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METRONIDAZOLE AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Metronidazole is a synthetic 5-nitroimidazole compound, which exhibits antiprotozoal and antibacterial activity.
    B) Tinidazole is a synthetic antiprotozoal agent, and is considered a second generation 2-methyl-5-nitroimidazole.

Specific Substances

    A) METRONIDAZOLE
    1) Bayer-5360
    2) Metronidazole
    3) RP 8823
    4) Trichopol
    5) 2-(2-methyl-5-nitroimidazol-1-yl)ethanol
    ORNIDAZOLE
    1) Ro-7-0207
    2) 1-Chloro-3-(2-methyl-5-nitroimidazol-1-yl)propan-2-ol
    3) CAS 16773-42-5
    SECNIDAZOLE
    1) PM-185184
    2) RP-14539
    3) CAS 3366-95-8
    TINIDAZOLE
    1) Tinidazol
    2) Tinidazolum
    3) CP-12574
    4) CAS-19387-91-8
    5) Molecular Weight - 247.3
    6) Molecular Formula - C(8)H(13)N(3)O(4)S

    1.2.1) MOLECULAR FORMULA
    1) METRONIDAZOLE: C6H9N3O3

Available Forms Sources

    A) FORMS
    1) METRONIDAZOLE
    a) Metronidazole is available as 500 mg/100 mL intravenous solution, 375 oral capsules, 250 mg and 500 mg oral tablets, 0.75% topical cream, 0.75 topical gel/jelly, 0.75 topical lotion, and 750 mg oral extended-release tablets (Prod Info FLAGYL(R) 375 oral capsules, 2013; Prod Info FLAGYL(R) oral tablets, 2013; Prod Info FLAGYL(R) intravenous injection, 2013; Prod Info FLAGYL ER(R) oral extended release tablets, 2013; Prod Info METROGEL-VAGINAL(R) vaginal gel, 2003).
    2) TINIDAZOLE
    a) Tinidazole is available in 250 mg and 500 mg tablets (Prod Info tinidazole oral tablets, 2011).
    B) USES
    1) METRONIDAZOLE is effective in the treatment and prophylaxis of various bacterial infections including symptomatic trichomoniasis, asymptomatic trichomoniasis, amebiasis, and anaerobic bacterial infections. It is also used in the treatment of women with bacterial vaginosis(Prod Info FLAGYL(R) 375 oral capsules, 2013; Prod Info FLAGYL(R) oral tablets, 2013; Prod Info FLAGYL(R) intravenous injection, 2013; Prod Info FLAGYL ER(R) oral extended release tablets, 2013; Prod Info METROGEL-VAGINAL(R) vaginal gel, 2003).
    2) TINIDAZOLE has been used in the treatment of susceptible protozoal infections and prophylactic treatment of anaerobic bacterial infections. It is primarily used in the treatment of trichomoniasis, giardiasis (caused by G. lamblia), and amebiasis or amebic liver abscess (caused by E. histolytica) (Prod Info tinidazole oral tablets, 2011).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) 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.
    B) PHARMACOLOGY: These chemicals are reduced in a process unique to anaerobic metabolism; the short-lived metabolite disrupts DNA and inhibits nucleic acid synthesis.
    C) TOXICOLOGY: Mechanism is not known.
    D) EPIDEMIOLOGY: Metronidazole is commonly prescribed. Acute toxicity is rare.
    E) WITH THERAPEUTIC USE
    1) 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.
    2) 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.
    F) WITH POISONING/EXPOSURE
    1) 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.
    2) SEVERE TOXICITY: CNS depression and seizures have been reported rarely. Dizziness, diplopia, disorientation, ataxia, and sensory neuropathy have been reported with chronic overdose.
    0.2.20) REPRODUCTIVE
    A) Data regarding metronidazole use during pregnancy are conflicting. Although metronidazole is contraindicated during the first trimester of pregnancy, it is classified as FDA pregnancy category B and several sources suggest that it poses a low risk to pregnant women. A CDC guideline for the treatment of trichomoniasis recommends the use of a 2-g single dose of metronidazole at any stage of pregnancy. Metronidazole is secreted in human breast milk at similar concentrations as found in plasma. Considering the importance of the drug to the mother, either discontinue breastfeeding, discontinue therapy, or have the mother pump and discard her breast milk during therapy and for 24 hours after discontinuation/
    0.2.21) CARCINOGENICITY
    A) At the time of this review, adequate data concerning an association between carcinogenicity and metronidazole in humans is lacking.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Metronidazole plasma concentrations are not clinically useful or readily available.
    C) A CBC should be obtained if leukopenia is suspected clinically.
    D) Monitor serum electrolytes and glucose, and liver enzymes in symptomatic patients.
    E) 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.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MILD TO MODERATE TOXICITY
    1) Patients may only need observation.
    B) SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Orotracheal intubation for airway protection should be performed early in cases of CNS depression or repeated seizure activity.
    2) 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.
    C) DECONTAMINATION
    1) PREHOSPITAL: Most patients remain asymptomatic; prehospital decontamination is not routinely recommended.
    2) HOSPITAL: Consider decontamination if a patient presents promptly after a large oral overdose, is not vomiting, and does not have CNS depression or seizures.
    D) AIRWAY MANAGEMENT
    1) Perform early in patients with CNS depression or seizures.
    E) ANTIDOTE
    1) None.
    F) NAUSEA
    1) Antiemetics may be used to control nausea.
    G) TACHYCARDIA
    1) 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.
    H) HYPOTENSION
    1) 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.
    I) HEADACHE
    1) Oral analgesics can be given if tolerated. If the patient is nauseated, IV analgesics can be given.
    J) SEIZURES
    1) 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.
    K) ENHANCED ELIMINATION
    1) Hemodialysis and hemoperfusion are UNLIKELY to be of value for metronidazole.
    L) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic patients with unintentional ingestions can be monitored at home.
    2) 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.
    3) 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.
    4) 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.
    M) PITFALLS
    1) Falsely attributing patient's symptoms to metronidazole when the true underlying cause is due to another etiology. Patients should avoid ethanol for 3 days after exposure.
    N) PHARMACOKINETICS
    1) Metronidazole is metabolized in the liver and is a CYP450 2C9 inhibitor. Sixty to 80% is excreted renally with 20% unchanged in the urine. Six to 18% is excreted in the feces. Half-life is approximately 8 hours.
    O) DIFFERENTIAL DIAGNOSIS
    1) CNS infection, intracranial hemorrhage, isoniazid overdose, sympathomimetic toxidrome, ethanol/barbiturate/other sedative withdrawal if seizing.

Range Of Toxicity

    A) 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. Encephalopathy has been reported in patients taking metronidazole with cumulative doses from 0.25 g to 182 g. Patients may present with cerebellar dysfunction, altered mental status, and seizures. Most patients recover following the discontinuation of metronidazole. 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.
    B) 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.

