照组ABR反应阈无显著变化。耳蜗铺片、毛细胞计数显示庆大霉素组外毛细胞严重缺失，以底回最明显，庆大霉素加水杨酸钠组外毛细胞损失较庆大霉素组轻（P〈0．05）。对照组无明显外毛细胞缺失。结论 水杨酸钠经中耳局部给药途径可减轻庆大霉素所致听功能损害和毛细胞缺失，可在一定程度上有效预防庆大霉素的耳毒性。     

Relationship between the nephrotoxicity and ototoxicity induced by gentamicin in the guinea pig

Guinea pigs were treated with daily single subcutaneous injections of 60 mg gentamicin per kg for 3 weeks. Renal, cochlear and vestibular functions were monitored before, during and after treatment. The degree and onset of gentamicin oto- and nephrotoxocity differed during the treatment period. Alterations to the kidney functions were observed from the first week while the onset of ototoxicity occurred later, at the third and fourth week for the cochlear and vestibular functions respectively. Moreover, when treatment ended, renal function demonstrated signs of recovery, while auditory and vestibular function continued to worsen. Deficits in cochlear function and structural changes (missing outer hair cells) correlated with gentamicin serum concentrations, while vestibular alterations (loss in nystagmic reactions) did not. No distinct relationship could be established between auditory and vestibular loss and the renal parameters monitored. The results suggest that gentamicin-induced nephro- and oto-toxicity are dissociated phenomena and that cochleotoxicity was dependent on aminoglycoside serum level.     

Comparison of vestibular and cochlear ototoxicity from transtympanic streptomycin administration.

HYPOTHESIS: The relative dose-related cochlear and vestibular ototoxicity produced by transtympanically injected streptomycin (SM) compared to that of gentamicin (GM) was assessed. BACKGROUND: Although SM, the first aminoglycoside used transtympanically, is thought to be selectively vestibulotoxic, it has been replaced by GM in current clinical use. Little experimental data exist that directly demonstrate the relative cochlear and vestibular ototoxicity resulting from transtympanic administration of SM compared to GM. METHODS: Histologic evaluation was performed on inner ears from Mongolian gerbils to study vestibular and cochlear damage. Comparisons were made between animals receiving single (1 x SM) and five daily (5 x SM) injections of SM/Gelfoam-slurry and similarly injected and noninjected controls. These data were compared to results obtained using GM (1 x GM and 5 x GM) reported previously. RESULTS: Two weeks after injection, parallel qualitative and quantitative changes were seen in posterior cristae and cochlear sensory epithelia in the 1 x and 5 x SM injected groups, similar to those resulting from GM injections. Statistically significant decreases in number of hair cells were seen when 5 x SM injected ears were compared to 1 x SM injected ears and control ears. Increased damage was seen with increased dosage of each drug. Whenever damage was observed to the posterior crista sensory cells, damage was also seen in cochlear hair cells. CONCLUSIONS: In this model, SM and GM produced significant cochlear damage when vestibular damage occurred. These results suggest that, in the gerbil, SM and GM are ototoxic but not selectively vestibulotoxic. Increasing the number of transtympanic injections generally increases the damage to sensory hair cells in the posterior crista and the cochlea. A variation in interanimal susceptibility to ototoxic effects exists, but the amount of damage is consistent in cochlear and vestibular hair cells from the same animal. No evidence for selective vestibular ototoxicity from transtympanic SM was found.     

Unbiased quantification of Scarpa's ganglion neurons in aminoglycoside ototoxicity

While most studies have demonstrated damage to the cochlear and vestibular endorgan as the primary site of aminoglycoside toxicity, the effect on the primary afferent neurons of the vestibular ganglion remains to be determined. This study used the unbiased stereology-optical fractionator method to obtain estimates of the vestibular ganglion neuronal number. Archival temporal bone specimens from seven subjects with a history of gentamicin (n=3) and streptomycin (n=4) aminoglycoside ototoxicity were used. The post-ototoxicity survival time ranged from two months to 8 years, with an average of 2.2 years. Seven archival human temporal bone specimens from age-matched subjects with no history of audiovestibular symptoms or ototoxicity served as controls. Group means were compared using unpaired, two-tailed student's t test. The average vestibular ganglion neuronal number in the aminoglycoside ototoxicity group was 20, 733 neurons (CV=0.073), which was significantly lower (p<0.005) than the average number in the age-matched control group of 24, 902 neurons (CV=0.109). These findings may be consistent with either retrograde degeneration or a direct neurotoxic effect of the aminoglycosides on the vestibular ganglion neuron.     

