Metronidazole toxicosis

Metronidazole is a bactericidal antibiotic, antiprotozoal, and amebicide commonly used in both human and veterinary medicine to treat anaerobic infections, giardiasis, and protozoal organisms. It also has effects on cell-mediated immunity and is used in the treatment of inflammatory bowel disease. Metronidazole is a very safe medication with few side effects, but toxicity is well-recognized in human medicine and companion animals. Acute signs of toxicosis occur most often at doses greater than 60 mg/kg/day, but toxicity has been reported with chronic administration as low as 26 mg/kg/day.

The mechanism of toxicity is uncertain. It has been hypothesized that metronidazole binds to benzodiazepine receptor sites on GABA channels of cerebellar and central vestibular inhibitory interneurons. Reduced inhibition from these interneurons leads to hyperexcitability of the cerebellum and central vestibular nuclei and, thus, clinical signs of cerebellar or central vestibular dysfunction. This theory is supported by the recent finding that administration of a benzodiazepine (diazepam) shortens the duration of clinical signs related to metronidazole toxicity.

Signalment

Metronidazole toxicosis occurs in all ages and breeds of dogs and cats.

Neurologic exam

The onset of clinical signs appears to be dose-dependent. Acute onset of signs after starting metronidazole is more common with higher doses ( > 60mg/kg/day), while delayed onset occurs at lower doses ( > 30 mg/kg/day). Metronidazole intoxication in dogs most commonly causes vomiting, vestibular ataxia, and vertical nystagmus suggestive of central vestibular dysfunction. Clinical signs are usually symmetrical so head tilt is uncommon. Cats with metronidazole toxicity are more likely to develop forebrain signs of seizures, altered mental status, behavior change, and visual deficits.

Diagnosis

A presumptive diagnosis of metronidazole toxicity can be made with compatible clinical signs in a patient receiving a dose higher than 30 mg/kg/day. Serum metronidazole level can be determined but is usually unnecessary.

Treatment

Simply stopping the metronidazole eventually leads to resolution of clinical signs, but it might take 1-2 weeks for the signs to resolve. Treatment with diazepam has been shown to greatly reduce the duration of clinical signs from an average of 14 days with discontinuation of metronidazole alone to three days with administration of diazepam. The recommended dose of diazepam is 0.5mg/kg IV once followed by 0.5 mg/kg PO q8hr until resolution of clinical signs.

Prognosis

The prognosis for full recovery is very good.

Metronidazole dosing recommendation

Many veterinary formularies still list metronidazole doses up to 90 mg/kg/day. Since intoxication has been reported as low as 26 mg/kg/day, the dose of metronidazole should be kept below 30mg/kg/day unless necessary. Most conditions for which metronidazole is used do not require a dose higher than this.
 

Last updated: January 1, 2021