Ototoxicity resulting from combined administration of metronidazole and gentamicin

Hypothesis: The hypothesis that metronidazole can augment the ototoxicity of gentamicin was tested. Background: Metronidazole and gentamicin are antibiotics that are used in combination to provide broad- spectrum antimicrobial coverage. It has been observed clinically that an increased ototoxic effect occurs when these agents are used in combination. Methods: Groups of guinea pigs were given various doses of gentamicin alone, various doses of gentamicin in combination with metronidazole, or metronidazole alone. Auditory damage was determined electrophysiologically by measurement of the compound action potential. Hair cell damage was quantified by immunofluorescent microscopy. Results: Electrophysiologic data revealed an augmented ototoxic effect when metronidazole was given with both a moderate and a high dose of gentamicin. Thresholds (dB SPLp) for the compound action potential (N1) for animals receiving a medium dose of gentamicin alone (50 mg/kg) were approximately 20-dB SPLp. This threshold increased to approximate y 50-dB SPLp when metronidazole (35 mg/kg) was administered along with the medium-dose gentamicin. Additionally, animals receiving high-dose gentamicin (75 mg/kg) alone demonstrated increased N1 thresholds from 85 to 95 when metronidazole (35 mg/kg) was added to the gentamicin regimen. This effect was evident histopathologically by increased cochlear hair cell damage. Outer hair cell loss for animals receiving medium-dose gentamicin alone did not differ from that of controls. When metronidazole (35 mg/kg) was combined, however, outer hair cell loss increased to approximately 50%. Conclusions: These data support the clinical observation of augmented ototoxicity in patients receiving combined gentamicin and metronidazole. Caution should be used when administering these two agents together. Clinicians should consider other antibiotic strategies whenever possible.