Protective effects of alpha-tocopherol against gentamicin-induced Oto-vestibulo toxicity: an experimental study

OBJECTIVE: Free radicals are involved in gentamicin ototoxicity and vestibular dysfunction and it has been demonstrated that free radical scavengers, such as alpha-tocopherol, are able to inactive free radicals, attenuating tissue damage This study was designed to investigate the possible protective effects of alpha-tocopherol against gentamicin-induced oto-vestibulo toxicity. MATERIAL AND METHODS: Adult albino guinea pigs were divided into four groups and were treated for 2 weeks as follows: Group A, controls; Group B, gentamicin plus corn oil; Group C, gentamicin only; and Group D, gentamicin plus alpha-tocopherol. To evaluate vestibular function, the animals underwent sinusoidal oscillations in the dark about their vertical and longitudinal axes to evoke horizontal and vertical vestibulo-ocular reflexes (VORs), respectively. Electrocochleographic recordings were performed using an implanted round window electrode. The compound action potentials (CAPs) at 2, 4, 8 and 16 kHz were measured every 5 days Morphological changes were analysed by means of scanning electron microscopy. RESULTS: Gentamicin induced a consistent reduction in VOR responses and a progressive high-frequency hearing loss of 50-60 dB sound pressure level. Alpha-Tocopherol co-therapy slowed the progression of hearing loss and significantly attenuated the final threshold shifts The impairment of vestibular function was reduced, as evidenced by an increased VOR gain. The massive loss of outer hair cells in the cochlear basal turn and of cristae ampullaris stereocilia in gentamicin-treated animals was not observed in the cochlea of animals protected with alpha-tocopherol. CONCLUSION: This study supports the hypothesis that alpha-tocopherol interferes with gentamicin-induced free radical formation, and suggests that this drug may be useful in preventing aminoglycoside oto-vestibulo toxicity.     

甲磺酸去铁胺抗庆大霉素耳毒性作用及机理研究

目的探讨铁螯合剂甲磺酸去铁胺（ｄｅｆｅｒｏｘａｍｉｎｅｍｅｓｙｌａｔｅ,ＤＦＯ）对抗庆大霉素（ｇｅｎｔａｍｉｃｉｎ,ＧＭ）耳毒性作用及其机理。方法豚鼠随机分为ＧＭ组（１７只）、ＤＦＯ组（８只）、ＧＭ＋ＤＦＯ组（１７只）及对照组（８只）,采用听性脑干反应（ａｃｏｕｓｔｉｃｂｒａｉｎｓｔｅｍｒｅｓｐｏｎｓｅ,ＡＢＲ）、耳蜗铺片及透射电镜技术,观察用药前后听反应阈及形态学变化,检测血清尿素氮、肌苷以及ＧＭ浓度,同时测定耳蜗和肾皮质组织中丙二醛、超氧化物歧化酶和铁离子含量。结果ＧＭ组８ｋＨｚＡＢＲ阈移为４０～６０ｄＢ;ＧＭ＋ＤＦＯ组阈移为１５～２５ｄＢ,差异有显著性（Ｐ＜０．０５）。形态学改变与听力变化一致。ＤＦＯ对ＧＭ血药浓度没有影响。ＧＭ组肾功明显损伤,但肾皮质丙二醛、超氧化物歧化酶和铁离子变化差异无显著性（Ｐ＞０．０５）,ＧＭ＋ＤＦＯ组耳蜗组织丙二醛和铁离子含量较ＧＭ组明显减少（Ｐ＜０．０５）,超氧化物歧化酶含量明显高于ＧＭ组（Ｐ＜０．０５）。结论自由基和铁离子在ＧＭ的耳毒性中起重要作用,ＤＦＯ能有效减轻ＧＭ的耳毒性作用,可能成为有希望的预防药物。     

