Ototoxicity
Department of Pediatric Otolaryngology, The Children's Hospital of Philadelphia, Pennsylvania 19104-4399, USA.
OBJECTIVE: To determine the ototoxic effects of five commonly
used topical antimycotic agents-clotrimazole, miconazole, nystatin, tolnaftate,
and gentian violet-in the guinea pig.
DESIGN: 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.
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