Metronidazole (Flagyl)

• Core Dose: 500 mg IV or PO every 8 hours for serious anaerobic infections in adults
• Onset/Duration: Excellent oral bioavailability (~100%); half-life ~6–8 hours
• Key Dangers: Peripheral neuropathy, encephalopathy, seizures (with prolonged/high-dose therapy); disulfiram-like reaction with alcohol
• Special Considerations: Covers anaerobes and protozoa only (no aerobic coverage). Must pair with Gram-negative/Gram-positive agents. CNS penetration excellent for brain abscess. IV and PO dosing interchangeable when gut absorption intact

• Generic Name: Metronidazole
• Brand Names: Flagyl, Metro IV, various generics

Nitroimidazole antibiotic with antiprotozoal activity. Provides primarily anaerobic bacterial coverage with no clinically meaningful aerobic Gram-positive or Gram-negative activity.

Mechanism of Action:

• Prodrug taken up by anaerobic bacteria and protozoa and reduced by intracellular electron transport proteins (ferredoxin-like systems)
• Reduced nitro group forms reactive nitro radicals that interact with DNA
• Causes DNA strand breaks, loss of helical structure, and inhibition of nucleic acid synthesis
• Results in cell death
• Aerobic organisms lack the low-redox-potential electron transport systems required to reduce metronidazole, explaining selective activity against anaerobes and protozoa

Pharmacokinetics:

• Absorption: Oral bioavailability ~90–100%; oral and IV doses typically interchangeable at same dose when GI absorption intact
• Distribution: Volume of distribution ~0.6–0.9 L/kg; penetrates well into CNS, CSF, abscesses, bone, liver, vaginal secretions
• Metabolism: Primarily hepatic (oxidation, glucuronidation); several metabolites, some retain antimicrobial activity
• Elimination: Renal and biliary excretion of parent drug and metabolites; half-life ~6–8 hours in normal hepatic function
• Dose adjustments more critical in severe hepatic impairment; standard dosing generally acceptable with isolated renal impairment
• Metabolite accumulation may occur in severe renal failure

Empiric and Targeted Therapy:

• Intra-abdominal infections: Perforated viscus, diverticulitis with abscess, peritonitis (combined with Gram-negative coverage)
• Pelvic infections: PID, tubo-ovarian abscess, post-partum/post-abortal infections (with cephalosporin and doxycycline)
• CNS infections: Anaerobic brain abscess, subdural empyema, necrotizing lung infections (aspiration-related)
• Skin/soft tissue infections: Diabetic foot infections with anaerobic component
• Protozoal infections: Trichomoniasis, giardiasis, amebiasis
• C. difficile infection: Now second-line/adjunct when vancomycin/fidaxomicin unavailable or IV adjunct in fulminant disease with ileus

Available Forms:

• IV Solution: 500 mg/100 mL premixed bags (5 mg/mL) for intermittent IV infusion
• Oral: 250 mg, 500 mg tablets/capsules widely available
• Oral Suspension: Institution-dependent or compounded for pediatrics

Standard Adult Dosing:

Absolute Contraindications:

• Documented hypersensitivity to metronidazole or other nitroimidazole derivatives (tinidazole)
• Use of disulfiram within last 2 weeks (risk of psychotic reactions)
• Alcohol or propylene glycol use during therapy and 24–48 hours after (disulfiram-like reaction)

Major Precautions:

• Seizure history or CNS disease: Associated with encephalopathy and seizures (especially high doses/prolonged use)
• Severe hepatic impairment: Reduced clearance, increased neurotoxicity risk; dose reduction and monitoring required
• Prolonged/high-dose therapy: Increased risk of peripheral neuropathy and CNS toxicity
• Pregnancy: Generally compatible in many indications (especially 2nd/3rd trimester); avoid high-dose/prolonged therapy in 1st trimester when alternatives available
• Lactation: Excreted in breast milk; short courses generally acceptable; consider timing or pumping-and-dumping with high-dose regimens
• Concurrent warfarin: Metronidazole can increase INR via CYP2C9 inhibition; closer monitoring and dose adjustment may be necessary

Common:

• Nausea, vomiting, abdominal discomfort, diarrhea
• Metallic taste in mouth; dry mouth
• Headache, dizziness, mild fatigue
• Dark or reddish-brown urine (harmless metabolite effect)

Serious:

• Peripheral neuropathy (numbness, paresthesias, gait disturbance) with prolonged/high-dose therapy
• Encephalopathy, ataxia, seizures, or cerebellar syndrome (usually reversible after discontinuation)
• Severe hypersensitivity reactions (Stevens-Johnson syndrome, anaphylaxis – rare)
• Hematologic abnormalities (leukopenia, neutropenia, thrombocytopenia)
• Severe hepatotoxicity (rare, more likely with underlying liver disease)

• Disulfiram: Concurrent or recent use (within 2 weeks) may cause psychotic reactions; contraindicated
• Alcohol: Disulfiram-like reaction (flushing, tachycardia, nausea); avoid during therapy and 24–48 hours after
• Warfarin: Metronidazole inhibits CYP2C9, increasing INR; monitor closely and adjust warfarin dose as needed
• Lithium: May increase lithium levels; monitor lithium concentrations
• Phenytoin/Phenobarbital: May alter levels of both drugs; monitor phenytoin levels

Renal Impairment:

• Standard dosing generally acceptable with isolated renal impairment
• Metabolite accumulation may occur in severe renal failure; monitor closely

Hepatic Impairment:

• Mild to moderate: Monitor closely; may require dose reduction
• Severe: Reduce total daily dose by ~50%; individualize interval based on severity; monitor for neurotoxicity

Pregnancy:

• Generally compatible in many indications, especially 2nd and 3rd trimesters
• Avoid high-dose or prolonged therapy in 1st trimester when alternatives are available

Lactation:

• Excreted in breast milk
• Short courses generally acceptable
• Consider timing of doses or pumping-and-dumping with high-dose regimens

Clinical Monitoring:

• Clinical response: resolution of fever, leukocytosis, local signs of infection; ensure adequate source control
• Neurologic status: watch for neuropathy, ataxia, confusion, or seizures in high-dose or >2–3 weeks therapy
• C. difficile monitoring: stool frequency, abdominal exam, signs of toxic megacolon

Laboratory Monitoring:

• Liver function tests (AST/ALT, bilirubin) for prolonged therapy or underlying liver disease
• CBC with differential for patients on prolonged therapy
• INR in patients on warfarin when metronidazole started or stopped

• 1. Lexicomp. (2024). Metronidazole: Drug information. Wolters Kluwer.
• 2. Brook, I. (2016). Metronidazole and other nitroimidazoles. In J. E. Bennett, R. Dolin, & M. J. Blaser (Eds.), Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases (8th ed.). Elsevier.
• 3. Johnson, S., Lavergne, V., Skinner, A. M., Gonzales-Luna, A. J., Garey, K. W., Kelly, C. P., & Wilcox, M. H. (2021). Clinical practice guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 focused update guidelines on management of Clostridioides difficile infection in adults. Clinical Infectious Diseases, 73(5), e1029–e1044. https://doi.org/10.1093/cid/ciab549
• 4. Antimicrobial Therapy, Inc. (2021). Metronidazole. In Sanford Guide to Antimicrobial Therapy.
• 5. Lofmark, S., Edlund, C., & Nord, C. E. (2010). Metronidazole is still the drug of choice for treatment of anaerobic infections. Clinical Infectious Diseases, 50(Suppl 1), S16–S23. https://doi.org/10.1086/647939