Metronidazole neurotoxicity

Neurotoxicity is a recognised adverse effect of metronidazole, an antimicrobial used in cats and dogs to treat a variety of conditions. By doing this module you will:

  • Be aware of how metronidazole neurotoxicity can present in practice.

  • Understand what is known about the relationship between metronidazole dose and neurotoxicity.

  • Be aware of how to reduce the risk of neurotoxicity developing.

  • Know what you can do if it presents in practice.

Metronidazole is a nitroimidazole antibacterial and antiprotozoal agent. It has a concentration-dependent bactericidal effect against susceptible bacteria. The exact mechanisms of action against bacteria and protozoans are not completely understood. After being taken up by anaerobic organisms, metronidazole is reduced to an unidentified polar compound that is believed responsible for the drug’s antimicrobial activity, which involves disrupting bacterial DNA and nucleic acid synthesis. Metronidazole is also trichomonacidal and amoebicidal and is believed to have an immunomodulatory effect (Plumb 2018; Ramsey 2017). 

Metronidazole is lipophilic and oral bioavailability is high, but there can be interpatient variability in dogs and cats. After absorption, metronidazole is rapidly distributed into most body tissues and fluids, including the central nervous system. It is mainly metabolised in the liver via several pathways. Elimination of unchanged drug and its metabolites occurs via urine and faeces. (Plumb 2018)

Metronidazole is available as tablets, oral suspension, and solution for injection (which is unlicensed in animals). It is also available as tablets in combination with spiramycin (a macrolide antibiotic, to give a broad antibacterial spectrum). (See table 1 for details). Metronidazole is also available as veterinary special formulations in the form of metronidazole benzoate tablets or paste (unlicensed). There is anecdotal evidence that metronidazole benzoate is more palatable for cats than metronidazole base (Trepanier 2009). This may be because metronidazole benzoate has a less bitter taste than metronidazole base due to being less soluble in aqueous solutions (Plumb 2018). The dose of metronidazole base is different from that for the benzoate: 1mg of metronidazole base is equal to 1.6 mg of metronidazole benzoate. For example, if the calculated metronidazole dose is 200 mg (of the base), the corresponding dose using metronidazole benzoate is 320 mg. (Plumb 2018)

In cats and dogs, the uses of metronidazole include:

  • treating giardiasis (Plumb 2018)

  • as perioperative surgical prophylaxis in colorectal surgery (Plumb 2018)

  • treating anaerobic infections (Plumb 2018)

  • treating clostridial enteritis (Plumb 201)

  • treating Helicobacter infection, in combination with other drugs (Plumb 2018)

  • treating chronic diarrhoea with no underlying cause (Hall 2011)

  • managing inflammatory bowel disease (Jergens et al. 2010; Olsen 2005)

  • treating hepatic encephalopathy (to reduce ammonia-producing anaerobes in the gut) (Lidbury et al 2016).

It is also used in cats to treat feline tritrichomoniasis (Payne & Artzer 2009) and in dogs to treat other protozoal infections (Plumb 2018). 

In this module we have not evaluated the efficacy of metronidazole for any of these uses. Authorised brands of metronidazole are not licensed for all these uses (see table 1). 

The licensed dosage for the treatment of giardiasis and anaerobic infections is 50mg/kg daily by mouth in divided doses, for 5–7 days (see table 1 for details). When in combination with spiramycin, a lower dose of metronidazole is used. A variety of dosages have been used for other indications (all unlicensed) (Plumb 2018). 

Long-term treatment with metronidazole (either alone, or as adjunctive therapy) is used in the management of inflammatory bowel disease in cats and dogs (Caylor et al. 2001; Jergens et al. 2010; Trepanier 2009), typically at doses of 15mg/kg to 30mg/kg daily (Trepanier 2009; Jergens et al. 2010).

Table 1. Metronidazole formulations

(References: VMD Product Database; Plumb 2018; Ramsey 2017; Datapharm 2018)

Reported adverse effects of metronidazole include anorexia, nausea, vomiting, diarrhoea, lethargy, weakness, hepatotoxicity, haematuria, neutropenia (Caylor & Cassimatis 2001; Plumb 2018) and neurological signs (see tables 2 and 3). 

In 2016, the Veterinary Medicines Directorate received 13 reports of adverse reactions to metronidazole used in the treatment of protozoal or anaerobic infections. Signs included ataxia, convulsions and neuromuscular disorders (VMD 2018). The true rate of adverse effects is unknown and it is likely that many go unreported. 

Neurological abnormalities described in published case reports of metronidazole neurotoxicity involving six cats include weakness, tetraparesis, ataxia, blindness, disorientation, hyperactivity, vertical nystagmus, decreasing placing reactions and hypermetria/tremors and seizures. An acute onset was reported in all cases (see table 2). One cat was euthanised after 12 days of supportive care (Olson et al. 2005). All other patients recovered completely over several days to 2 weeks after stopping metronidazole and with initial supportive care.

