Ototoxicity of common topical antimycotic preparations.
OBJECTIVE
To determine the ototoxic effects of five commonly used topical antimycotic agents-clotrimazole, miconazole, nystatin, tolnaftate, and gentian violet-in the guinea pig.


METHODS
A controlled animal study in which the ototoxicity of commonly used topical antifungal agents was investigated by measurement of hair cell loss.


METHODS
Several readily available topical antimycotic preparations were instilled into the middle ears of female Hartley guinea pigs over a 1-week period. Two weeks after the last instillation, the animals were euthanized. An active control group was treated with neomycin to confirm the adequacy of the treatment in delivering a known ototoxin; an untreated control group defined the normal distribution of hair cells. The temporal bones were removed, and the cochleas were fixed and dissected. The basilar membranes were examined under the scanning electron microscope. A map of hair cell survival was made for each row in segments of each turn.


RESULTS
The untreated control animals had no discernible hair cell loss in the two lower turns. In the apical turn and sometimes the third turn, loss of hair cells was a common finding, this is a known effect of aging in this species. The animals treated with neomycin had damage consistently in the basal turn, sometimes extending into the second turn, as well as the expected hair cell loss in the apical turn. Clotrimazole, miconazole, or tolnaftate did not cause any hair cell loss in the first two turns. Hair cell loss in the third and fourth turns was similar to that of the untreated control group. Likewise, nystatin exhibited no evidence of ototoxicity. Of note, however, the preparation used in this study left a persistent residue in the round window niche. Of the first four animals treated with gentian violet, three developed pronounced behavioral signs of vestibular damage, and three demonstrated extensive middle ear inflammation and extensive new bone growth. Hair cell counts were not attempted because the extreme bone growth interfered with successful perfusion and dissection.


CONCLUSIONS
Extrapolating from guinea pigs to humans requires caution. However, it is likely that guinea pigs are, if anything, more susceptible to topical ototoxins than are humans. The specific antimycotics clotrimazole, miconazole, and tolnaftate appear to be safe. Gentian violet has the potential for severe damage. The persistent residue left by the nystatin preparation is cause for concern and is a reminder that both the active ingredient and vehicle must be considered in evaluation of safety.
Tom
L W
LW
Department of Pediatric Otolaryngology, The Children's Hospital of Philadelphia, Pennsylvania 19104-4399, USA.
D000287:Administration, Topical; D000818:Animals; D000935:Antifungal Agents / Q000633:toxicity*; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects*; D003022:Clotrimazole / Q000633:toxicity; D005260:Female; D005840:Gentian Violet / Q000633:toxicity; D006168:Guinea Pigs; D006198:Hair Cells, Auditory / Q000187:drug effects*; D008825:Miconazole / Q000633:toxicity; D008855:Microscopy, Electron, Scanning; D009355:Neomycin / Q000633:toxicity; D009761:Nystatin / Q000633:toxicity; D014047:Tolnaftate / Q000633:toxicity
D000935:Antifungal Agents; D014047:Tolnaftate; D009761:Nystatin; D008825:Miconazole; D003022:Clotrimazole; D009355:Neomycin; D005840:Gentian Violet