Elephant specific information, if available, is in blue.

Chemistry – A synthetic, nitroimidazole antibacterial and antiprotozoal agent, metronidazole occurs as white to pale yellow crystalline powder or crystals with a pKa of 2.6. It is sparingly soluble in water or alcohol. Metronidazole base is commercially available as tablets or solution for IV injection and metronidazole HCl is available as injectable pow­der for reconstitution. The hydrochloride is very soluble in water.

Storage/Stability/Compatibility – Metronidazole tablets and HCl powder for injection should be stored at temperatures less than 30°C and protected from light. The injection should be protected from light and freezing and stored at room temperature.

Specific recommendations on the reconstitution, dilution, and neutralization of metron­idazole HCl powder for injection are detailed in the package insert of the drug and should be referred to if this product is used. Do not use aluminum hub needles to reconstitute or transfer this drug as a reddish-brown discoloration may result in the solution.

The following drugs and solutions are reportedly compatible with metronidazole ready-to-use solutions for injection: amikacin sulfate, aminophylline, carbenicillin disodium, cefazolin sodium, cefotaxime sodium, cefoxitin sodium, cefuroxime sodium, cephalothin sodium, chloramphenicol sodium succinate, clindamycin phosphate, disopyramide phos­phate, gentamicin sulfate, heparin sodium, hydrocortisone sodium succinate, hydromor­phone HCl, magnesium sulfate, meperidine HCl, morphine sulfate, moxalactam disodium, multielectrolyte concentrate, multivitamins, netilmicin sulfate, penicillin G sodium, and tobramycin sulfate.

The following drugs and solutions are reportedly incompatible (or compatibility data conflicts) with metronidazole ready-to-use solutions for injection: aztreonam, cefamandole naftate and dopamine HCl.

Pharmacology – Metronidazole is bactericidal against susceptible bacteria. Its exact mechanism of action is not completely understood, but it is taken up by anaerobic organisms where it is reduced to an unidentified polar compound. It is believed that this com­pound is responsible for the drug’s antimicrobial activity by disrupting DNA and nucleic acid synthesis in the bacteria.

Metronidazole has activity against most obligate anaerobes including Bacteroides sp. (including B. fragilis), Fusobacterium, Veillonella, Clostridium sp., peptococcus, and pep­tostreptococcus. Actinomyces is frequently resistant to metronidazole.

Metronidazole is also trichomonacidal and amebicidal in action and acts as a direct amebicide. Its mechanism of action for its antiprotozoal activity is not understood. It has therapeutic activity against Entamoeba histolytica, Trichomonas, Giardia, and Balantidium coli. It acts primarily against the trophozoite forms of Entamoeba rather than encysted forms.

Uses/Indications – Although there are no veterinary-approved metronidazole products, the drug has been used extensively in the treatment of Giardia in both dogs and cats. It is also used clinically in small animals for the treatment of other parasites (Trichomonas and Balantidium coli) as well as treating both enteric and systemic anaerobic infections.

In horses, metronidazole has been used clinically for the treatment of anaerobic infections.

Pharmacokinetics – Metronidazole is relatively well absorbed after oral administration. The oral bioavailability in dogs is high, but interpatient variable with ranges from 50-100% reported. The oral bioavailability of the drug in horses averages about 80% (range 57-100%). If given with food, absorption is enhanced in dogs, but delayed in humans. Peak levels occur about one hour after dosing.

Metronidazole is rather lipophilic and is rapidly and widely distributed after absorption. It is distributed to most body tissues and fluids, including to bone, abscesses, the CNS, and seminal fluid. It is less than 20% bound to plasma proteins in humans.

Metronidazole is primarily metabolized in the liver via several pathways. Both the metabolites and unchanged drug are eliminated in the urine and feces. Elimination half-lives of metronidazole in patients with normal renal and hepatic function in various species are reported as: humans 6-8 hours, dogs 4-5 hours, and horses 2.9-4.3 hours.

Contraindications/Precautions/Reproductive Safety – Metronidazole is contraindicated in animals hypersensitive to the drug or nitroimidazole derivatives. It has also been recommended not to use the drug in severely debilitated, pregnant or nursing animals. Metronidazole should be used with caution in animals with hepatic dysfunction.

Metronidazole has been implicated as being a teratogen in some laboratory animal stud­ies, but no information is available for dogs and cats. Unless the benefits to the mother outweigh the risks to the fetuses, it should not be used during pregnancy, particularly dur­ing the first 3 weeks of gestation.

Adverse Effects/Warnings – Adverse effects reported in dogs include neurologic disorders, lethargy, weakness, neutropenias, hepatotoxicity, hematuria, anorexia, nausea, vomit­ing and diarrhea.

Neurologic toxicity may be manifested after acute high dosages or, more likely, with chronic moderate to high-dose therapy. Symptoms reported are described below in the Overdosage section.

Overdosage/Acute Toxicity – Signs of intoxication associated with metronidazole in dogs and cats, include anorexia and/or vomiting, depression, mydriasis, nystagmus, ataxia, head-tilt, deficits of proprioception, joint knuckling, disorientation, tremors, seizures, bradycardia, rigidity and stiffness. These effects may be seen with either acute overdoses or in some animals with chronic therapy when using “recommended” doses.