Table 2. Published case reports of neurotoxicity in cats on oral metronidazole

Clinical signs of neurotoxicity described in case reports involving 31 dogs include anorexia and/or intermittent vomiting usually shortly before the acute onset of various, often progressive, neurological signs: depression, disorientation, wide-based stance, truncal ataxia, intention tremors, generalised (vestibular) ataxia, progressive (spastic) tetraparesis, spontaneous and positional bilateral vertical nystagmus and strong responsive mydriasis, (intermittent) head tilt, torticollis, weakness, inability to walk, upper motor neuron paraparesis, extensor rigidity of all limbs, opistothonus and seizures. 

Table 3. Published case reports of neurotoxicity in dogs on oral metronidazole

In dogs, the most common signs on neurological examination are cerebellar and central vestibular dysfunction; in cats, forebrain signs are seen too. This is consistent with the description of degeneration and selective loss of Purkinje cells in dogs that received toxic doses of metronidazole in an experiment (Schärer 1972). The dogs, which were given four to six doses of metronidazole 250mg/kg, exhibited clinical signs within 4–6 days and before developing histological signs in the brain. Clinical signs included muscle spasms of the hind limbs and lumbar muscles, weakness, dorsiflexion of the tail, and opisthotonus. Most dogs died within 1 week of the onset of clinical signs. 

Similar histopathologic changes were noted in clinical cases of metronidazole neurotoxicity in two dogs: one had mild swelling of axon sheaths in the vestibular-cerebellar white matter tracts and the other had bilateral but asymmetric areas of leukomalacia near the radix of the vestibular nerve (Dow et al. 1989). In a cat, multifocal, fairly well-dermarcated foci of necrosis in the brainstem extending from the diencephalon to the medulla oblongata of a cat has been described (Olson et al. 2005). 

The exact mechanism of metronidazole neurotoxicity is unknown. It has been proposed that the drug or its metabolites may interrupt RNA or protein synthesis and lead to axonal swelling and subsequent degeneration (Caylor & Cassimatis 2001; Olson et al. 2005). It is also hypothesised to be related to the affinity of metronidazole for gamma-aminobutyric acid (GABA) receptor sites in the vestibulocerebellum (Evans et al. 2003). 

  • Avoid high doses and prolonged use of moderate to high doses. The published case reports indicate that neurological signs develop after receiving high doses (above 60mg/kg/day) even after treatment for a few days, but that they can they can also develop with lower doses (30–60mg/kg) used for several weeks. According to the summaries of products characteristics (SPCs), treatment with metronidazole at 50mg/kg doses should not be continued for more than 5–7 days.

  • Use metronidazole only when clinically indicated and monitor its effects. When treating a bacterial infection, a culture indicating sensitivity to metronidazole is desirable to justify any off-label use. Longer-term treatment should only be used if there is a recognised clinical need with regular evaluation of clinical efficacy and use of the lowest effective dose. Because susceptibility to metronidazole toxicity seems to vary individually (Hajek et al. 2017), no specific monitoring can be recommended.

  • Take care when calculating the number of tablets per dose. The SPC for Metrobactin (metronidazole) tablets recommends a dose of 50mg/kg daily. However, a guide for dispensing tablets in the SPC gives the number of whole tablets (or portions) according to weight ranges for cats and dogs. For the highest weight in each band, the number of tablets corresponds to a dose of 50mg/kg, but for the lower weights in the ranges, following the guide results in doses of more than 50mg/kg. For some of the body weights, the dose comes out at well above 60mg/kg (the highest being 99mg/kg for a 1.26kg animal). Care is needed in calculating the number of tablets needed to give the appropriate dose. The company that markets Metrobactin (Dechra) has told us it is reviewing the dispensing guide in the SPC.

  • Lower doses in liver dysfunction. If used in animals with liver dysfunction, specialists and formularies recommend reducing to one-third of the usual dose (Trepanier 2013; Plumb 2018). Note that the SPCs of Eradia, Metrobactin and Spizabactin contraindicate the products’ use in hepatic dysfunction.

  • Use of metronidazole is not recommended in animals with a previous history of toxicity, because of the possibility of permanent subclinical damage to the nervous system (Evans et al. 2003).

  • Watch out for interactions. Cimetidine may decrease metronidazole metabolism, so increasing the likelihood of neurotoxicity. In contrast, phenobarbital may increase metronidazole metabolism leading to lower blood concentrations.