Clinical Effects

Summary Of Exposure

    A) 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.
    B) PHARMACOLOGY: These chemicals are reduced in a process unique to anaerobic metabolism; the short-lived metabolite disrupts DNA and inhibits nucleic acid synthesis.
    C) TOXICOLOGY: Mechanism is not known.
    D) EPIDEMIOLOGY: Metronidazole is commonly prescribed. Acute toxicity is rare.
    E) WITH THERAPEUTIC USE
    1) 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.
    2) 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.
    F) WITH POISONING/EXPOSURE
    1) 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.
    2) SEVERE TOXICITY: CNS depression and seizures have been reported rarely. Dizziness, diplopia, disorientation, ataxia, and sensory neuropathy have been reported with chronic overdose.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Oculogyric crisis and arm tremor occurred after a 1000-mg metronidazole ingestion by a 33-year-old woman (Kirkham & Gott, 1986).
    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) OTOTOXICITY was reported in 2 adults within 48 hours of metronidazole use. Tinnitus preceded hearing loss in both patients, and audiogram revealed sensorineural hearing loss. One patient recovered completely within 6 weeks, while the other had ongoing high-frequency loss at 3 months and then was lost to follow-up (Iqbal et al, 1999).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) TINIDAZOLE: A healthy individual developed a severe toxic reaction following administration of tinidazole 1.6 g IV. Symptoms included a brief fainting episode, low blood pressure, nausea, and tiredness which persisted for several hours. The reaction was not considered to be allergic (JEF Reynolds , 1998).
    B) BLOOD PRESSURE FINDING
    1) WITH THERAPEUTIC USE
    a) Blood pressure fluctuation (from 100/70 to 180/90 mm Hg), dyspnea, and excessive diaphoresis were reported in a man who developed peripheral neuropathy and encephalopathy after taking metronidazole (total cumulative dosage of metronidazole: 128.5 g) for 10 weeks for a liver abscess. Metronidazole was discontinued and the autonomic dysregulation gradually resolved several hours later (Park et al, 2011).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) Insomnia may be observed (Prod Info Tindamax(TM),, 2004; Prod Info Flagyl ER tablets, metronidazole, G.D, 1998).
    B) VERTIGO
    1) WITH THERAPEUTIC USE
    a) Vertigo may be observed (Prod Info Tindamax(TM),, 2004; Prod Info Flagyl ER tablets, metronidazole, G.D, 1998).
    C) CENTRAL NERVOUS SYSTEM DEPRESSION
    1) WITH THERAPEUTIC USE
    a) CNS depression may be observed (Prod Info Tindamax(TM),, 2004; Prod Info Flagyl ER tablets, metronidazole, G.D, 1998).
    D) TOXIC ENCEPHALOPATHY
    1) WITH THERAPEUTIC USE
    a) Encephalopathy has been reported in patients taking metronidazole (Furukawa et al, 2015; Wu et al, 2015; Park et al, 2011; Kalia et al, 2010; Arik et al, 2001) with cumulative doses from 0.25 g to 182 g. Patients may present with cerebellar dysfunction, altered mental status, and seizures. Most patients recover following the discontinuation of metronidazole (Wu et al, 2015).
    b) CASE REPORT: A 58-year-old woman with a history of diabetic nephropathy and chronic renal failure developed encephalopathy approximately 2 days after beginning a course of metronidazole (dose adjusted for renal failure) for treatment of a postoperative wound infection. The patient presented with dysarthria, and bilateral dysmetria and dysdiadochokinesia. MRI of the brain revealed cerebral and cerebellar atrophy, and ischemic, gliotic lesions within the periventricular white matter, pons, and basal ganglia. Drug toxicity was suspected, and metronidazole was discontinued. Rapid recovery from neurological deficits occurred within 1 day of drug discontinuation, and 2 days later, neurological examination findings were returning to within normal limits (Arik et al, 2001).
    c) CASE REPORT: A 43-year-old man presented with a 4-day history of slurred speech, generalized weakness, vertigo, and ataxia, approximately 2 months after starting metronidazole therapy (400 mg orally 3 times daily) for an amebic liver abscess. His neurological exam showed horizontal nystagmus to the left and positive cerebellar signs. Laboratory results revealed elevated liver enzymes; CSF examination revealed 2 cells/mm(3) with glucose of 37 mg/dL, protein 33 mg/dL, chloride 121 mmol/L and negative for cryptococcal antigen. A brain MRI revealed symmetrical areas of altered signal intensity, appearing hyperintense on T2W and fluid-attenuated inversion-recovery images and involving the dentate nuclei, dorsal pons, and splenium of the corpus callosum. Diffusion restriction on diffusion-weighted/apparent diffusion coefficient mapping was also observed. He recovered following the cessation of metronidazole therapy (Kalia et al, 2010).
    d) CASE REPORT: A 67-year-old man presented with a 3-week history of painful paresthesias of all 4 limbs, 10 weeks after starting metronidazole (500 mg 3 times daily parenterally for 3 weeks and then 500 mg 3 times daily orally; total cumulative dose: 75 g) and cephalosporin therapy for a liver abscess. A nerve conduction study was normal, except for a delayed H-reflex bilaterally. On day 24 of symptoms onset, a diagnosis of Guillain-Barre syndrome was considered and he was treated with IV immunoglobulin. However, his symptoms did not improve. On day 29, another nerve conduction study revealed that the amplitudes of the motor and sensory nerve action potential in the lower limb were slightly reduced. At this time, his condition worsened and he developed dysarthria and limb ataxia. A brain MRI showed signal abnormalities in the splenium of the corpus callosum and bilateral dentate nuclei. He developed dyspnea, excessive diaphoresis, and blood pressure fluctuation (from 100/70 to 180/90 mm Hg) approximately 8 hours later. At this time, the total cumulative dosage of metronidazole was 128.5 g. Metronidazole was discontinued and the autonomic dysregulation gradually resolved several hours later. Although his dysarthria returned to near normal within a week, there was only partial improvement in the burning sensations at 6 months follow-up (Park et al, 2011).
    e) CASE REPORT: In a patient with metronidazole-induced encephalopathy, MRI imaging showed gadolinium-enhanced lesions in the corpus callosum, but a follow-up MRI showed prominent cystic changes in the bilateral white matter and corpus callosum (Furukawa et al, 2015).
    E) SECONDARY PERIPHERAL NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) CHRONIC EXPOSURE
    1) Peripheral neuropathy has been noted in children receiving chronic therapy (Prod Info Tindamax(TM),, 2004; Prod Info Flagyl ER tablets, metronidazole, G.D, 1998).
    2) CASE REPORTS: Two cases of metronidazole-induced MRI changes have been reported in patients with a history of hepatic dysfunction. The authors recommended a decreased dosage in patients with liver dysfunction to prevent accumulation of metronidazole, which can lead to CNS dysfunction and peripheral neuropathy (Horlen et al, 2000).
    b) CASE SERIES: Peripheral neuropathy was reported in 11 of 13 pediatric patients with Crohn disease (85%) following 4 to 11 months of oral metronidazole therapy (mean daily doses 19 mg/kg). Peripheral neuropathy was detected by neurologic examinations, reduced nerve conduction velocities, or both; only 6 of the 11 children were symptomatic (Duffy et al, 1985).
    c) CASE REPORT: A 67-year-old man presented with a 3-week history of painful paresthesias of all 4 limbs, 10 weeks after starting metronidazole (500 mg 3 times daily parenterally for 3 weeks and then 500 mg 3 times daily orally; total cumulative dose: 75 g) and cephalosporin therapy for a liver abscess. A nerve conduction study was normal, except for a delayed H-reflex bilaterally. On day 24 of symptoms onset, a diagnosis of Guillain-Barre syndrome was considered and he was treated with IV immunoglobulin. However, his symptoms did not improve. On day 29, another nerve conduction study revealed that the amplitudes of the motor and sensory nerve action potential in the lower limb were slightly reduced. At this time, his condition worsened and he developed dysarthria and limb ataxia. A brain MRI showed signal abnormalities in the splenium of the corpus callosum and bilateral dentate nuclei. He developed dyspnea, excessive diaphoresis, and blood pressure fluctuation (from 100/70 to 180/90 mm Hg) approximately 8 hours later. At this time, the total cumulative dosage of metronidazole was 128.5 g. Metronidazole was discontinued and the autonomic dysregulation gradually resolved several hours later. Although his dysarthria returned to near normal within a week, there was only partial improvement in the burning sensations at 6 months follow-up (Park et al, 2011).