Combined administration of kanamycin and furosemide does not result in loss of vestibular function in Guinea pigs

Aminoglycoside antibiotics are known to damage the vestibular and auditory sensory epithelia. Although loop diuretics enhance the cochleotoxic effect of aminoglycosides, it is not known whether concomitant administration of an aminoglycoside and a loop diuretic affects the vestibular system. The aim of our study was to investigate the effect of co-administration of kanamycin and furosemide upon the otolith organs and to compare it to the known vestibulotoxic effect of gentamicin. Five guinea pigs were injected with a single dose of both kanamycin (400 mg/kg, s.c.) and furosemide (100 mg/kg, i.v.), 5 animals received gentamicin (100 mg/kg, i.p.) for 10 days, and 5 untreated animals served as controls. After 7 days, vestibular function was assessed by measuring vestibular short-latency evoked potentials (VsEPs) to linear acceleration stimuli and cochlear function by auditory brainstem responses (ABRs) to clicks. Hair cell densities were determined in phalloidin-stained whole mounts of the utricles and saccules, and in midmodiolar sections of resin-embedded cochleae. Co-administration of kanamycin and furosemide had no significant effect on VsEPs and hair cell densities in the utricles and saccules were not reduced. ABR thresholds were increased to a great extent (by ～60 dB), and histologically a severe loss of cochlear hair cells was observed. The effect of gentamicin, both on vestibular and cochlear function, was just the opposite. VsEP thresholds to horizontal stimulation were elevated and suprathreshold amplitudes showed a decrease, whereas cochlear function was not reduced. With this protocol, we have a tool to selectively induce cochlear or vestibular damage, which may be of interest to researchers and clinicians alike.     

Evaluation of inner hair cell and nerve fiber loss as sufficient pathologies underlying auditory neuropathy

Auditory neuropathy is a hearing disorder characterized by normal function of outer hair cells, evidenced by intact cochlear microphonic (CM) potentials and otoacoustic emissions (OAEs), with absent or severely dys-synchronized auditory brainstem responses (ABRs). To determine if selective lesions of inner hair cells (IHCs) and auditory nerve fibers (ANFs) can account for these primary clinical features of auditory neuropathy, we measured physiological responses from chinchillas with large lesions of ANFs (about 85%) and IHCs (45% loss in the apical half of the cochlea; 73% in the basal half). Distortion product OAEs and CM potentials were significantly enhanced, whereas summating potentials and compound action potentials (CAPs) were significantly reduced. CAP threshold was elevated by 7.5 dB, but response synchrony was well preserved down to threshold levels of stimulation. Similarly, ABR threshold was elevated by 5.6 dB, but all waves were present and well synchronized down to threshold levels in all animals. Thus, large lesions of IHCs and ANFs reduced response amplitudes but did not abolish or severely dys-synchronize CAPs or ABRs. Pathologies other than or in addition to ANF and IHC loss are likely to account for the evoked potential dys-synchrony that is a clinical hallmark of auditory neuropathy in humans.     

Time course of apoptotic cell death in guinea pig cochlea following intratympanic gentamicin application

CONCLUSIONS: The present study showed that the molecular signal that promotes the death of cochlear hair cells (HCs) induced by intratympanic gentamicin application is significant before the manifestation of morphological and functional changes. OBJECTIVES: The effect of agents that protect the HCs from aminoglycoside ototoxicity is influenced by the timing of their administration. However, morphological, functional and molecular changes in the cochlea in the early stage following aminoglycoside application have rarely been studied. Therefore, we examined the chronological changes in the cochlea following intratympanic gentamicin application. MATERIALS AND METHODS: Small pieces of gelatin sponge soaked with gentamicin (40 mg/ml) were placed on the round window membrane of mature guinea pigs, and the tympanic bulla was filled with gentamicin solution. They were euthanized at 6, 12, 18, 24, and 48 h following gentamicin application. Auditory brainstem responses (ABRs) were measured before gentamicin application and immediately before euthanasia, and the extent of missing and TUNEL-positive HCs was evaluated. RESULTS: ABR thresholds significantly increased 18 h or later following gentamicin application, and the loss of HCs was seen at 24 and 48 h. While functional and morphological changes were not evident until 18 h after gentamicin application, substantial amounts of TUNEL-positive HCs appeared at 12 h.     

