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Indications and clinical uses

Ronidazole is currently not an FDA-approved drug, but it has been used in cats to treat intestinal protozoal parasites. Studies for treatment of other organisms are not available. For treatment of feline Tritrichomonas foetus intestinal infections, it has been administered orally at a dose of 30 mg/kg twice daily for 2 weeks. However, twice-daily administration is more likely to produce CNS reactions, and pharmacokinetic data indicate that 30 mg/kg once daily may be equally effective. Efficacy for long-term remission has not been established, but temporary resolution of feline T. foetus intestinal infections has been observed.

Ronidazole

Ronidazole is a nitroimidazole antibiotic (similar to metronidazole) and available as a powder-on-feed antibiotic. Ronidazole is not approved for use in cats but has been used off-label to effectively treat tritrichomoniasis in naturally and experimentally infected cats (30 mg/kg orally every 12 hours for 14 days).²⁵ T. foetus reduces nitroimidazoles to their nitroso free radicals. Ronidazole has been reported to have better in vitro and 10-fold higher in vivo activity against T. foetus relative to metronidazole.^25,35,49 Ronidazole resistance is beginning to be reported in T. foetus isolates from cats with diarrhea.²⁶

Side effects include hepatoxicity and neurotoxicity. Neurotoxicity is associated with high doses and has been reported in cats.⁵⁹ The use of ronidazole is recommended only for confirmed cases of T. foetus, and dosing should not exceed 30 mg/kg once daily in cats, especially in cats at risk for neurotoxicity. Ronidazole is not registered for human or veterinary use in the United States; therefore its use in cats requires owner informed consent and client education of the potential human hazards.

Treatment

Ronidazole has been demonstrated to be effective at killing feline isolates of T. foetus in vitro and eradicated T. foetus from experimentally infected cats (on the basis of PCR).³² The recommended dose is 30 mg/kg q24h PO for 14 days. Ronidazole is not registered for human or veterinary use in the United States and is currently banned for use in food-producing animals because of human hazards. Neurotoxicosis may be a common and serious side effect. Therefore, treatment with ronidazole should only be considered in cases of confirmed T. foetus infection where informed consent has been obtained. Follow-up testing by PCR is recommended if diarrhea persists longer than 2 weeks post treatment. Importantly, negative results should be interpreted with caution as PCR cannot prove the absence of infection and prolonged asymptomatic carriage of the organism after antimicrobial therapy may be common.

Ronidazole

Ronidazole is the drug of choice for treatment of Tritrichomonas foetus infections, which are less responsive to metronidazole and tinidazole.^8-10 Resistance to ronidazole has been identified in some isolates of T. foetus and is associated with treatment failure in infected cats.¹¹ Resistance is thought to result from increased oxygen-scavenging capacity by the parasite, whereby oxygen competes effectively with ronidazole and other nitroimidazoles for ferredoxin-bound electrons.

Ronidazole is absorbed rapidly and completely after oral administration to cats. Some compounded formulations may have decreased efficacy as a result of low ronidazole content or differences in drug release at the site of action (the large bowel). A modified-release formulation that is delivered to the colon may have improved efficacy.¹² Decreased appetite, vomiting, and neurologic signs can occur in dogs and cats, especially at doses above 30 mg/kg q12h in cats and at doses as low as 10 mg/kg/d in dogs.¹³ Once daily dosing is probably sufficient because of the long half-life of the drug in cats.¹² Doses of 20 mg/kg or less may not effectively clear infection with T. foetus. Neurologic signs result from γ-aminobutyric acid (GABA) antagonism in the CNS and include ataxia, decreased mentation, agitation, tremors, and hyperesthesia, which occur up to 9 days after the start of treatment and resolve when the drug is discontinued.¹³

Ronidazole

Ronidazole, from the same chemical group as metronidazole, has greater in vitro activity against, and is the preferred treatment for, intestinal infections in cats caused by the organism Tritrichomonas foetus. It has been administered at a dose of 30 mg/kg once or twice daily for 14 days, and studies in cats demonstrate that is one of the few drugs associated with eradication of this organism.²⁴

Although central nervous system reactions are associated with ronidazole treatment in cats, these are usually associated with high doses. Because of the long half-life, it may be possible to administer this drug once daily and avoid adverse effects.