    F) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures may be observed (Prod Info Tindamax(TM),, 2004; Prod Info Flagyl ER tablets, metronidazole, G.D, 1998).
    2) WITH POISONING/EXPOSURE
    a) Seizures have been reported in cancer patients treated with irradiation and doses of metronidazole up to 10 g (Frytak et al, 1978).
    b) CASE REPORTS
    1) A 12-year-old boy experienced a grand mal seizure 2.5 hours following a 4-g (250 mg Q6H) total IV dose of metronidazole. The child had a total of 8 seizures during 3 hours and developed neurologic abnormalities that lasted 11 weeks (Bailes et al, 1983).
    G) NEUROLOGICAL FINDING
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Cerebellar toxicity developed in a 61-year-old transplant recipient after taking metronidazole 1.2 g daily for 77 days. He presented with marked bilateral upper and lower limb cerebellar signs, with finger-nose ataxia, severe truncal and gait ataxia, dysdiadochokinesis, and past-pointing. An MRI of the brain revealed increased T2-signal intensity in the dentate nuclei bilaterally, which was more noticeable on the fluid-attenuated inversion recovery (FLAIR) sequences. Brain CT results were normal. He recovered gradually following the discontinuation of metronidazole and addition of supportive therapy (Graves et al, 2009).
    b) CASE REPORT: A 50-year-old man developed ataxia and dysarthric speech following treatment with lactulose and metronidazole (500 mg orally 3 times daily) for hepatic encephalopathy and subacute bacterial peritonitis. An MRI of the brain showed bilateral enhancement of the cerebellar dentate nuclei. Approximately 1 hour after he received a single dose of metronidazole 500 mg, his serum metronidazole level was 50 mcg/mL (toxic range, greater than 11.5 mcg/mL). Following the discontinuation of metronidazole, his symptoms improved significantly over the next 2 weeks (Deenadayalu et al, 2005).
    c) CASE REPORT: A 59-year-old woman developed a global cerebellar syndrome with ataxic gait, dysarthric speech, and paresthesias after she took metronidazole 750 mg orally every 6 hours for 28 days. Cefamandole and clindamycin were also given IV. Neurologic symptoms resolved 6 days after discontinuation of metronidazole therapy (Kusumi et al, 1980).
    d) CASE REPORT: A 37-year-old woman with a history of Crohn's disease presented with lower limb numbness and paresthesia which progressed to include all limbs, 3 months after starting vitamin B12, ciprofloxacin, and metronidazole 1500 mg/day (cumulative dose: 180 g). She developed slurred speech and marked gait instability 2 weeks after presentation and dysarthria, glove and stocking hypoesthesia, upper and lower limb dysmetria and ataxic gait a month after presentation. A brain CT scan showed bilateral symmetrical hypodensities in the dentate nuclei and midbrain. All laboratory tests were normal. Following metronidazole discontinuation, her symptoms gradually improved and a brain MRI 10 days later did not show any cerebellar or midbrain signal abnormalities. At 2-year follow-up, she only had stocking hypoesthesia (Cacao et al, 2015).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 50-year-old man developed neurotoxicity including dizziness, diplopia, disorientation, slowed speech, and severe ataxia after taking metronidazole continually for approximately 12 weeks. It was estimated that the patient took 200 g of metronidazole over the 12-week period. Symptoms improved within 3 to 4 days of drug cessation, but the patient's gait remained unsteady. Electrophysiological studies indicated severe sensory polyneuropathy that affected the lower and upper limbs, with moderate axonal asymmetrical motor neuropathy affecting the lower limbs. The authors suggested that the underlying pathogenesis of metronidazole-induced neuropathy was secondary to axonal degeneration (Gupta et al, 2003).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting occur commonly, particularly following large doses (Prod Info Tindamax(TM),, 2004; Prod Info Flagyl ER tablets, metronidazole, G.D, 1998).
    B) TASTE SENSE ALTERED
    1) WITH THERAPEUTIC USE
    a) Metallic taste occurs commonly, particularly following large doses (Prod Info Tindamax(TM),, 2004; Prod Info Flagyl ER tablets, metronidazole, G.D, 1998).
    C) ALCOHOL INTOLERANCE
    1) WITH THERAPEUTIC USE
    a) DISULFIRAM-LIKE REACTION: Metronidazole has been reported to cause a disulfiram-like effect following intermittent concomitant administration with alcohol ingestion, but well-controlled studies have not substantiated this effect.
    1) Case reports have described nausea, flushing, headache, dyspnea, and hypotension following inadvertent use of alcoholic beverages in patients receiving metronidazole (Alexander, 1985).
    D) PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Pancreatitis was reported in a 61-year-old woman who underwent coronary artery bypass surgery and developed postsurgical aspiration pneumonia that was treated with metronidazole. Laboratory values indicated an increase in serum amylase and lipase levels along with abdominal pain. Signs and symptoms improved within 1 week of drug cessation (Sura et al, 2000).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Elevated liver enzymes has been observed (Kalia et al, 2010).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 58-year-old woman intentionally ingested metronidazole 12.5 g and developed a moderate increase in liver enzymes; jaundice or other signs or symptoms of liver toxicity were absent. Enzymes returned to normal 5 days after exposure (Bank, 1995).
    B) HEPATIC FAILURE
    1) WITH THERAPEUTIC USE
    a) PREDISPOSING CONDITION: Patients with Cockayne syndrome (CS), a rare autosomal recessive disorder, have small stature, intellectual disability, and features of accelerated pathologic aging. Metronidazole is contraindicated in patients with CS. Eight patients with CS developed acute hepatic failure after receiving metronidazole. Three patients died 6 to 11 days after starting metronidazole. Acute neurologic deficit developed in 2 of these patients (Wilson et al, 2015).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL URINE
    1) WITH THERAPEUTIC USE
    a) URINE DISCOLORATION: Darkening of the urine (probably representing drug metabolites) has been reported in approximately 1 in 100,000 patients (Prod Info Tindamax(TM),, 2004; Prod Info Flagyl ER tablets, metronidazole, G.D, 1998; Bruce, 1971).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Dark urine (green/black) was reported in a 15-year-old girl after an acute ingestion of 15 to 20 metronidazole tablets. Laboratory analysis revealed specific gravity of 1.025; positive results for bilirubin, protein, nitrite, and leukocyte esterase; and blood on macroscopic urinalysis. Urine began to clear 23 hours after ingestion, and the patient was discharged with no further signs or symptoms of toxicity. The authors suggested that a metabolite of metronidazole may have caused the discoloration. Of note, urine toxicology screening was not possible during this time (Oker et al, 1998).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia has been reported in about 1% of patients receiving therapeutic metronidazole doses (Prod Info Flagyl ER tablets, metronidazole, G.D, 1998), and transient leukopenia has occurred with tinidazole use (Prod Info Tindamax(TM),, 2004).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) FIXED DRUG ERUPTION
    1) WITH THERAPEUTIC USE
    a) Hypersensitivity reactions including urticaria and erythema, fixed drug eruptions, and a pityriasis rosea-like eruption have been reported (Prod Info Tindamax(TM),, 2004; Prod Info Flagyl ER tablets, metronidazole, G.D, 1998; Maize & Tomecki, 1977; Naik & Singh, 1977).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) DISORDER OF ENDOCRINE SYSTEM
    1) WITH THERAPEUTIC USE
    a) Displacement of estradiol from sex hormone-binding globulin was shown in vitro, but it occurred only at very high metronidazole concentrations (Fagan et al, 1985).