Uptake of amikacin by hair cells of the guinea pig cochlea and vestibule and ototoxicity: Comparison with gentamicin

The distribution of amikacin (AK), an exclusive cochleo-toxic aminoglycosidic antibiotic (AA), and of gentamicin (GM), which is both cochleo- and vestibulo-toxic, has been studied in cochlear and vestibular hair cells. Guinea pigs were treated during six days with one daily injection of AK (450 mg/kg/day) or GM (60 mg/kg/day). AAs were detected, using immunocytochemical technique with scanning laser confocal microscopy, in isolated cells from guinea pigs sacrificed from 2 to 30 days after the end of the treatments. Results demonstrate a rapid uptake (as soon as after 2-day treatment) of both AAs by cochlear and vestibular hair cells and a very slow clearance. Particularly GM and AK are detected in type I and type II hair cells of the utricles and cristae ampullaris. The presence of these two molecules with different toxic potentialities towards cochlear and vestibular hair cells indicates that the selective ototoxicity of aminoglycosides cannot be explained simply on the basis of particular uptake and accumulation in the different sensory hair cells.     

alpha-Tocopherol protective effects on gentamicin ototoxicity: an experimental study

Gentamicin, acting as an iron chelator, activates membrane lipid peroxidation (MPL) and induces free radical formation, as observed in vitro and in vivo. Antioxidants, such as alpha-tocopherol, are able to suppress MLP, thus attenuating tissue damage. The present study was designed to investigate the possible protective effects of alpha-tocopherol on gentamicin ototoxicity. The study was carried out on albino guinea pigs (250-350 g). The animals were divided into four groups: group A (n = 4), injected with corn oil daily at a dose of 100 mg/kg body weight intramuscularly (IM); group B (n = 10), treated with corn oil at a dose of 100 mg/kg body weight and gentamicin base at a dose of 100 mg/kg body weight (IM); group C (n = 10). treated with gentamicin alone at a dose of 100 mg/kg body weight (IM); and group D (n = 10), treated with gentamicin at the same dose plus alpha-tocopherol acetate at dose of 100 mg/kg body weight (IM). Electrocochleographic recordings were made from an implanted round-window electrode. All animals were treated for 14 days. The compound action potentials (CAPs) were measured at 2-16 kHz at days 0, 10, 14 and 18 after treatment. Changes in cochlear function were characterized as CAP threshold shifts. Morphological changes were analysed by scanning electron microscopy. Gentamicin induced progressive high-frequency hearing loss of 50-60 dB SPL. alpha-Tocopherol co-therapy slowed the progression of hearing loss. The significant loss of outer hair cells (OHCs) in the cochlear basal turn in gentamicin-treated animals was not observed in the cochleas of animals protected with alpha-tocopherol. This study supports the hypothesis that alpha-tocopherol interferes with gentamicin-induced free radical formation, and suggests that this drug may be useful in protecting OHC function from aminoglycoside ototoxicity, thus reducing hearing loss.     

Assessment of vestibular ototoxicity of ear drops by recording of vestibular evoked potentials to acceleration impulses

INTRODUCTION: The cochlear ototoxicity of several ear drops is well documented in the literature, but very few studies exist on the vestibular ototoxicity of these topical drugs. GOAL OF STUDY: To develop an animal model for the assessment of the vestibular ototoxicity of ear drops. MATERIALS AND METHODS: Two animal groups, consisting of five fat sand rats (FSRs) each, underwent unilateral labyrinthectomy. Normal saline was topically applied into the middle ear cavity of rats in the first group for 7 days (control group). Rats in the second group were treated in the same way by topical gentamicin solution. Cochlear function was assessed by the recording of auditory evoked potential (ABPs) thresholds, and vestibular function was assessed by the recording of vestibular evoked potentials (VsEPs) to angular accelerations. RESULTS: In the control group, except for the amplitude of the first wave, there was no significant difference in the VsEPs recorded before and after topical application. In the gentamicin group, VsEPs could not be recorded after 7 days, and ABPs were recorded in one case only, with a threshold of 100 dB sound pressure level (SPL). CONCLUSION: VsEPs seem to be a reliable measure for evaluating the vestibular ototoxicity of topical ear drops.     

