Introduction
Flagyl (metronidazole) is a nitroimidazole antimicrobial agent with potent activity against anaerobic bacteria and protozoa. First introduced in the 1960s, it remains a cornerstone therapy for various anaerobic infections and certain parasitic infections. This comprehensive monograph provides evidence-based information for healthcare professionals regarding the appropriate use of Flagyl.
Mechanism of Action
Metronidazole exerts its bactericidal and antiprotozoal effects through a complex biochemical mechanism. The drug enters microbial cells where it is reduced by ferredoxin or flavodoxin-mediated electron transport proteins, forming reactive nitroso-free radicals. These reactive intermediates interact with microbial DNA, causing strand breaks and inhibition of nucleic acid synthesis, ultimately leading to cell death. The selective toxicity against anaerobic microorganisms occurs because aerobic cells lack the necessary electron transport proteins to reduce metronidazole to its active form.
Indications
FDA-approved indications include:
- Treatment of symptomatic trichomoniasis
- Treatment of asymptomatic trichomoniasis to prevent transmission
- Treatment of intestinal amebiasis and amebic liver abscess
- Treatment of anaerobic bacterial infections including:
- Intra-abdominal infections - Skin and skin structure infections - Gynecologic infections - Bacterial septicemia - Bone and joint infections - CNS infections - Lower respiratory tract infections - Endocarditis
Off-label uses include:
- Treatment of Clostridioides difficile infection
- Helicobacter pylori eradication (as part of combination therapy)
- Surgical prophylaxis in colorectal procedures
- Treatment of bacterial vaginosis
- Treatment of giardiasis
Dosage and Administration
Adults:- Trichomoniasis: 2 g orally as single dose or 500 mg twice daily for 7 days
- Amebiasis: 500-750 mg orally three times daily for 5-10 days
- Anaerobic infections: 500 mg IV every 6-8 hours or 7.5 mg/kg every 6 hours
- C. difficile infection: 500 mg orally three times daily for 10-14 days
- Amebiasis: 35-50 mg/kg/day orally in 3 divided doses for 10 days
- Anaerobic infections: 30 mg/kg/day IV in 4 divided doses
- No dosage adjustment necessary
- Hemodialysis: Administer dose after dialysis session
- Use with caution in severe hepatic impairment
- Consider reduced dosing frequency
Pharmacokinetics
Absorption: Well absorbed orally (≥80% bioavailability); not significantly affected by food Distribution: Widely distributed throughout body tissues and fluids, including CSF, bone, abscesses, and placental barrier; Vd: 0.6-1.1 L/kg; protein binding: <20% Metabolism: Extensively hepatic via CYP450 enzymes (primarily CYP2A6, CYP3A4) to active and inactive metabolites Elimination: Primarily renal (60-80%) with some fecal excretion; elimination half-life: 6-8 hoursContraindications
- Hypersensitivity to metronidazole, other nitroimidazole derivatives, or any component of the formulation
- First trimester of pregnancy for trichomoniasis treatment
- Concurrent administration with disulfiram or within 2 weeks of disulfiram therapy
- Concurrent administration with alcohol or alcohol-containing products
Warnings and Precautions
Black Box Warning: Carcinogenicity in rodents; use should be reserved for approved indications Seizures and peripheral neuropathy: May occur; discontinue if neurological abnormalities develop C. difficile-associated diarrhea: May occur and range from mild to life-threatening Embryofetal toxicity: Avoid use during first trimester for trichomoniasis treatment Hepatic impairment: Use with caution in patients with severe liver disease Blood dyscrasias: Leukopenia and neutropenia have been reportedDrug Interactions
Disulfiram: Psychotic reactions reported with concurrent use Alcohol: Disulfiram-like reaction (flushing, nausea, vomiting, tachycardia) Warfarin: Potentiates anticoagulant effect; monitor INR closely Lithium: May increase lithium concentrations Cyclosporine: May increase cyclosporine concentrations Phenytoin: May decrease phenytoin metabolism CYP3A4 inducers: May decrease metronidazole concentrations CYP3A4 inhibitors: May increase metronidazole concentrationsAdverse Effects
Common (≥1%):- Nausea (10-12%)
- Metallic taste (5-10%)
- Headache (5-8%)
- Anorexia (4-6%)
- Vomiting (3-5%)
- Diarrhea (2-4%)
- Abdominal discomfort (2-3%)
- Dizziness (2-3%)
- Seizures
- Peripheral neuropathy
- Encephalopathy
- Aseptic meningitis
- Optic neuropathy
- Stevens-Johnson syndrome
- Agranulocytosis
- Pancreatitis
- Hepatitis
Monitoring Parameters
- Clinical response to therapy
- Complete blood count with differential (especially with prolonged therapy)
- Neurological symptoms (numbness, paresthesia, seizures)
- Liver function tests (in patients with hepatic impairment or prolonged therapy)
- Signs of superinfection or C. difficile infection
- For IV administration: monitor for thrombophlebitis
Patient Education
- Complete full course of therapy even if feeling better
- Avoid alcohol and alcohol-containing products during therapy and for at least 3 days after completion
- May cause metallic taste; this is temporary and will resolve after treatment
- Take with food if gastrointestinal upset occurs
- Report any numbness, tingling, or seizures immediately
- Use effective contraception during treatment
- May cause darkening of urine; this is harmless
- Do not crush or chew extended-release tablets
References
1. FDA Prescribing Information: Flagyl (metronidazole) 2. Gilbert DN, et al. The Sanford Guide to Antimicrobial Therapy. 52nd ed. 3. Lexicomp Online. Metronidazole monograph. 4. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing. 5. Johnson & Johnson. Flagyl package insert. 6. Freeman CD, et al. Metronidazole: A therapeutic review and update. Drugs. 1997;54(5):679-708. 7. Löfmark S, et al. Metronidazole is still the drug of choice for treatment of anaerobic infections. Clin Infect Dis. 2010;50 Suppl 1:S16-23. 8. McDonald LC, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66(7):e1-e48.
This monograph is intended for educational purposes only and should not replace clinical judgment. Always consult current prescribing information and clinical guidelines.