Reproductive

    3.20.1) SUMMARY
    A) Data regarding metronidazole use during pregnancy are conflicting. Although metronidazole is contraindicated during the first trimester of pregnancy, it is classified as FDA pregnancy category B and several sources suggest that it poses a low risk to pregnant women. A CDC guideline for the treatment of trichomoniasis recommends the use of a 2-g single dose of metronidazole at any stage of pregnancy. Metronidazole is secreted in human breast milk at similar concentrations as found in plasma. Considering the importance of the drug to the mother, either discontinue breastfeeding, discontinue therapy, or have the mother pump and discard her breast milk during therapy and for 24 hours after discontinuation/
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) The effects of metronidazole on organogenesis in humans are unknown (Prod Info PYLERA(R) oral capsules, 2012).
    B) METRONIDAZOLE
    1) Published data from case-control studies, cohort studies, and 2 meta-analyses are available on more than 5000 women who used metronidazole during pregnancy; most were first-trimester exposures. An increased risk of cleft lip (with and without cleft palate) in infants exposed to metronidazole was demonstrated in 1 study; however, these findings were not confirmed (Prod Info FLAGYL(R) oral tablets, 2015).
    2) Adrenal neuroblastoma with hepatic metastasis was diagnosed in a 15-day-old male infant following a normal birth (Apgar score, normal; weight, 3640 g). The 32-year-old mother had received oral metronidazole 250 mg twice daily and IV metronidazole 500 mg daily (both for 10 days) in the first trimester of pregnancy for the treatment of Gardnerella vaginalis. A causal relationship between adrenal neuroblastoma and metronidazole treatment could not be reliably established (Carvajal et al, 1995).
    C) LACK OF EFFECT
    1) METRONIDAZOLE
    a) Metronidazole crosses the placenta. Data regarding metronidazole use during pregnancy are conflicting. More than 10 clinical trials (n=5000) were conducted to assess antibiotic use (including metronidazole) for bacterial vaginosis during pregnancy, and most of them did not show an increased risk for adverse fetal outcomes. Three studies did not show an increased risk of infant cancer after metronidazole exposure during pregnancy, although the ability of these studies to detect cancer was limited (Prod Info FLAGYL(R) oral tablets, 2015).
    3.20.3) EFFECTS IN PREGNANCY
    A) CONGENITAL ANOMALY
    1) While one series of 55 patients treated with metronidazole during the first trimester showed a higher than expected incidence of congenital anomalies (Peterson et al, 1966), other series have not confirmed these findings (Sands, 1966; Rodin & Hass, 1966; Rosa et al, 1987).
    B) PREGNANCY CATEGORY
    1) Metronidazole crosses the placenta. Data regarding metronidazole use during pregnancy are conflicting. Although metronidazole is contraindicated during the first trimester of pregnancy, it is classified as FDA pregnancy category B and several sources suggest that it poses a low risk to pregnant women (Prod Info FLAGYL(R) oral tablets, 2015). A CDC guideline for the treatment of trichomoniasis recommends the use of a 2-g single dose of metronidazole at any stage of pregnancy (Centers for Disease Control and Prevention (CDC), 2015).
    C) LACK OF EFFECT
    1) METRONIDAZOLE
    a) Based on data from the population-based Hungarian Case-Control Surveillance of Congenital Abnormalities, evaluation of medically recorded cases of vaginal metronidazole treatment during the second to third months of pregnancy found that it was not associated with congenital hydrocephalus in newborns. Researchers evaluated metronidazole use in pregnant women who delivered infants with congenital abnormalities (CA) (n=22,843) and pregnant women who delivered healthy infants (n=38,151). Women in the CA group had a nonsignificantly higher rate of metronidazole exposure during pregnancy compared with women in the control group (1.7% vs 1.5%), with a recommended dosage regimen of one 500-mg vaginal suppository daily for a mean of 7.8 (CA) and 8.2 (control) days, respectively. Metronidazole treatment during the second to third months of pregnancy was significantly associated with congenital hydrocephalus (prevalence odds ratio (POR), 10.7; 95% confidence interval (CI), 1.1 to 104.5); however, significance was not maintained after adjustment to include only medically recorded cases of metronidazole exposure (POR, 4.3; 95% CI, 0.3 to 52.7) (Kazy et al, 2005).
    b) In a prospective cohort study conducted in Israel, metronidazole exposure during pregnancy did not increase the risk of major fetal malformations. Of all women with maternal metronidazole exposure (n=228), 86.2% were exposed in the first trimester, 9.8% in the second trimester, and 4% in the third trimester. Most received oral metronidazole (90.4%) at a mean daily dose of 973.3 mg for a mean duration of 7.9 days. The control group (n=629) included pregnant women who were counseled for nonteratogenic exposures. Among live-born infants, there was no significant increase in the rate of major anomalies in the metronidazole group compared with the control group (1.6% vs 1.4%; relative risk (RR), 1.13; 95% confidence interval (CI), 0.3 to 4.23; p=0.739). The major fetal malformation rate did not significantly differ between the metronidazole-exposed group and control group despite including elective pregnancy terminations due to prenatally diagnosed malformations (2.6% vs 2.1%; RR, 1.26; 95% CI, 0.45 to 3.52; p=0.777) or after excluding chromosomal abnormalities and genetic disorders (2.1% vs 1.7%; RR, 1.2; 95% CI, 0.38 to 3.79). Although there was no difference between groups in rate of preterm births or mean gestational age, exposed infants had a lower mean birth weight than the controls (3253.3 g vs 3374.5 g' p=0.004) (Diav-Citrin et al, 2001).
    c) In a cohort study involving 124 women, use of metronidazole during pregnancy was not associated with an elevated risk of congenital abnormalities, preterm delivery, or low birth weight (Sorensen et al, 1999).
    d) Of children exposed in utero to metronidazole, no significant increase in relative risk for all cancers was observed. The authors suggested that although not statistically significant, a slight increase in risk for neuroblastomas (relative risk, 2.6; 95% confidence interval, 0.89 to 7.59) requires further study (Thapa et al, 1998).
