Ronidazole

Overview

Ronidazole is a nitroimidazole antibiotic and antiparasitic drug primarily used in cats for the treatment of Tritrichomonas foetus infections.  Ronidazole is considered the treatment of choice for Tritrichomonas foetus infection in cats. It has also been described as an alternative treatment for giardiasis in cats and dogs; however, its use and dosage in dogs are not well established.

The drug is not commercially available in the United States and must be compounded from bulk powder. Compounded gelatin capsules are generally preferred, as ronidazole is very bitter and flavored liquid formulations may be less acceptable.

Mechanism of Action (MOA): Ronidazole is converted by hydrogenosomes within trichomonads into polar autotoxic anion radicals. These reactive metabolites damage microbial DNA and cell organelles, an action that is specific for anaerobic bacteria and protozoa. Ronidazole appears to have greater activity against T. foetus than metronidazole, although resistance has been documented.

Indications

Ronidazole is used primarily for confirmed Tritrichomonas foetus infection in cats. Potentially useful as an alternative treatment for giardiasis. 

• Tritrichomonas foetus infection (cats): Considered the treatment of choice for confirmed T. foetus infections and may result in resolution of diarrhea in affected cats.
• Giardiasis (dogs and cats): Ronidazole has also been described as an alternative treatment for giardiasis in cats and dogs. although its use and dosage in dogs are not well established.

Dosage (Reference)

Dog

In dogs, ronidazole has been used as an extra-label treatment for giardiasis in a kennel study; other references list no canine indication and no canine dose. In the reported study, drug therapy was combined with hygiene control measures and environmental disinfection.

Cat

In cats, Ronidazole is used as an extra-label treatment for confirmed Tritrichomonas foetus infections.

Warnings & Precautions

Ronidazole should be used carefully because of its potential neurotoxic effects and safety concerns associated with nitroimidazole compounds.

• Hypersensitivity: Contraindicated in patients with known hypersensitivity to ronidazole or other 5-nitroimidazole drugs (e.g., metronidazole).
• Neurotoxicity: Reversible neurologic adverse effects may occur during treatment and have been reported even at lower dosages, although the risk appears greater at higher doses.
• Human exposure: Potentially carcinogenic. People who are or may become pregnant should not handle this drug; wear impervious gloves when handling and pilling and wash hands carefully afterwards. Do not open or crush the capsules – give them whole. Compounding should be carried out in a biological safety cabinet.
• Pregnancy and nursing: Safety during pregnancy and lactation has not been established. Use during pregnancy should be avoided; if treatment is considered essential, it should be given only when the potential maternal benefit outweighs the potential risk to the offspring.
• Food animals: Prohibited for use in food-producing animals.
• Carcinogenicity evidence: Laboratory findings: benign mammary tumors in rats and benign and malignant pulmonary tumors in mice at dosages of 20 mg/kg/day and above, and the compound is embryotoxic and potentially teratogenic.
• Nursing queens: It is not known whether ronidazole passes into milk; use a milk replacer if a nursing queen must be treated.
• Handling a treated animal: Once treatment has started, wear disposable gloves when cleaning the litter box, double-bag the feces and throw them in the trash rather than flushing them.

Drug Interactions

Reported interactions with ronidazole are based on information from metronidazole, a closely related nitroimidazole compound; they have been reported in humans or are theoretical, and may be of significance in veterinary patients. Additional monitoring is recommended when these drugs are used concurrently.

• Alcohol: May induce a disulfiram-like reaction characterized by nausea, vomiting, and abdominal cramps.
• Cimetidine: May decrease the metabolism of ronidazole and increase the risk of dose-related adverse effects.
• Ketoconazole: May decrease the metabolism of ronidazole and increase the risk of dose-related adverse effects.
• Ciclosporin and tacrolimus: Ronidazole may increase serum concentrations of ciclosporin or tacrolimus.
• Fluorouracil: Ronidazole may increase serum concentrations of fluorouracil and the risk of toxicity.
• Lithium: Ronidazole may increase lithium serum concentrations and the risk of lithium toxicity.
• Oxytetracycline: May antagonize the therapeutic effect of ronidazole.
• Phenobarbital, rifampin and phenytoin: May increase the metabolism of ronidazole and reduce its blood concentrations and efficacy.
• Warfarin and other coumarin anticoagulants: Ronidazole may prolong INR and prothrombin time in patients receiving coumarin anticoagulants such as warfarin; avoid concurrent use where possible and intensify monitoring if it cannot be avoided.

