Tinidazole

Overview

Tinidazole (Tindamax®) is a 5-nitroimidazole antimicrobial with antiprotozoal and antibacterial activity. It is similar to metronidazole but does not appear to offer significant advantages over metronidazole or ronidazole. In dogs and cats, it is used primarily as an alternative treatment for giardiasis and may also have potential use against anaerobic infections, trichomoniasis, amebiasis, and balantidiasis.

Tinidazole has a longer duration of action than metronidazole in dogs and cats.

Mechanism of Action (MOA): Tinidazole is taken up by anaerobic organisms, where it is reduced to an unidentified polar compound that disrupts DNA and nucleic acid synthesis, resulting in bactericidal activity. Tinidazole is a nitroimidazole antiprotozoal whose activity is thought to involve intracellular reduction to reactive intermediates that damage DNA. Its precise antiprotozoal mechanism remains incompletely understood, particularly against Giardia and Entamoeba.

Indications

Tinidazole is used primarily as an alternative antiprotozoal agent in dogs and cats. It may also be useful for selected anaerobic bacterial infections, and has been described as a substitute for metronidazole for a variety of anaerobic infections in small animals, although veterinary clinical experience remains limited.

• Giardiasis: Alternative treatment in dogs and cats.
• Anaerobic infections: Potentially useful, particularly infections associated with dental disease; activity against Porphyromonas spp. found in canine gingiva is described as excellent.
• Trichomoniasis: May be useful; limited veterinary efficacy data are available.
• Amebiasis: Potential use based on antiprotozoal activity against Entamoeba histolytica.
• Balantidiasis: Potential use; efficacy in animals has not been established.
• Tritrichomonas foetus (cats): Used as an alternative when ronidazole is unavailable; shedding falls but the infection is not reliably eradicated.

Dosage (Reference)

Dog

Tinidazole is used primarily as an alternative treatment for giardiasis. Although it may also be useful for other protozoal infections, efficacy data in dogs are limited.

Cat

Tinidazole has been used as an alternative treatment for giardiasis and has also been evaluated for Tritrichomonas foetus infection.

Warnings & Precautions

Tinidazole should be used cautiously in dogs and cats because veterinary experience is limited. Particular attention should be given to patients with hepatic disease, neurologic disorders, or hematologic abnormalities.

• Contraindications: Do not use in animals with known hypersensitivity to tinidazole or other 5-nitroimidazoles (e.g., metronidazole); reported reactions in people have ranged from urticaria to Stevens-Johnson syndrome.
• Hepatic dysfunction: Tinidazole is metabolized by the liver; use with caution in patients with hepatic disease.
• Blood dyscrasias: Use cautiously in patients with hematologic disorders; tinidazole may produce transient leukopenia and neutropenia.
• Neurologic disease: Avoid tinidazole in animals with known hypersensitivity to metronidazole or other nitroimidazoles. In seizure-prone animals, preferentially use an alternative; if tinidazole is necessary, use cautiously and discontinue if neurological signs develop
• When to discontinue: Stop tinidazole promptly if abnormal neurologic signs appear; convulsive seizures and peripheral neuropathy have been reported in people treated with it.
• Pregnancy: Tinidazole crosses the placenta. If use is considered in pregnant animals, weigh the potential benefits against the potential risks.
• Lactation: Tinidazole is excreted into milk at concentrations similar to serum, and in people it can still be detected in milk for up to 72 hours after a dose. If treatment of a nursing dam is necessary, use a milk replacer.
• Carcinogenic potential: Avoid unnecessary use. Reserve tinidazole for conditions in which it is indicated; carcinogenicity has been reported with chronic administration of another nitroimidazole (metronidazole), and although it has not been reported for tinidazole itself, the human product label carries this as a boxed warning.
• Breeding animals: Decreased fertility and testicular changes have been reported in male rats given tinidazole.

Drug Interactions

The following interactions have been reported or are theoretical based on experience with metronidazole and may be clinically relevant in veterinary patients receiving tinidazole.