    e) Oral metronidazole treatment during pregnancy was not associated with an increase in congenital abnormalities, according to the population-based Hungarian Case-Control Surveillance of Congenital Abnormalities. Researchers evaluated data on pregnant women who delivered infants with congenital abnormalities (CA) (n=17,300) and pregnant women who delivered healthy infants (n=30,663; matched for sex, birth week, and residence). Oral metronidazole exposure during pregnancy was significantly higher in the CA group compared with control group (3.8% vs 3.4%; p=0.01), with second- to third-month exposure reported in 0.66% and 0.53% of patients, respectively. Most women exposed to oral metronidazole received one 2-g dose or three 250-mg doses/day for 1 week. Exposure to other drugs was similar between the CA and control groups. Based on an analysis of case-control pairs, cleft lip with or without cleft palate was significantly associated with metronidazole exposure in the second to third months of pregnancy (odds ratio, 8.54; 95% confidence interval, 1.06 to 68.86), although this association was not confirmed through a comparison of cases and the total control group (Czeizel & Rockenbauer, 1998).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Metronidazole is secreted in human breast milk at similar concentrations as found in plasma (Prod Info FLAGYL(R) oral tablets, 2015; Prod Info Flagyl(R) ER extended release oral tablets, 2010; Prod Info metronidazole USP RTU(R) injection, 2009). Considering the importance of the drug to the mother, either discontinue breastfeeding, discontinue therapy, or have the mother pump and discard her breast milk during therapy and for 24 hours after discontinuation (Prod Info FLAGYL(R) oral tablets, 2015).
    B) LACK OF EFFECT
    1) METRONIDAZOLE
    a) During administration of metronidazole 400 mg orally 3 times daily to 12 breastfeeding mothers, the mean milk-to-plasma ratio was 0.9 for metronidazole and 0.76 for hydroxymetronidazole; the mean milk concentration for metronidazole was 15.5 mcg/mL and 5.7 mcg/mL for hydroxymetronidazole. The concentrations of metronidazole in infant plasma ranged from 1.3 to 2.4 mcg/mL and 1.1 to 2.4 mcg/mL for hydroxymetronidazole. No adverse effects were attributable to the metronidazole in the infants. Assuming a daily intake of 500 mL of milk, the breastfeeding infant would ingest 6.25 mg of metronidazole daily; this is less than 10% of the recommended daily dose in infants. Based on these findings, it was suggested that oral doses of 400 mg 3 times daily are safe for breastfeeding mothers (Passmore et al, 1988).
    b) In one study, 15 nursing mothers with puerperal endometritis were treated with metronidazole. Mean maternal and infant plasma levels were 12.5 mcg/mL (range 3.7 to 17.9 mcg/mL) and 2.4 mcg/mL (range 0.6 to 4.7 mcg/mL), respectively. Corresponding maternal and infant plasma levels for women receiving 600 mg of metronidazole daily were 5 mcg/mL (range 1 to 11.6 mcg/mL) and 0.8 mcg/mL (range 0.3 to 1.4 mcg/mL). The maternal milk-to-plasma ratio was calculated to be 1. The maximum intake by an infant in the study was 3 mg/kg, assuming a daily intake of 500 mL of breast milk. No adverse reactions were observed in the infants (Heisterberg & Branebjerg, 1983).
    c) A study examined 10 nursing infants of mothers receiving a single 200-mg dose of metronidazole who were noted to have breast milk concentrations of metronidazole ranging from 1 to 7.7 mcg/mL at 4 to 12 hours. In most mothers, breast milk concentrations were about 100% of the corresponding serum drug concentrations, although a range of 45% to 180% was reported. Serum metronidazole concentrations were measured in the infants, and 5 infants were noted to have very low serum levels and the other 5 had no detectable levels. The authors noted that no infants developed adverse effects (Gray, 1961).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) METRONIDAZOLE
    a) Male animals treated with metronidazole doses similar to the maximum recommended clinical dose for 6 weeks or longer experienced infertility, severe degeneration of the seminiferous epithelium in the testes, decreased testicular spermatid counts, and decreased epididymal sperm counts. Fertility was restored in most animals 8 weeks after therapy discontinuation (Prod Info FLAGYL(R) oral tablets, 2015).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, adequate data concerning an association between carcinogenicity and metronidazole in humans is lacking.
    3.21.3) HUMAN STUDIES
    A) BRONCHOGENIC CARCINOMA
    1) CASE SERIES: In a long-term follow-up study of 15 to 25 years, the risk of cancer was studied in a cohort of 771 women exposed to metronidazole for the treatment of vaginal trichomoniasis. The only significant increased risk found was a 2.5 times the risk for bronchogenic carcinoma. Although this ratio is adjusted for smoking status, at least 9 of the 12 women with this cancer had a history of smoking, thus a definite relationship to metronidazole cannot be assumed (Beard et al, 1988).
    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) MICE AND RATS: Metronidazole was carcinogenic in several studies of mice and rats. Pulmonary tumors occurred in all 6 reported mice studies, including 1 study of mice that were administered the drug only every fourth week. An increase of both pulmonary neoplasms and malignant lymphomas were seen with lifetime feeding regimens of the drug to mice. Male mice treated with a similar dose as the maximum recommended daily human dose, based on body surface area comparisons (approximately 1500 mg/m(2)), showed an increase in malignant liver tumors. Hepatic and mammary tumors were increased in female rats given oral metronidazole compared with controls (Prod Info FLAGYL(R) 375 oral capsules, 2013; Prod Info FLAGYL(R) oral tablets, 2013; Prod Info FLAGYL ER(R) oral extended release tablets, 2013; Prod Info FLAGYL(R) intravenous injection, 2013).
    B) LACK OF EFFECT
    1) Two hamster studies of lifetime tumorigenicity showed negative results (Prod Info FLAGYL(R) 375 oral capsules, 2013).(Prod Info FLAGYL(R) oral tablets, 2013; Prod Info FLAGYL ER(R) oral extended release tablets, 2013; Prod Info FLAGYL(R) intravenous injection, 2013).