白藜芦醇拮抗庆大霉素耳毒性的实验研究

目的观察白黎芦醇（resveratrol,Res）对抗庆大霉素耳毒性的作用.方法将豚鼠随机分为庆大霉素（gentamicin, GM）组、白藜芦醇剂量I＋GM组 （ResI ）、白黎芦醇剂量II＋GM组（ResII）、白黎芦醇剂量III＋GM组（ResIII）及对照组.采用听性脑干反应（ABR）、耳蜗铺片及透射电镜技术,观察用药前后各组动物听阈及耳蜗毛细胞形态学改变,并检测血清丙二醛、超氧化物岐化酶含量、肾功能以及庆大霉素血药浓度.结果 ResIII组血液中丙二醛较GM组明显减少（P〈0.05）,GM＋Res各组超氧化物歧化酶活性均明显高于GM组（P〈0.05）,同时GM组1、8 kHz ABR 4 周平均阈移与ResIII剂量组间差异显著（P〈0.05）.形态学改变与听力变化一致.Res对庆大霉素血药浓度没有影响.结论大剂量Res能有效减轻GM的耳毒性作用,且不影响庆大霉素的抗菌作用.     

Comparative study of the influence of aminoglycoside antibiotics on the activity of the horizontal semicircular canal in the frog.

This work is an electrophysiological study made in the frog. The technique allows one to test and to compare the actions of a number of aminoglycoside antibiotics, directly introduced into the labyrinthic cavity, on the spontaneous activity of a vestibular receptor--the horizontal semicircular canal. The effects of aminoglycoside solutions have been compared with those of physiological solutions (NaCl 7 g/l, Ringer) and of penicillin (not ototoxic). The results obtained show: (1) After the introduction of a physiological solution the activity disappears only very briefly (electrical artefact, probably); after a few minutes the activity returns to its initial value. A similar phenomenon is obtained with penicillin. (2) When used at a dose of 10 microgram, all the aminoglycosides studied generally induced an important and lasting decrease in semicircular canal activity. (3) These aminoglycosides have been classified according to their vestibular local toxicity. Their descending order of influence is as follows: streptomycin, dihydrostreptomycin, amikacin (BBK 8), neomycin, sisomycin, gentamicin and lividomycin, tobramycin, kanendomycin. (4) A parallel can be drawn between local vestibular toxicity and clinical ototoxicity. The role and importance of the hemolabyrinthic barrier are noted and the notion of ototoxicity is discussed.     

庆大霉素慢性耳中毒对听觉和传出神经功能的影响

目的：探讨庆大霉素慢性耳中毒对听觉和传出神经功能的影响。方法：在庆大霉素应用前后通过观察对侧噪声（ＣＬＮ）对听神经复合动作电位（ＣＡＰ）的影响确定内侧橄榄耳蜗（ＭＯＣ）系统功能,通过测试在４,６,８,１０和１２ｋＨｚ的ＣＡＰ反应阈确定听功能。结果：注射庆大霉素后３周和１１周。ＣＬＮ对ＣＡＰ的抑制效应呈进行性、不可逆性消除,且以１１周最明显,ＣＡＰ反应阈分别上升１０和２５ｄＢ,与耳蜗传出神经和毛细胞     