• Busulfan: Tinidazole may increase the serum concentration of busulfan.
• Cholestyramine: Reported to decrease the absorption of metronidazole; the interaction may apply to tinidazole.
• Cimetidine: May decrease tinidazole metabolism, increasing the risk of dose-related adverse effects.
• Cisapride: Tinidazole may increase the serum concentration of cisapride.
• Cyclosporine, Tacrolimus (systemic): Tinidazole may increase their serum concentrations, reportedly by inhibiting their metabolism.
• Ethanol: May cause a disulfiram-like reaction (e.g., nausea, vomiting, cramps); avoid alcohol during treatment and for 3 days afterwards.
• Fluorouracil (systemic): Tinidazole may increase the serum concentration of fluorouracil and the risk of toxicity.
• Ketoconazole: May decrease tinidazole metabolism, increasing the likelihood of dose-related adverse effects.
• Oxytetracycline: Reported to antagonize the therapeutic effects of metronidazole; the interaction may apply to tinidazole.
• Phenobarbital, Rifampin: May increase tinidazole metabolism, reducing blood concentrations.
• Warfarin and other coumarin anticoagulants: May prolong prothrombin time (PT); avoid concurrent use when possible or monitor closely.

Side Effects & Overdose

Side Effects

Clinical experience with tinidazole in dogs and cats is limited. Adverse effects are expected to be similar to those of other 5-nitroimidazoles, with gastrointestinal effects being the most common.

• Gastrointestinal effects: Vomiting, inappetence, and diarrhea are the most likely adverse effects. Administering the medication with food may help reduce these effects.
• Neurotoxicity: Neurotoxic signs may occur, as reported with other 5-nitroimidazoles (e.g., metronidazole and ronidazole); high doses have caused ataxia, tremors, nystagmus and seizures, signs attributed to inhibition of GABA that respond to benzodiazepines such as diazepam.
• Human safety record: In people, tinidazole reportedly causes fewer side effects than metronidazole; the commonest are gastrointestinal, and seizures, transient myelosuppression and hypersensitivity reactions are rare.

Overdose

Information regarding tinidazole overdose in veterinary patients is limited.

• Treatment: Management is symptomatic and supportive.
• Decontamination: Gastric lavage or induction of emesis may be helpful following acute oral overdose.
• Poison consultation: Consultation with a 24-hour poison control center that provides veterinary-specific information is recommended for suspected or confirmed overdoses.
• Reported lethal doses: In rodent studies the oral LD50 was greater than 3.6 g/kg in mice and greater than 2 g/kg in rats.
• Hemodialysis: A 6-hour session has been reported to remove 43% of the amount of drug in the body in people.

Key Notes

Practical clinical points for the use of tinidazole in dogs and cats:

• Alternative to metronidazole: Although similar to metronidazole, tinidazole has not demonstrated significant clinical advantages over metronidazole or ronidazole.
• Longer duration of action: Tinidazole has a longer duration of action than metronidazole in dogs and cats.
• Administration with food: Giving the medication with food may help minimize gastrointestinal adverse effects.
• Palatability: Tinidazole is reportedly very bitter tasting. When compounded, capsules or flavored oral suspensions may improve acceptance.
• Food animals: As a nitroimidazole, tinidazole is prohibited for use in animals intended for food production.
• Availability: There is no veterinary-labeled tinidazole; every use in dogs and cats is extra-label, and no drug is approved for treatment of giardiasis in dogs and cats in the US.
• Pharmacokinetics: Oral absorption is practically complete in both species; the volume of distribution is about 0.66 L/kg in dogs and 0.54 L/kg in cats, and the elimination half-life is about 4.4 hours in dogs and 8.4 hours in cats, so dogs clear the drug about twice as fast as cats.
• What to follow: Monitoring is limited to clinical efficacy in treating the infection; no specific tests are necessary.
• Effect on blood chemistry: Tinidazole can interfere with enzymatic assays coupled to the oxidation-reduction of nicotinamide adenine and give falsely low values, including zero, for AST, ALT, LDH, triglycerides and hexokinase glucose.
• Client information: Tell owners to contact the practice immediately if the animal shows behavior changes, eyes moving back and forth (nystagmus), convulsions or difficulty walking or climbing stairs, and to keep alcohol away from the animal while it is being treated.
• Compounded suspension: If tablets cannot be given, four 500 mg tablets can be crushed and made up with cherry syrup to a final volume of 30 mL, giving 67 mg/mL; shake well before each dose and discard after 7 days at room temperature.
• Storage: Store tablets at controlled room temperature, 20°C to 25°C (68°F to 77°F), protected from light.
• Stewardship: The World Health Organization classes tinidazole as an Important antimicrobial for human medicine.