Side Effects & Overdose

Side Effects

Adverse effects of ronidazole are primarily neurologic and gastrointestinal. Most reported neurologic effects are reversible following drug discontinuation.

• Neurotoxicity: Reversible neurologic toxicity may occur during treatment.
• Tremors: May be an early sign of neurologic toxicity.
• Lethargy: Reported in affected patients.
• Anorexia: May occur as either a neurologic or gastrointestinal adverse effect.
• Ataxia: Loss of coordination may develop during treatment.
• Nystagmus: Abnormal eye movements have been reported.
• Seizures: May occur in patients experiencing neurotoxicity.
• Behavioral changes: Agitation and other behavior changes have been reported.
• Vomiting: Gastrointestinal upset may occur during therapy.
• Onset and resolution: In reported T. foetus-infected cats receiving at least 30 mg/kg PO q12h, neurologic signs occurred no earlier than three days after treatment began and resolved within one to four weeks after ronidazole was discontinued.
• Owner-reported signs: Fever and muscle twitching or weakness have also been reported in cats; owners should be told to contact the practice immediately if any of these signs appear.
• Long-term canine exposure: In dogs given 30 mg/kg per day for two years, with 40 mg/kg/day during the first month, some testicular toxicity was reported, although no tumors developed.
• Stopping treatment: Discontinue ronidazole if neurologic signs develop during treatment; treat supportively and, if necessary, consider a benzodiazepine such as diazepam.

Overdose

Specific overdose information is limited. Excessive exposure may increase the likelihood of neurologic toxicity.

• Neurotoxicity: Overdose may result in neurologic adverse effects similar to those seen during routine treatment.
• Supportive care: Provide appropriate supportive treatment until clinical signs resolve.
• Diazepam: May be considered in patients with neurotoxicity to competitively inhibit GABA receptors in the CNS.
• Toxic dose in dogs: In dogs, neurotoxicity has been reported at doses of 50 to 200 mg/kg, with seizures, tremors and ataxia.
• Poison control: Consult a 24-hour poison control service able to give veterinary-specific advice for any suspected overdose.

Key Notes

Practical clinical points that help optimize the use of ronidazole in dogs and cats:

• T. foetus activity: Ronidazole has greater activity against Tritrichomonas foetus than metronidazole, although resistance has been documented.
• Treatment response: Resolution of diarrhea has been reported in approximately 60–70% of cats treated for T. foetus infection.
• Large-intestine delivery: Formulations designed to delay drug release until reaching the large intestine may help reduce neurotoxicity while maintaining efficacy.
• Pharmacokinetics: In cats the drug is rapidly and completely absorbed after oral dosing with a bioavailability approaching 100%, a steady-state volume of distribution of about 0.7 L/kg, clearance of about 0.8 mL/kg/minute and an elimination half-life of about 10 hours.
• Colon-targeted formulation: A guar gum-coated colon-targeted formulation releases almost nothing for the first 6 hours and peaks at about 14.5 hours, as the drug reaches the colon; in a controlled trial it cleared infection in 84% of treated cats with no observed neurologic adverse effects.
• Laboratory interference: A related nitroimidazole can cause falsely decreased AST, ALT, LDH, triglyceride and hexokinase glucose readings with some assay methods; whether ronidazole does the same is not known.
• What can be dispensed: No veterinary-labeled product is available in the United States and there is no human-labeled product. For small-animal use ronidazole is compounded from bulk powder, as capsules prepared from 100% bulk powder by a compounding pharmacy working in a bio-safety hood, and chemical-grade powder is supplied for an individual animal. An injectable solution of 3.2 mg/mL in 5% dextrose in water has been prepared and given to research animals.