Genotoxicity

    A) Mutagenic activity was observed during in vitro assay systems (eg, the Ames test) used to evaluate metronidazole. Mammal in vivo studies did not demonstrate genotoxic potential (Prod Info FLAGYL(R) 375 oral capsules, 2013; Prod Info FLAGYL(R) oral tablets, 2013; Prod Info FLAGYL ER(R) oral extended release tablets, 2013; Prod Info FLAGYL(R) intravenous injection, 2013).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Metronidazole plasma concentrations are not clinically useful or readily available.
    C) A CBC should be obtained if leukopenia is suspected clinically.
    D) Monitor serum electrolytes and glucose, and liver enzymes in symptomatic patients.
    E) 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.

Radiographic Studies

    A) MRI
    1) In patients with metronidazole-induced cerebellar toxicity, MRI of the brain often shows lesions involving the dentate nuclei (bilateral and symmetric) in the cerebellum. The tectum, red nucleus, periaqueductal gray matter, and dorsal pons, dorsal medulla, and the corpus callosum may also be affected. In all cases involving corpus callosum, the splenium is also affected. All lesions are generally reversible after withdrawal of metronidazole (Sharma et al, 2009).
    2) CASE REPORT: In a patient with metronidazole-induced encephalopathy, MRI imaging showed gadolinium-enhanced lesions in the corpus callosum, but a follow-up MRI showed prominent cystic changes in the bilateral white matter and corpus callosum (Furukawa et al, 2015).
    3) CASE REPORT: A 43-year-old man presented with a 4-day history of slurred speech, generalized weakness, vertigo, and ataxia, approximately 2 months after starting metronidazole therapy (400 mg orally 3 times daily) for an amebic liver abscess. His neurological exam showed horizontal nystagmus to the left and positive cerebellar signs. Laboratory results revealed elevated liver enzymes; CSF examination revealed 2 cells/mm(3) with glucose of 37 mg/dL, protein 33 mg/dL, chloride 121 mmol/L and negative for cryptococcal antigen. A brain MRI revealed symmetrical areas of altered signal intensity, appearing hyperintense on T2W and fluid-attenuated inversion-recovery images and involving the dentate nuclei, dorsal pons, and splenium of the corpus callosum. Diffusion restriction on diffusion-weighted/apparent diffusion coefficient mapping was also observed. He recovered following the cessation of metronidazole therapy (Kalia et al, 2010).
    4) CASE REPORT: Cerebellar toxicity (severe ataxia, dysdiadochokinesis, and past-pointing) developed in a 61-year-old transplant recipient after taking oral metronidazole 1.2 g daily for 77 days. An MRI of the brain revealed increased T2-signal intensity in the dentate nuclei bilaterally, more noticeable on the fluid-attenuated inversion recovery (FLAIR) sequences. A brain CT was normal. He recovered gradually following the discontinuation of metronidazole and supportive therapy (Graves et al, 2009).
    5) CASE REPORT - A 58-year-old woman with a history of diabetic nephropathy and chronic renal failure developed encephalopathy approximately 2 days after beginning a course of metronidazole (dose adjusted for renal failure) for treatment of a postoperative wound infection. The patient presented with dysarthria, and bilateral dysmetria and dysdiadochokinesia. Magnetic resonance imaging of the brain revealed cerebral and cerebellar atrophy, and ischemic, gliotic lesions within the periventricular white matter, pons, and basal ganglia. Drug toxicity was suspected, and metronidazole was discontinued. Rapid recovery from neurological deficits occurred within 1 day of drug discontinuation, and 2 days later, neurological examination findings were returning to within normal limits (Arik et al, 2001).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) 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.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic patients with unintentional ingestions can be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) 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.

Monitoring

    A) Monitor vital signs and mental status.
    B) Metronidazole plasma concentrations are not clinically useful or readily available.
    C) A CBC should be obtained if leukopenia is suspected clinically.
    D) Monitor serum electrolytes and glucose, and liver enzymes in symptomatic patients.
    E) 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.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Most patients remain asymptomatic; prehospital decontamination is not routinely recommended.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY: Consider decontamination if a patient presents promptly after a large oral overdose, is not vomiting, and does not have CNS depression or seizures.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor vital signs and mental status.
    2) Metronidazole plasma concentrations are not clinically useful or readily available.
    3) A CBC should be obtained if leukopenia is suspected clinically.
    4) Monitor serum electrolytes and glucose, and liver enzymes in symptomatic patients.
    5) 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.
    6) 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.
    B) NAUSEA
    1) Antiemetics may be used to control nausea.
    C) TACHYCARDIA
    1) 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.
    D) HYPOTENSIVE EPISODE
    1) 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.
    E) HEADACHE
    1) Oral analgesics can be given if tolerated. If the patient is nauseated, IV analgesics can be given.
    F) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis and hemoperfusion are UNLIKELY to be of value for metronidazole.
    2) Metronidazole is rapidly removed by hemodialysis. In one study 45% of a 500-mg was removed during 4 hours of hemodialysis (Somogyi et al, 1983). In another study 24% to 35% was removed during 4 hours (Lau et al, 1986).
    3) CASE REPORT - A 62-year-old man, with end-stage renal disease and on dialysis 3 times per week, ingested 17 500-mg tablets of metronidazole (8.5 grams) on the day of his scheduled hemodialysis session. The patient had also taken 4 doses of metronidazole over the previous 2 days (1 tablet twice daily). Gastrointestinal decontamination was not performed and the patient continued with his scheduled hemodialysis session. The pre-dialysis venous metronidazole concentration, 9.5 hours post-ingestion, was 120 mcg/mL. The patient underwent 4 hours of hemodialysis, with a blood flow rate of 450 mL/min at a dialysate flow rate of 800 mL/min. His post-dialysis venous metronidazole, obtained 1 hour after dialysis, was 32 mcg/mL. The patient's total body metronidazole concentration decreased from 5.5 to 1.5 grams (47% of the ingested 8.5-gram dose) (Burda et al, 2005). Following the overdose ingestion, the patient did not exhibit any evidence of metronidazole toxicity (ie, nausea, vomiting, diarrhea, neurotoxicity, or hepatotoxicity). The authors speculate that early hemodialysis may have prevented the occurrence of prolonged high concentrations of metronidazole's potentially neurotoxic hydroxyl metabolite, thereby preventing the development of neurotoxicity in this patient.
    B) PERITONEAL DIALYSIS
    1) Peritoneal dialysis is less efficient. During a 7.5-hour period, 10% of the dose was removed (Cassey et al, 1983).