Metronidazole should be stopped immediately if toxicity is suspected. Supportive care consisting of intravenous fluid may be needed. Diazepam (a GABA -receptor agonist) was reported to be helpful in a retrospective analysis of 21 cases of metronidazole intoxication (Evans et al. 2003): the mean recovery time for dogs treated with diazepam (a single intravenous bolus of 0.2–0.6mg/kg followed by oral doses of 0.3–0.7mg/kg 8-hourly for 3 days) was 38.8 hours compared with 11.6 days for untreated dogs. Prognosis is generally good if metronidazole is promptly stopped (Saxon 1993; Evans et al. 2003; Hajek et al. 2017). 

Adverse effects of metronidazole should be reported to the Veterinary Medicines Directorate (VMD) and/or the company that markets the product. It is important to mention the species, breed and age of the patient, the indication for treatment, the dose used (mg/kg/day), treatment duration and the adverse effect(s) observed, and also, the name of the medicine, batch number and marketing authorisation number (if known).

Clients should be told that side effects on the nervous system usually only occur with high doses or prolonged use of metronidazole. Nevertheless they should look out for signs of nervous system toxicity, such behaviour changes, staggering, difficulty walking, loss of coordination, head tilt, eye twitching or seizures, and if they develop, to stop the drug and seek urgent veterinary advice.

Neurotoxicity is a recognised adverse effect of metronidazole in dogs and cats. Evidence from published case reports suggest that the risk may be reduced by not exceeding a daily dose of 50mg/kg/day for short-term use (1 week) or 30mg/kg for longer-term use (unlicensed). Clients should be warned about the likely signs of neurotoxicity to watch out for. They should be advised to stop the drug immediately if signs of neurotoxicity develop, and to seek urgent veterinary advice. Treatment of metronidazole toxicity includes supportive care and intravenous fluids; diazepam therapy has been reported to be helpful. Some of the suggested dispensing doses in the summary of product characteristics/data sheet for Metrobactin (a brand of metronidazole) result in potentially toxic doses for some body weights. Care is needed when calculating the dose of metronidazole for prescribing and dispensing.

PODCAST

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References

 

Caylor KB, Cassimatis MK. Metronidazole neurotoxicosis in two cats. J Anim An Hosp Assoc 2001; 37: 258–62. 

Dow SW et al. Central nervous system toxicosis associated with metronidazole treatment of dogs: five cases (1984-1987). JAVMA 1989; 195: 365–8.

Datapharm. Electronic Medicines Compendium (online). [Accessed 3 September 2018].

Ercan MT.  Scintigraphic visualization of acute pancreatitis in cats with 99Tcm-citrate. Nucl Med Comm 1993; 314: 798–804.

Evans J et al. Diazepam as a treatment for metronidazole toxicosis in dogs: a retrospective study of 21 cases. J Vet Intern Med 2003; 17: 304–10. 

Fitch R et al. A warning to clinicans: metronidazole neurotoxicity in a dog. Progr Vet Neurol 1991; 2: 307-

Flieshardt C et al. Hyperacute vestibulocerebellar symptoms occur after several weeks of metronidazole treatment in three dogs. In: Tierarztl Praxis 2009; 37: 194–8.

Hajek I et al. Toxic encephalopathy associated with high-dose metronidazole therapy in a dog: a case report. Vet Med Czech 2017; 62: 105–10. 

Hall EJ. Antibiotic-responsive diarrhea in small animals. Vet Clin Small Anim 2011; 41: 273–286. 

Jergens AE et al. Comparison of oral prednisone and prednisone combined with metronidazole for induction therapy of canine inflammatory bowel disease: a randomized-controlled trial. J Vet Intern Med 2010; 24: 269–77. 

Lidbury JA et al. Hepatic encephalopathy in dogs and cats. J Vet Emerg Crit Care 2016; 26: 471–87.

Olson EJ et al. Putative metronidazole neurotoxicosis in a cat. Vet Pathol 2005; 42: 665–9. 

Payne PA, Artzer M. The biology and control of Giardia spp and Tritrichomonas foetus. Vet Clin Small Anim 2009; 39: 993–1007.

Plumb’s Veterinary Drugs. Metronidazole [online]. [Accessed 2 September 2018].

Ramsey I, ed., 2017 BSAVA Small Animal Formulary 9th Ed. Gloucester BSAVA.

Saxon B. Reversible central nervous system toxicosis associated with metronidazole therapy in three cats. Progr Vet Neurol 1993; 4: 25–7.

Schärer K. [Selective alterations of Purkinje cells in the dog after oral administration of high doses of nitroimidazole derivatives]. Verh Dtsch Ges Pathol 1972;56:407–10.

Trepanier L. Idiopathic inflammatory bowel disease in cats. J Fel Med Surg 2009; 11: 32-8.

Veterinary Medicines Directorate. Product Information Database (online).  [Accessed on 30.8.2018]

Veterinary Medicines Directorate. Veterinary pharmacovigilance in the United Kingdom, Annual review 2016 (online). [Accessed on 30.8.2018].