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Professional Version

Nitroimidazoles Use in Animals

By

Melissa A. Mercer

, DVM, MS, DACVIM-LA, Virginia Maryland College of Veterinary Medicine

Medically Reviewed Sep 2022 | Modified Nov 2022

The 5-nitroimidazoles are a group of drugs that have both antiprotozoal and antibacterial activity. Nitroimidazoles with activity against trichomonads and amebae include metronidazole, tinidazole, nimorazole, flunidazole, and ronidazole. Metronidazole and nimorazole are effective in treatment of giardiasis, whereas dimetridazole, ipronidazole, and ronidazole control histomoniasis in poultry. Several nitroimidazoles have activity against trypanosomes.

Metronidazole, ronidazole, and other nitroimidazoles are active against anaerobic bacteria. Metronidazole is the compound that has been the most studied and is discussed as the prototype of the group. Extralabel use of nitroimidazoles is prohibited in food-producing animals in the US.

Metronidazole

Metronidazole has been used for many years in therapeutic management of trichomoniasis, giardiasis, and amebiasis. Metronidazole undergoes reduction in bacteria where it is metabolized to cytotoxic derivatives that bind to DNA, causing loss of the helical structure, strand breakage, and impairment of DNA function. It is active against obligate anaerobic bacteria; however, aerobic bacteria lack the reductive pathway necessary for its mechanism of activity. It is not active against facultative anaerobes, obligate aerobes, or microaerophilic bacteria other than Campylobacter fetus.

At concentrations readily attained in serum after PO or parenteral administration, metronidazole is active against Bacteroides fragilis, B melaninogenicus, Fusobacterium spp, and Clostridium perfringens and other Clostridium spp. It is generally less active against non–spore-forming, gram-positive bacilli such as Actinomyces, Propionibacterium, Bifidobacterium, and Eubacterium spp. Metronidazole is also somewhat less active against gram-positive cocci such as Peptostreptococcus and Peptococcus spp; however, the less sensitive strains are usually not obligate anaerobes.

Metronidazole is bactericidal at concentrations equal to or slightly higher than the minimal inhibitory concentration. The precise mode of action is unclear, but reduction in an anaerobic environment yields a compound that then binds to DNA, causing loss of the helical structure, strand breakage, and impairment of DNA function. Only susceptible organisms (bacteria and protozoa) appear to be capable of metabolizing the drug.

The pharmacokinetic pattern of metronidazole generally follows that expected of a highly lipid-soluble, basic drug. It is readily but variably absorbed from the GI tract (bioavailability 60%–100%), with serum concentrations peaking within 1–2 hours, and becomes widely distributed in all tissues. Metronidazole has been administered rectally, where it is rapidly absorbed. However, rectal administration lowers the bioavailability to approximately 30%. Metronidazole penetrates the blood-brain barrier and also attains therapeutic concentrations in abscesses and in empyema fluid. It is only slightly bound to plasma proteins.

Biotransformation is quite extensive, and parent drug and metabolites are excreted via both the renal and biliary routes. Primary metabolism occurs in the liver. The elimination half-life is ~4.5 hours in dogs and 1.5–3.3 hours in horses.

The principal clinical indications for metronidazole include the treatment of specific protozoal infections (amebiasis, trichomoniasis, giardiasis, and balantidiasis) and anaerobic bacterial infections such as those that may occur in abdominal abscesses, peritonitis, empyema, genital tract infections, periodontitis, otitis media, osteitis, arthritis, and meningitis, and in necrotic tissue. Metronidazole has been successfully used to prevent infection after colonic surgery. Nitroimidazoles also act as radiosensitizers, and metronidazole has been used as an adjunct to the radiotherapy of solid tumors.

Adverse effects are not commonly associated with metronidazole. High doses may induce clinical signs of neurotoxicity in dogs, such as tremors, muscle spasms, ataxia, and even convulsions. After IV dosing, CNS excitement has been observed. Reversible bone marrow depression has been reported. Metronidazole may produce a reddish brown discoloration of the urine due to unidentified pigments.

In horses, anorexia and salivation are common after administration PO. Carcinogenicity and teratogenicity have been reported in laboratory mice after prolonged exposure to metronidazole, and therefore it has been banned in food-producing animals and should be avoided in pregnant animals.

Metronidazole is not approved for any veterinary species in the US, and therefore its use is considered extralabel use. Recommended dosages for metronidazole in dogs and cats are indication specific: giardiasis: 25 mg/kg, PO, every 12 hours for 5 days; inflammatory GI conditions or inflammatory bowel disease (IBD): 10–15 mg/kg, PO, every 12 hours; hepatic encephalopathy: 7.5 mg/kg, PO, every 8–12 hours. Small animals with hepatic dysfunction require lower dose rates of 15–20 mg/kg, PO, every 24 hours. In horses, dosages of 15–25 mg/kg, PO, every 6–8 hours are recommended. Neonatal foals (< 2 weeks of age) require lower doses of 10 mg/kg, PO, every 12 hours.

In the US, nitroimidazoles (including metronidazole) are prohibited from extralabel drug use (ELDU) in all food-producing animal species. Because metronidazole is not approved for any veterinary species in the US, it is prohibited from use in food-producing animals.

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