METRONIDAZOLE AND RELATED AGENTS
- USES: Metronidazole is a synthetic 5-nitroimidazole compound. Secnidazole and tinidazole are related compounds and are long-acting 5-nitroimidazole derivatives. These drugs have antiprotozoal and antibacterial activity and are used in the treatment of protozoal and anaerobic bacterial infections. Metronidazole and tinidazole are used for the treatment of trichomoniasis, amebic liver abscesses, intestinal amebiasis, pelvic inflammatory disease, bacterial vaginosis, giardiasis, and Clostridium difficile-associated diarrhea, as well as for perioperative prophylaxis. Secnidazole is used to treat giardiasis, intestinal amebiasis, bacterial vaginosis, and vaginal trichomoniasis, but secnidazole is not currently available in the United States. PHARMACOLOGY: These chemicals are reduced in a process unique to anaerobic metabolism; the short-lived metabolite disrupts DNA and inhibits nucleic acid synthesis. TOXICOLOGY: Mechanism is not known. EPIDEMIOLOGY: Metronidazole is commonly prescribed. Acute toxicity is rare. MILD TO MODERATE TOXICITY: METRONIDAZOLE: Most patients remain asymptomatic. Dark (green/black) urine and increased liver enzymes have been reported. TINIDAZOLE: At the time of this review, there are no reports of human overdose with tinidazole. SEVERE TOXICITY: CNS depression and seizures have been reported rarely. Dizziness, diplopia, disorientation, ataxia, and sensory neuropathy have been reported with chronic overdose. ADVERSE EFFECTS: METRONIDAZOLE: Characteristic adverse effects include nausea, vomiting, anorexia, headache, and vertigo. Peripheral neuropathy has been reported in children receiving chronic therapy. Leukopenia has been reported in approximately 1% of patients receiving therapeutic dosing. In 2 patients, sensorineural hearing loss occurred within 48 hours of use. An expected reaction in a patient who takes metronidazole and drinks ethanol is a disulfiram-like reaction; patients taking these agents should avoid ingestion of ethanol during treatment and for 3 days after cessation of treatment. Nausea, vomiting, abdominal cramps, flushing, anxiety, confusion, vertigo, and headache may occur. In severe reactions, patients may become hypotensive. TINIDAZOLE: Overall the adverse effects reported with tinidazole are similar to those of metronidazole. In clinical studies, adverse effects were mild and self-limited with therapy.
Range of Toxicity:
METRONIDAZOLE AND RELATED AGENTS
- TOXICITY: METRONIDAZOLE: ADULTS: Single doses up to 15 g have been tolerated well. Seizures and peripheral neuropathy have occurred after 5 to 7 days of doses of 6 to 10.4 g every other day. CHILDREN: Not well established. However, peripheral neuropathy has been reported in children taking a mean dose of 19 mg/kg/day of metronidazole for 4 to 11 months. THERAPEUTIC DOSES: METRONIDAZOLE: ADULTS: Varies according to indication. Typical doses range from 250 to 2000 mg once to three times daily. CHILDREN: Varies according to indication. Typical doses range from 7.5 to 30 mg/kg/day divided every 8 hours. TINIDAZOLE: ADULTS: A single 2 g oral dose. CHILDREN (3 YEARS OF OLDER): 50 mg/kg/day up to 3 days.
METRONIDAZOLE AND RELATED AGENTS
- Support: MILD TO MODERATE TOXICITY: Patients may only need observation. SEVERE TOXICITY: Treatment is symptomatic and supportive. Orotracheal intubation for airway protection should be performed early in cases of CNS depression or repeated seizure activity. DISULFIRAM-LIKE REACTION: Manage hypotension with IV fluids. If hypotension persists, use direct-acting vasopressors such as epinephrine or norepinephrine. Benzodiazepines may be used for associated agitation or anxiety. Fomepizole inhibits alcohol dehydrogenase, preventing the formation of acetaldehyde, and could theoretically be useful in treating severe disulfiram-like reactions, although there is limited experience with this therapy.
- Decontamination: PREHOSPITAL: Most patients remain asymptomatic; prehospital decontamination is not routinely recommended. HOSPITAL: Consider decontamination if a patient presents promptly after a large oral overdose, is not vomiting, and does not have CNS depression or seizures.
- Airway management: Perform early in patients with CNS depression or seizures.
- Antidote: None.
- Nausea: Antiemetics may be used to control nausea.
- Tachycardia: If the patient cannot tolerate fluids, IV fluids can be given. If anxiety from a disulfiram-like reaction is present, a benzodiazepine can be given.
- Hypotensive episode: If patient is hypotensive, it is either from a disulfiram-like reaction or a co-ingestant. Secure intravenous access and put patient in supine position. Initiate treatment with IV fluids. Initiate pressors if necessary and titrate to a mean arterial pressure of at least 60 mmHg. If a pressor is needed to increase blood pressure, a direct-acting agent such as norepinephrine or epinephrine is best. Insert foley bladder catheter and monitor urine output.
- Headache: Oral analgesics can be given if tolerated. If the patient is nauseated, IV analgesics can be given.
- Seizure: Seizures are rare and often self-limited but may be a result of CNS stimulation. Treatment includes IV benzodiazepines. If seizures persist, use propofol or barbiturates.
- Monitoring of patient: Monitor vital signs and mental status. Metronidazole plasma concentrations are not clinically useful or readily available. A CBC should be obtained if leukopenia is suspected clinically. Monitor serum electrolytes and glucose, and liver enzymes in symptomatic patients. No specific lab work is needed in most patients but may be helpful in ruling out other causes of altered mental status or seizures if they occur. Consider head CT and lumbar puncture to rule out intracranial mass, bleeding or infection for patients with CNS manifestations. Acute toxicity has not been reported with this drug. However, standard treatment measures may be indicated in ingestions of greater than 1 to 2 grams.
- Enhanced elimination procedure: Hemodialysis and hemoperfusion are UNLIKELY to be of value for metronidazole.
- Patient disposition: HOME CRITERIA: Asymptomatic patients with unintentional ingestions can be monitored at home. OBSERVATION CRITERIA: Patients with deliberate ingestions should be sent to a healthcare facility for observation for at least 4 hours. Any patient with symptoms should be sent to a healthcare facility and observed until symptoms improve or resolve. ADMISSION CRITERIA: Patients with significant seizure activity, marked disulfiram-like reaction and/or persistent abnormal vital signs should be admitted. Patients with seizures, severe hypotension or any other life-threatening result of toxicity should be admitted to an intensive care setting. CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.