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Metronidazole: Uses, toxicity and management of neurologic sequllae
The mechanism of metronidazole neurotoxicity is unknown.
Metronidazole is a synthetic nitroimidazole compound used with increasing frequency in small animal practice. Evans et al in the J Vet Intern Med [17:304-310] recently described its uses, toxicities and treatment of neurologic signs that may occur as an untoward side effect.
It is commonly prescribed in the treatment of inflammatory bowel disease, gastritis associated with helicobacter, giardiasis and empirical treatment of diarhea.
Metronidazole has also been used successfully to alter intestinal flora in dogs with hepatic encephalopathy and exocrine pancreatic insufficiency. Use of this antibacterial has been advocated in the treatment of osteomyelitis and periodontal diseases. The mechanism of action for these effects are a matter of controversy. It is believed that the drug disrupts DNA and nucleic acid synthesis in bacteria. Its antiprotozoal activity is not adequately explained.
Metronidazole has excellent bioavailability with peak serum levels in the canine one hour after oral intake. This rather lipophilic antibiotic is distributed to most body tissues and fluids, including bone, abscesses, the central nervous system (CNS) and seminal fluid. There is extensive metabolism in the liver before renal and fecal excretion. The elimination half-life in the dog varies from three to 13 hours. Adverse effects in dogs and cats include neurologic disorders, lethargy, weakness, neutropenia, hepatotoxicity, hematuria, anorexia, nausea, vomiting and diarrhea. Neurotoxic effects include encephalopathy, cerebellovestibular signs and periopheral neuropathy. Neurotoxicity following prolonged therapy is most often related to cumulative dose and duration of treatment. Most canines who develop neurologic signs secondary to metronidazole administration have received weeks to months of therapy, but toxicity after short-term therapy at relatively low dosages (<60 mg/kg/day) has been reported. In general, higher dosages may produce signs in a shorter time period than moderate to low dosages. Reversible CNS dysfunction may produce signs including ataxia, recumbency, opisthotonus, positional ystagmus, muscle spasms and occassionally seizures. Cerebrospinal fluid analysis may reveal mildly elevated protein levels. In humans, a predominantly sensory polyneuropathy may follow large, cumulative doses. Nerve conduction studies suggest sensory axonal degeneration with low-amplitude or absent sensory potentials and minimal, if any, involvement of motor fibers. Sural nerve biopsies of human patients with sensory polyneuropathy, including teased fiber studies and electron microscopy, demonstrated primary axonal pathology with degeneration of both myelinated and unmyelinated fibers. Ahmeda et al in the journal, Neurology (45, 588) reported that magnetic resonance imaging in a single human case with encephalopathy and ataxia showed reversible T2-weighted hyperintensities in the cerebellum, supatentorial white matter and corpus collosum.
Mechanism of neurotoxicity
The mechanism of metronidazole neurotoxicity is unknown. Suggested mechanisms include inhibition of neuronal protein synthesis by binding to RNA and thiamine antagonism. Neuropathological studies in dogs revealed axonal swelling in vestibulocerebellar pathways and brain stem leukomalacia. It seems that most affected dogs recover within a week or two of drug withdrawal. Evans et al suggest that dogs treated with diazepam had a more rapid resolution of clinical signs than dogs treated with supportive therapy alone. In this study, the authors evaluated potential differences in the recovery time between dogs with metronidazole toxicosis treated with diazepam and a similar group that did not receive diazepam as part of the therapy. Diazepam is believed to facilitate the effects of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) within the vestibular system. Evans et al treated patients with a single IV bolus of diazepam followed by TID oral treatment for three days. Dogs treated with diazepam had an average response time of 13 hours (range 20 minutes to 24 hours) and an average recovery time of 38 hours (range 24-72 hours). Dogs that were not treated with diazepam had an average response time of 4.25 days (range 2-10) and an average recovery time of 11.6 days (range 5-21).
Results of this investigation demonstrated that diazepam tended to speed-up recovery for dogs with metronidazole toxicosis. From the similarities in the plasma half-life of metronidazole and the average response time of the diazepam treated group, the authors speculated that once metronidazole is displaced from the benzodiazepine receptor by diazepam, normal metabolism of the displaced drug then occurs, resulting in the rapid clinical improvement observed. Furthermore, once metronidazole is displaced, the exogenous benzodiazepine not only restores, but also improves, normal benzodiazepine-induced chloride conductance, thereby enhancing an inhibitory effect on excitatory neurons.
Cats have been reported to develop CNS signs as a result of metronidazole intoxication. Fenner described this clinical condition in cats (WR Fenner. Diseases of the Brain, Spinal Cord, and Peripheral Nerves. In the Cat Diseases and Clinical Management, 2nd edition, 1994; 1507-1568). Typical signs include forebrain involvement with ataxia, weakness, disorientation, diminished postural reactions, seizures and apparent blindness. It should be remembered that severe vestibular signs may mimic generalized seizures. Treatment periods with metronidazole ranged from five days to 10 months prior to the onset of signs. Aside from the neurologic examination, the physical examination and laboratory tests were generally normal. Cats may exhibit changes in behavior after receiving diazepam.
Diazepam given to cats for several days may rarely be associated with hepatic failure. It is therefore questionable if diazepam should be employed in cats with metronidazole toxicity. Cats often begin to improve within 48 hours after discontinuation of the metronidazole and initiation of supportive therapy. Metronidazole remains a valuable aid in the therapy of many clinical conditions as long as the clinician remains aware of potential side effects and their management.
Editor's Note : Comments and questions can be directed to Pierre S. Bichsel, DVM or Ronald Lyman, DVM at the Animal Emergency and Referral Center, 3984 S. US Highway 1, Ft. Pierce, FL 34982; (772) 466-0460.