Treatment

A nitroimidazole drug, ronidazole, is the drug of choice for the treatment of T. blagburni in cats.¹⁹ The dosage is 30 mg/kg orally (PO) once a day for 14 consecutive days. In a retrospective study of 104 cats infected with T. blagburni, 64% of cats treated with ronidazole had a good response to treatment, while about 36% of cats had an inadequate response or a relapse shortly after treatment.¹⁶ It is important that the amount of ronidazole be accurately calculated for each cat on the basis of its body weight. There is no evidence that higher doses of ronidazole are more effective, and they could increase the risk of neurotoxicity.²⁰ Clinical signs of neurotoxicity include lethargy, inappetence, ataxia, and seizures. These signs generally resolve upon cessation of drug therapy, but can last for 1 to 2 weeks. The drug must be immediately discontinued if signs of neurotoxicity are observed.

Cats that have persistent diarrhea despite ronidazole administration should be further evaluated for other enteropathogens or a persistent T. blagburni infection. Additional considerations for a suboptimal response to ronidazole therapy include quality control problems at the compounding pharmacy or inadequate dosing of the ronidazole. Consider repeating the treatment regime with an appropriate dose and formulation of ronidazole only if the cat is not exhibiting any signs of neurotoxicity.

Ronidazole is not approved by the United States Food and Drug Administration (FDA) for use in companion animals, and veterinarians are advised to obtain informed consent before using this drug. The drug is obtained from compounding pharmacies and is best compounded into capsules because of the drug’s bitter taste. In light of the poor host specificity of T. blagburni and the intimate association between infected cats and their human companions, the potential for zoonotic transmission should be considered. A single case of human infection with T. blagburni has been documented in the literature to date. In that case, the infection presented as epididymitis and meningoencephalitis following immunosuppression and peripheral blood stem cell transplantation.²¹

Control

Pigeons suffering from hexamitiasis can be treated successfully with ronidazole (100 mg/L) or metronidazole (1 g/L) over 7 days. Dimetridazole (400 mg/L) is equally effective, but pigeons suffering from polyuria may ingest extremely high amounts of the product, resulting in acute toxicity.

In severe cases, it is advisable to use an antimicrobial simultaneously with the 5-nitro-imidazoles to control secondary bacterial invasion of the lesions. Trimethoprim (200 mg/L) or enrofloxacin (100 mg/L) are suited for this purpose.

Treatment and Prognosis

The treatment of choice for T. foetus infections is the nitroimidazole drug ronidazole (Table 80-2). Before ronidazole was discovered as an effective treatment, multiple other treatment regimens had been attempted in cats with T. foetus infections with generally poor responses.^12,25,41 In some cases, temporary improvement was noted with a variety of drugs, but relapse was invariable. Some of the apparent clinical improvement may have been due to secondary effects of drugs on the intestinal bacterial flora, although treatment may also prolong trophozoite shedding.

A number of drugs have also been tested in vitro to determine T. foetus susceptibility patterns.⁴² Ronidazole has been the most effective drug used clinically to date and is currently recommended at a dose of 30 mg/kg PO q24h for 14 days.⁴³ Clinical signs can relapse after administration of ronidazole, but generally resolve again after the treatment regimen is repeated. The pharmacokinetics have been determined for ronidazole in cats.^44,45 Higher doses of ronidazole and twice-daily dose regimens can result in neurologic signs.⁴⁶ This likely relates to the high oral bioavailability and slow elimination of the drug by cats.⁴⁴ To date, all reported cases of ronidazole-related neurotoxicity have been reversible, but irreversible neurotoxicity can occur in some cats. Not all cats treated with high doses of ronidazole develop toxicity. In one study, a dose of 50 mg/kg PO q12h was used in research cats with no reported adverse effects.⁴⁷ Ronidazole is teratogenic and should not be used to treat pregnant or lactating queens or very young kittens. A delayed-release (guar gum) formulation offers promise for targeted delivery of ronidazole to the colon and reduced likelihood of systemic adverse effects in cats.⁴⁵

Some strains of T. foetus are resistant to ronidazole.⁴⁸ Poor compounding can be another reason for failure of treatment in some situations. Ronidazole also has activity against Giardia.⁴⁹ However, to lessen potential for selection of resistant strains, ronidazole should be reserved for use for T. foetus infections, because multiple other drugs are effective for treatment of giardiasis.