Acute overdoses should be handled by attempting to limit the absorption of the drug us­ing standard protocols. Extreme caution should be used before attempting to induce vomiting in patients demonstrating CNS effects or aspiration may result. If acute toxicity is seen after chronic therapy, the drug should be discontinued and the patient treated supportively and symptomatically. Neurologic symptoms may require several days before showing signs of resolving.

Drug Interactions – Metronidazole may prolong the PT in patients taking warfarin or other coumarin anticoagulants. Avoid concurrent use if possible; otherwise, intensify monitoring. Phenobarbital or phenytoin may increase the metabolism of metronidazole, thereby decreasing blood levels. Cimetidine may decrease the metabolism of metronidazole and increase the likelihood of dose-related side effects occurring. Alcohol may induce a disulfiram-like (nausea, vomiting, cramps, etc.) reaction when given with metronidazole.

Drug/Laboratory Interactions – Metronidazole causes falsely decreased readings of AST (SGOT) and ALT (SGPT) when determined using methods measuring decreases in ultra­violet absorbance when NADH is reduced to NAD.

Doses –

Horses:

For susceptible anaerobic infections:

a) 15 – 25 mg/kg PO q6h (Sweeney et al. 1986)

b) 20 – 25 mg/kg PO q12h as crushed tablets in an aqueous suspension. (Baggot, Wilson, and Hietela 1988)

Elephants:

a) 15 mg/kg per rectum (Gulland and Carwardine, 1987)

b) 15 mg/kg per rectum ~ q 24 h (pharmacokinetic study)

Elephant References:

a) Gulland,F.M. and Carwardine,P.C. 1987. Plasma metronidazole levels in an Indian elephant (Elephas maximus) after rectal administration. Veterinary Record 120:440

Summary: A female Asian elephant was treated for a mixed aerobic and anaerobic tusk sulcus infection with 15/kg metronidazole administered rectally once daily for 10 days using 1 gram suppositories. Plasma metronidazole levels of 4.4, 7.7, and 6.6 ug/ml were achieved at three, six, and 24 hours respectively. These levels are similar to those obtained in man following therapeutic use of metronidazole suppositories. Plasma minimum inhibitory concentrations of metronidazole for the majority of human pathogens including Bacteriods species, Fusobacter species, and Clostridia species are in the range of 0.3 to 3 ug/ml. After seven days of antibiotic therapy and daily flushing of the gingival sulcus with dilute hydrogen peroxide through a 4FG plastic urinary catheter, clinical recovery was achieved. No digestive disturbances were noted.

b) Sander SJ, Siegal-Willott JL, Ziegler J, Lee E, Tell L, Murray S: Pharmacokinetics of a single dose of metronidazole after rectal administration in captive asian elephants (Elephas maximus). J Zoo Wildl Med 2016, 47(1):1-5.

Abstract: Metronidazole is a nitroimidazole antibacterial and antiprotozoal drug with bacteriocidal activity against a broad range of anaerobic bacteria. It is a recognized treatment for elephants diagnosed with anaerobic bacterial infection or protozoal disease or exhibiting signs of colonic impaction, diarrhea, and colic. This study evaluated the pharmacokinetics of rectally administered metronidazole (15 mg/kg) in five adult female Asian elephants (Elephas maximus). Serum samples were collected from each animal for 96 hr after rectal administration of metronidazole. Serum concentrations of metronidazole and its primary metabolite, hydroxymetronidazole, were measured via ultraperformance liquid chromatography. Data were analyzed via a noncompartmental pharmacokinetic approach. Results indicated that serum levels of metronidazole were quantifiable at the 0.25 hr time point and absent in all elephants by the 96 hr time point. The serum peak concentration (mean ± SD, 13.15 ±
2.59 lg/ml) and area under the curve from time 0 to infinity (mean ± SD, 108.79 ± 24.77 hr µg/ml) were higher than that reported in domestic horses after similar usage. Concurrently, the time of maximum serum concentration (mean ± SD, 1.2 ±0.45 hr) and terminal elimination half-life (harmonic mean ± pseudo-SD, 7.85 ±0.93 hr) were longer when compared to equine reports. Rectal administration of metronidazole was well tolerated and rapidly absorbed in all study elephants. Based on the findings in this study, metronidazole administered at a single dose of 15 mg/kg per rectum in the Asian elephant is likely to result in serum concentrations above 4 µg /ml for 8 hr and above 2 µg /ml for 24 hr after treatment is administered. Dosing recommendations should reflect the mean inhibitory concentration of metronidazole for each pathogen.

Monitoring Parameters –

1) Clinical efficacy

2) Adverse effects (clients should report any neurologic symptomatology)

Client Information – Report any neurologic symptoms to veterinarian (see Overdose sec­tion).

Dosage Forms/Preparations/FDA Approval Status/Withholding Times –

Veterinary-Approved Products: None

Human-Approved Products:

Metronidazole Tablets 250 mg, 500 mg; Capsules 375 mg; Flagyl® (Searle); Metric 21® (Fielding); Protostat® (Ortho); Flagyl 375® (Searle); generic; (Rx)

Metronidazole HCl Powder for Injection 500 mg/vial; Flagyl®IV (Searle); (Rx)

Metronidazole 500 mg/100 ml injection (ready to use); Flagyl®I.V. (Searle); Metro®I.V. (McGaw); Metronidazole Redi-Infusion® (Elkins-Sinn); Metronidazole® (Abbott); (Rx)