甲磺酸去铁胺对抗庆大霉素耳毒性的实验研究

目的观察铁螯合剂———甲磺酸去铁胺（ｄｅｆｅｒｏｘａｍｉｎｅｍｅｓｙｌａｔｅ,ＤＦＯ）对抗庆大霉素（ｇｅｎｔａｍｉｃｉｎ,ＧＭ）耳毒性的作用。方法将豚鼠随机分为ＧＭ组、ＤＦＯ组、ＧＭ＋ＤＦＯ组及对照组,采用听性脑干反应（ＡＢＲ）、耳蜗铺片及透射电镜技术,观察用药前后听阈及形态学改变,并检测ＤＦＯ对庆大霉素血药浓度的影响。结果ＧＭ组８ｋＨｚＡＢＲ阈值逐渐升高４０～６０ｄＢ;ＧＭ＋ＤＦＯ组阈移为１５～２５ｄＢ,差异显著（Ｐ＜０．０５）。高频听阈损伤明显比低频更重（Ｐ＜０．０１）。形态学变化与听力变化平行。ＤＦＯ对庆大霉素血药浓度没有影响。结论证实ＤＦＯ能有效减轻ＧＭ的耳毒性作用,ＤＦＯ可能成为预防庆大霉素耳毒性的有效药物。     

Vestibular destruction by slow infusion of gentamicin into semicircular canals

Intratympanic or round window application of gentamicin is often used to alleviate disabling vertigo arising from unilateral Meniere's disease; however, treatment is often accompanied by hearing loss because the drug initially enters the cochlea before diffusing to the vestibular system. In order to enhance vestibular damage and reduce the risk of hearing loss, gentamicin was infused directly into the vestibular system. An osmotic pump containing 50, 100, 200 or 400 microg/ml of gentamicin was infused into the superior semicircular canal of the chinchilla for 7 days. Afterwards, vestibular damage was evaluated by measuring the decline in hair cell density in the utricle, saccule and superior semicircular canals. Auditory damage was assessed with distortion product otoacoustic emissions (DPOAE) and outer hair cell (OHC) and inner hair cell (IHC) loss. Infusion with the two lowest gentamicin concentrations resulted in significant hair cell loss and reduced duration of the nystagmus response, but had little or no effect on OHC or DPOAE. Higher doses of gentamicin damaged cochlear hair cells and reduced the DPOAE. In conclusion, slow infusion of a low dose of gentamicin into the semicircular canals mainly damages the vestibular hair cells and inactivates the nystagmus response without damaging cochlear hair cells or DPOAE.     

Inner ear histopathology in patients treated with Cis-Platinum.

Temporal bone histopathology was studied in five patients (aged 51–67) who received cis-diamminedichloroplatinum (DDP) chemotherapy for head and neck squamous cell carcinoma. In each case, a sensorineural hearing loss occurred during the course of treatment and temporal bones were acquired 3–5 hours postmortem for anatomical study. Scanning electron microscopy revealed acute degenerative changes in cochlear hair cells that appeared to be the result of drug treatment. However, the presence of age-related degeneration made it difficult to unequivocally identify hair cell loss due solely to ototoxicity. In one patient, a decrement in vestibular function was observed during DDP treatment. Postmortem examination showed severe degeneration of the maculae and cristae which could be correlated with the absence of caloric response seen after chemotherapy.     

Ototoxicity of Topical Gentamicin Preparations

Objective: To document that commercially available topical gentamicin-containing eardrops carry a risk of ototoxicity if they reach the middle ear through a tympanic membrane defect. Study Design: Clinical study, retrospective case-note review. Setting: Department of Otolaryngology, The Toronto Hospital, University of Toronto. Patients: Sixteen patients were identified with well-documented histories, physical findings and laboratory investigations consistent with topical gentamicin-induced ototoxicity. One patient with incapacitating unilateral Meniere's disease underwent successful intentional vestibular ablation using topical gentamicin/steroid drops. Results: In all cases of inadvertent ototoxicity, patients had used the drops for longer than 7 days (average 20.7 d) prior to symptoms developing. All patients developed vestibulotoxicity that was confirmed on ENG testing. Only 1 patient had a noticeable worsening of cochlear reserve. Deliberate and successful therapeutic ablation of vestibular function in a patient with unilateral Meniere's disease confirms the vestibulotoxic nature of commercially available topical gentamicin preparations. Conclusions: Physicians should consider the potential for ototoxicity if gentamicin-containing eardrops (and by extrapolation all topical aminoglycoside drops) are used for longer than 7 days in patients with a tympanic membrane defect. These preparations should not be used in the presence of healthy middle ear mucosa and should be discontinued shortly after the discharge has stopped. It is important to recognize that toxicity is primarily vestibular rather than cochlear.