Tinidazole, administered at 30 mg/kg for 14 days, suppressed T. foetus shedding to undetectable levels in two of four cats during a 33-week period posttreatment.⁵⁰ However, this drug is currently considered inferior to ronidazole because infection was not eliminated in all cats.

6.6.2 Non-statutory surveillance (GB)

During 1998 a total of 11,863 analyses were carried out in the UK on 1,965 samples. In 11,856 (99.9%) of these samples no residues above the action level were detected (compared with 99.5% in 1997). Of all the samples only three contained residues, and in two samples more than one compound was detected. The sampling plan included samples that are based on popular preparations of meat and animal products.

Nitroimidazoles

Nitroimidazoles are coccidiostat compounds that share a similar chemical structure. Their antibacterial and mutagenic activities derive from the reduction of the 5-nitro group. The reactive metabolites bind to bacterial DNA, thereby inhibiting DNA and protein synthesis in the organisms. The use of nitroimidazoles is prohibited in the EU (Council Regulation 2377/90, Commission Regulation 2205/2001), due to suspected mutagenic and carcinogenic properties. Because the identity of banned residues has to be confirmed unambiguously, MS with high specificity and identification capability is well suited to this kind of analysis.

In 1991, an LC method using UV/VIS detection was developed for multiresidue analysis of dimetridazole, ronidazole, ipronidazole and hydroxylated metabolites of dimetridazole and ronidazole, in poultry eggs, plasma and faeces, with LOQs in the range 5–10 μg per kg (Aerts et al., 1991). An LC–MS method for poultry eggs, muscle and liver was reported a few years later, but only for one member of the nitroimidazole group, dimetridazole (Cannavan and Kennedy, 1997). In that study, the sample extraction was performed with toluene or dicholoromethane, and further sample clean-up was done with silica cartridges. The lowest level at which the method was validated was 5 μg per kg. Sams et al. (1998) described an HPLC method for the detection of dimetridazole, ronidazole and their metabolites in poultry muscle and eggs. The method could be utilised for screening by UV detection or for confirmation with MS. The method was validated at a concentration level of 5 μg per kg. Another LC–MS method for the simultaneous detection of four nitroimidazoles (dimetridazole, hydroxydimetridazole, ronidazole and metronidazole) in poultry muscle was capable of detecting residues at levels below 5 μg per kg and was described by Hurtaud-Pessel et al. (2000). The sample preparation included extraction with phosphate buffer and ethyl acetate, and a final washing step with hexane-carbon tetrachloride and formic acid.

Two immunoassays involving either monoclonal or polyclonal antibodies have been described for the screening of nitroimidazole residues. The monoclonal immunoassay could detect five nitroimidazoles from turkey muscle (Stanker et al., 1993). However, the antibody recognised different nitro- imidazoles with extremely fluctuating efficiency, and, in practice, the assay could be used only for the detection of dimetridazole. In addition, the extraction procedure was tedious, with high solvent consumption. On the other hand, the polyclonal antibody had good cross-reactivity with metronidazole, di- metridazole, ronidazole, ipronidazole and their hydroxy metabolites (Fodey et al., 2003). The IC₅₀ values using standard solutions varied from 1.3 to 73.8 pg per l tested with an ELISA. Huet et al. (2005) reported an ELISA, using the abovementioned polyclonal antibody, for five nitroimidazoles in eggs and chicken muscle. The CCβ values varied from 1 μg per kg to 40 μg per kg, depending on the matrix and compound. Unfortunately, an overnight incubation was included in the assay procedure, which naturally hampered the applicability of the assay.