Abstracts

Case Reports

    A) ADULT
    1) A 15-year-old ingested 4.2 g of metronidazole and a 19-year-old ingested 12 g of metronidazole in suicide attempts. No adverse effects were noted and clinical laboratory findings in each case were normal (Lewis & Kenna, 1965).

Range Of Toxicity

Summary

    A) 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. Encephalopathy has been reported in patients taking metronidazole with cumulative doses from 0.25 g to 182 g. Patients may present with cerebellar dysfunction, altered mental status, and seizures. Most patients recover following the discontinuation of metronidazole. 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.
    B) 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.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) METRONIDAZOLE
    a) Usual oral therapeutic dose is 250 to 750 milligrams three times daily for five to ten days depending on indication (Prod Info Flagyl 375 capsules, metronidazole, G.D, 1999).
    b) TRICHOMONIASIS: 375 mg two times daily for seven consecutive days (Prod Info Flagyl 375 capsules, metronidazole, G.D, 1999).
    c) AMEBIASIS
    1) Acute Intestinal amebiasis: 750 mg orally three times daily for 5 to 10 days (Prod Info Flagyl 375 capsules, metronidazole, G.D, 1999).
    2) Amebic liver abscess: 750 mg orally three times daily for 5 to 10 days (Prod Info Flagyl 375 capsules, metronidazole, G.D, 1999).
    d) ANAEROBIC BACTERIAL INFECTIONS
    1) Usual adult dosage is 7.5 milligrams/kilogram every 6 hours. A maximum of 4 grams should not be exceeded during a 24-hour period (Prod Info Flagyl 375 capsules, metronidazole, G.D, 1999).
    e) Caution should be used in patients with hepatic insufficiency (Prod Info Flagyl 375 capsules, metronidazole, G.D, 1999).
    f) INTRAVENOUS DOSING: for treatment of anaerobic infections: loading dose 15 milligrams/kilogram infused over one hour (note: approximately 1 gram for a 70-kilogram adult), followed by 7.5 milligrams/kilogram infused over one hour every six hours. The maximum recommended dose is 4 grams intravenously in 24 hours. Parenteral therapy should be changed to oral as soon as possible (Prod Info Flagyl 375 capsules, metronidazole, G.D, 1999).
    2) TINIDAZOLE
    a) AMEBIASIS: A 2 gram dose/day for up to 3 days taken with food. For amebic liver abscess, a 2 gram dose/day for 3 to 5 days taken with food is recommended (Prod Info Tindamax(TM),, 2004).
    b) TRICHOMONIASIS: A single oral dose of 2 grams taken with food, in both males and females. Sexual partners should be treated at the same time with the same dose (Prod Info Tindamax(TM),, 2004).
    c) GIARDIASIS: A single oral dose of 2 grams taken with food (Prod Info Tindamax(TM),, 2004).
    7.2.2) PEDIATRIC
    A) ORAL
    1) ANAEROBIC INFECTIONS
    a) METRONIDAZOLE: 30 to 40 mg/kg/day orally divided every 6 to 8 hours. Maximum 500 mg/dose (Gollin et al, 2002; Rice et al, 2001; Banani & Talei, 1999; Brook, 1983).
    2) AMEBIC DYSENTERY OR LIVER ABSCESS
    a) METRONIDAZOLE: 35 to 50 mg/kg/day orally, divided every 8 hours for 10 days; up to 750 mg/dose (Prod Info Flagyl(R) 375 oral capsules, 2010; Prod Info Flagyl(R) oral tablets, 2010; Dykes et al, 1980).
    b) TINIDAZOLE: In children older than 3 years of age, 50 milligrams/kilogram/day (up to a total dose of 2 gram/day) for 3 to 5 days with food. NOTE: Based on limited data, therapy should not exceed 3 days. Children should be closely monitored when treatment exceeds three days (Prod Info Tindamax(TM),, 2004).
    3) BACTERIAL VAGINOSIS
    a) METRONIDAZOLE (12 years and older): 500 mg orally twice per day for 7 days (Workowski et al, 2010).
    4) CLOSTRIDIUM DIFFICILE
    a) METRONIDAZOLE: 30 mg/kg/day orally divided every 6 hours for 10 days. Maximum 500 mg/dose (American Society of Health-System Pharmacists, 1998).
    5) GIARDIA LAMBLIA
    a) METRONIDAZOLE: 15 to 22.5 mg/kg/day orally divided in 3 doses for 5 days, up to 250 milligrams/day (Sadjjadi et al, 2001; Ortiz et al, 2001; Heresi & Cleary, 1997; Misra et al, 1995; Dutta et al, 1994).
    b) TINIDAZOLE: In children older than three years of age, a single oral dose of 50 milligrams/kilogram (up to 2 grams) should be given with food (Prod Info Tindamax(TM),, 2004).
    6) HELICOBACTER PYLORI INFECTION
    a) METRONIDAZOLE: 20 mg/kg/day orally divided every 12 hours; maximum 500 mg/dose. Given in combination with amoxicillin 50 mcg/kg/day orally in 2 divided doses (maximum 1 g/dose) and omeprazole 1 mg/kg/day orally divided every 12 hours (maximum 20 mg/dose) for 7 to 14 days (Koletzko et al, 2011; Bourke et al, 2005; Gessner et al, 2005; Gold et al, 2000). Clarithromycin 15 to 20 mg/kg/day orally divided every 12 hours (maximum 500 mg/dose) can be used in place of amoxicillin (Koletzko et al, 2011; Gold et al, 2000).
    7) STD PROPHYLAXIS: SEXUAL ASSAULT
    a) METRONIDAZOLE: 12 years and older: 2 g orally as a single dose plus cefixime 400 mg orally (or ceftriaxone 250 mg IM) as a single dose plus azithromycin 1 g orally as a single dose (Workowski et al, 2010).
    8) TRICHOMONIASIS
    a) METRONIDAZOLE: 12 years and older: 2 g orally as a single dose (Workowski et al, 2010).
    B) INTRAVENOUS
    1) ANAEROBIC INFECTIONS
    a) METRONIDAZOLE: 22.5 to 30 mg/kg/day IV divided every 6 to 8 hours. Maximum 500 mg/dose (Emil et al, 2003; Gollin et al, 2002; Maltezou et al, 2001; Uhari et al, 1992; Kooi & Pit, 1990; Gutierrez et al, 1987; Foster et al, 1986).
    2) APPENDICITIS, PERFORATED
    a) METRONIDAZOLE: 2 years and older: 30 mg/kg/dose IV once daily in combination with ceftriaxone 50 mg/kg/dose IV once daily for 5 days. Maximum 1000 mg/dose; 1500 mg in obese children (Ostlie, 2011; St Peter et al, 2008; St Peter et al, 2006; Ostlie, 2011).
    3) SURGICAL PROPHYLAXIS
    a) METRONIDAZOLE: 7.5 to 15 mg/kg IV within 60 minutes before incision. Repeat intraoperatively within 2 half-lives (6 to 8 hours) if the operation is still in progress. Maximum 1 g/dose (Bratzler & Houck, 2004; None Listed, 1999; Foster et al, 1987; Dellinger et al, 1994).
    C) VAGINAL
    1) BACTERIAL VAGINOSIS
    a) METRONIDAZOLE: 12 years and older: One full applicator (0.5 g of 0.75% gel) intravaginally once a day for 5 days (Workowski et al, 2010).

Maximum Tolerated Exposure

    A) METRONIDAZOLE
    1) Single oral doses of metronidazole of 15 g have been tolerated with only minimal clinical effects (i.e., nausea, vomiting, and ataxia) (Prod Info Flagyl 375 capsules, metronidazole, G.D, 1999).
    2) Neurotoxic effects which have included seizures and peripheral neuropathy have occurred after 5 to 7 days of doses of 6 g to 10.4 g every other day (Prod Info Flagyl 375 capsules, metronidazole, G.D, 1999).
    3) Encephalopathy has been reported in patients taking metronidazole (Wu et al, 2015; Park et al, 2011; Kalia et al, 2010; Arik et al, 2001) with cumulative doses from 0.25 g to 182 g. Patients may present with cerebellar dysfunction, altered mental status, and seizures. Most patients recover following the discontinuation of metronidazole (Wu et al, 2015).
    4) CASE REPORT: Acute ingestion of 12 g metronidazole in a 19-year-old woman with no adverse effects has been reported (Lewis & Kenna, 1965).
    5) CASE REPORT: An ingestion of 12.5 g in a woman resulted in a transient increase in hepatic enzymes (Bank, 1995).
    6) CASE REPORT: A 62-year-old man did not exhibit any evidence of metronidazole toxicity (ie, nausea, vomiting, diarrhea, neurotoxicity, hepatotoxicity) after ingesting 8.5 g of metronidazole (Burda et al, 2005).
    7) CASE REPORT: A 37-year-old woman with a history of Crohn's disease developed cerebellar syndrome and axonal neuropathy after taking metronidazole 1500 mg/day for 3 months (cumulative dose: 180 g). Following metronidazole discontinuation, her symptoms gradually improved. At 2-year follow-up, she only had stocking hypoesthesia (Cacao et al, 2015).
    B) TINIDAZOLE
    1) At the time of this review, there are no reports of human overdose with tinidazole (Prod Info Tindamax(TM),, 2004).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) A 50-year-old man developed ataxia and dysarthric speech following treatment with lactulose and metronidazole (500 mg orally 3 times daily) for hepatic encephalopathy and subacute bacterial peritonitis. A magnetic resonance image of the brain showed bilateral enhancement of the cerebellar dentate nuclei. Approximately 1 hour after he received a single dose of metronidazole 500 mg, his serum metronidazole level was 50 mcg/mL (toxic range, greater than 11.5 mcg/mL). Following the discontinuation of metronidazole, his symptoms improved significantly over the next 2 weeks (Deenadayalu et al, 2005).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) METRONIDAZOLE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 870 mg/kg (RTECS , 2001)
    2) LD50- (ORAL)MOUSE:
    a) 3800 mg/kg (RTECS , 2001)
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 3640 mg/kg (RTECS , 2001)
    4) LD50- (ORAL)RAT:
    a) 3 g/kg (RTECS , 2001)
    B) TINIDAZOLE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) > 2,300 mg/kg (Prod Info Tindamax(TM),, 2004)
    2) LD50- (ORAL)MOUSE:
    a) > 3,600 mg/kg(Prod Info Tindamax(TM),, 2004)
    3) LD50- (INTRAPERITONEAL)RAT:
    a) > 2,000 mg/kg (Prod Info Tindamax(TM),, 2004)
    4) LD50- (ORAL)RAT:
    a) >2,000 mg/kg(Prod Info Tindamax(TM),, 2004)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) METRONIDAZOLE is an antiprotozoal agent commonly used in the treatment of Trichomonas Vaginalis. The drug is also used in the treatment of Amebiasis and giardiasis. Metronidazole is effective against many anaerobic bacteria also.
    B) TINIDAZOLE: is also a synthetic antiprotozoal agent. The nitro group of tinidazole is reduced by cell extracts of Trichomonas, which may be responsible for its antiprotozoal activity. However, the mechanism by which tinidazole exerts its activity against Giardia and Entamoeba species remains unknown (Prod Info Tindamax(TM),, 2004).

Toxicologic Mechanism

    A) METRONIDAZOLE: It has been postulated, but not proven, that the neurotoxicity described during metronidazole therapy is related to conversion by gut flora to a neurotoxic thiamine analog (Alston, 1985).

Physicochemical

Physical Characteristics

    A) METRONIDAZOLE is a white to pale yellow crystalline powder that is slightly soluble in alcohol and has a solubility in water of 10 mg/mL (at 20 degrees C) (Prod Info NORITATE(R) topical cream, 2003) and an osmolarity of 310 milliosmoles (mOsmol)/L (calc) (Prod Info metronidazole USP RTU(R) injection, 2009).

Ph

    A) METRONIDAZOLE: 5.5 (range: 4.5 to 7) (Prod Info metronidazole USP RTU(R) injection, 2009)

Molecular Weight

    A) METRONIDAZOLE: 171.16 (Prod Info NORITATE(R) topical cream, 2003)
    B) METRONIDAZOLE HYDROCHLORIDE: 207.62 (Fleeger, 1988)

Animal Toxicology

Clinical Effects

    11.1.3) CANINE/DOG
    A) Metronidazole 67.3 to 124 milligrams/kilogram produced anorexia, intermittent vomiting, generalized ataxia, and vertical, positional nystagmus in 5 dogs receiving metronidazole for periods of 3 to 14 days (Dow et al, 1989).

Range Of Toxicity

    11.3.1) THERAPEUTIC DOSE
    A) DOG
    1) 30 mg/kg/day administered in divided doses every 8 hours (Dow et al, 1989).
    11.3.2) MINIMAL TOXIC DOSE
    A) DOG
    1) Oral metronidazole 250 mg/kg/day for 4 to 6 days produced CNS dysfunction (nystagmus, opisthotonos, hind limb and lumbar muscle spasms, and dorsiflexion of the tail) in dogs (Scharer, 1972).
    2) Oral metronidazole 150 mg/kg/day for 4 weeks produced CNS dysfunction, including seizures, in one dog (Scharer, 1972).
    3) Oral metronidazole 67.3 to 129 mg/kg for 3 to 14 days produced CNS dysfunction in 5 dogs (Dow et al, 1989). Three of five dogs improved slowly and recovered completely over several months. Two dogs were euthanized because of severe neurologic dysfunction.

Kinetics

    11.5.1) ABSORPTION
    A) SPECIFIC TOXIN
    1) BIOAVAILABILITY - 59% to 100% following oral administration of metronidazole in dogs (Neff-Davis et al, 1981).

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