Introduction
Metronidazole is a nitroimidazole antibiotic and antiprotozoal agent that has been in clinical use since the 1960s. It remains a cornerstone therapy for anaerobic bacterial infections and certain parasitic infections worldwide. This synthetic antimicrobial demonstrates selective toxicity against anaerobic microorganisms through a unique mechanism of action.
Mechanism of Action
Metronidazole exerts its antimicrobial effects through a complex biochemical mechanism. The drug enters microbial cells where it is reduced by ferredoxin or flavodoxin-mediated electron transport proteins, which are present in anaerobic organisms. This reduction creates reactive nitro radical ions that damage microbial DNA through strand breakage and inhibition of nucleic acid synthesis. The selective toxicity arises because mammalian cells lack the electron transport proteins necessary to reduce metronidazole to its active form.
Indications
FDA-approved indications:- Treatment of symptomatic trichomoniasis
- Treatment of asymptomatic trichomoniasis to prevent transmission
- Treatment of giardiasis
- Treatment of amebic dysentery and amebic liver abscess
- Treatment of anaerobic bacterial infections including:
- Intra-abdominal infections - Gynecological infections - Bacterial septicemia - Bone and joint infections - CNS infections - Endocarditis - Pneumonia - Skin and skin structure infections
Common off-label uses:- Helicobacter pylori eradication (as part of combination therapy)
- Antibiotic-associated pseudomembranous colitis caused by Clostridium difficile
- Surgical prophylaxis in colorectal procedures
- Treatment of bacterial vaginosis
- Treatment of rosacea (topical formulation)
Dosage and Administration
Adult dosing:- Anaerobic infections: 500 mg IV every 6-8 hours or 7.5 mg/kg every 6 hours
- Trichomoniasis: 2 g orally as single dose or 500 mg twice daily for 7 days
- Giardiasis: 250 mg three times daily for 5-7 days
- Amebiasis: 500-750 mg three times daily for 5-10 days
- C. difficile infection: 500 mg orally three times daily for 10-14 days
- Surgical prophylaxis: 15 mg/kg IV completed 1 hour before surgery
- Anaerobic infections: 30 mg/kg/day divided every 6 hours
- Amebiasis: 35-50 mg/kg/day divided every 8 hours for 10 days
- Giardiasis: 15 mg/kg/day divided every 8 hours for 5-7 days
- Hepatic impairment: Reduce dose by 50% in severe liver disease
- Renal impairment: No dosage adjustment required for mild-moderate impairment; use with caution in severe renal failure
- Elderly: Consider reduced dosing due to possible decreased hepatic function
- Dialysis: Administer dose after hemodialysis
Pharmacokinetics
Absorption: Well absorbed orally (≥90% bioavailability); not significantly affected by food Distribution: Widely distributed throughout body tissues and fluids, including CSF, bone, abscesses, and placental barrier Protein binding: <20% Metabolism: Extensively hepatic via oxidation and glucuronidation; produces active metabolites Elimination: Half-life 6-8 hours; primarily renal excretion (60-80%) with some fecal elimination Steady state: Achieved within 1-2 days with regular dosingContraindications
- Hypersensitivity to metronidazole, other nitroimidazole derivatives, or any component of the formulation
- First trimester of pregnancy (relative contraindication for trichomoniasis treatment)
- Concurrent use with disulfiram or within 2 weeks of disulfiram therapy
- Concurrent alcohol consumption or alcohol-containing medications
Warnings and Precautions
Black Box Warning:- Carcinogenicity in rodents; clinical significance in humans unknown
- Potential mutagenic effects
- Seizures and peripheral neuropathy: Monitor for neurological symptoms
- Candida superinfection: May occur with prolonged use
- Blood dyscrasias: Leukopenia reported; monitor blood counts with prolonged therapy
- CNS effects: Dizziness, confusion, ataxia; caution in patients with CNS disorders
- Dialysis patients: May accumulate in end-stage renal disease
- Pregnancy: Category B; use only if clearly needed after first trimester
- Lactation: Secreted in breast milk; consider temporary discontinuation of breastfeeding
Drug Interactions
Major interactions:- Alcohol: Disulfiram-like reaction (flushing, nausea, vomiting, tachycardia)
- Warfarin: Enhanced anticoagulant effect; monitor INR closely
- Lithium: Increased lithium levels and potential toxicity
- Disulfiram: Psychotic reactions
- CYP450 inducers (phenobarbital, phenytoin): Decreased metronidazole levels
- CYP450 inhibitors (cimetidine): Increased metronidazole levels
- Oral contraceptives: Potential decreased efficacy
- Cyclosporine: Possible increased cyclosporine levels
- Fluorouracil: Enhanced toxicity potential
- Cholestyramine: Decreased metronidazole absorption
Adverse Effects
Common (≥1%):- Gastrointestinal: Nausea (10%), vomiting, diarrhea, abdominal cramping, metallic taste
- Neurological: Headache, dizziness
- Other: Darkened urine (harmless)
- Peripheral neuropathy (may be irreversible)
- Seizures
- Encephalopathy
- Pancreatitis
- Optic neuropathy
- Leukopenia, neutropenia
- Allergic reactions: rash, pruritus, urticaria
- Flushing, tachycardia with alcohol consumption
Monitoring Parameters
- Clinical response to therapy
- Complete blood count with prolonged therapy (>10 days)
- Neurological examination for signs of peripheral neuropathy
- Liver function tests in patients with hepatic impairment
- INR in patients on warfarin therapy
- Signs of superinfection or candidiasis
- adherence to alcohol avoidance
Patient Education
- Complete the full course of therapy even if feeling better
- Avoid alcohol and alcohol-containing products during treatment and for at least 48 hours after completion
- May cause metallic taste and darkened urine (harmless)
- Report any numbness, tingling, or pain in hands or feet
- Report seizures, dizziness, or confusion
- Do not crush or chew extended-release tablets
- Take with food if gastrointestinal upset occurs
- Use effective non-hormonal contraception if taking oral contraceptives
- Inform all healthcare providers about metronidazole use
References
1. FDA Prescribing Information: Flagyl (metronidazole) 2. Gilbert DN, et al. The Sanford Guide to Antimicrobial Therapy. 2022 3. Lexicomp Online: Metronidazole monograph 4. Clinical Pharmacology [Internet]: Metronidazole 5. Freeman CD, et al. Metronidazole: A therapeutic review and update. Drugs. 1997 6. Löfmark S, et al. Metronidazole is still the drug of choice for treatment of anaerobic infections. Clin Infect Dis. 2010 7. Johnson J, et al. ASCP Therapeutic Guidelines on Antimicrobial Therapy. 2021 8. USP DI: Metronidazole Drug Information 9. McEvoy GK, et al. AHFS Drug Information. 2022 10. Manufacturer's prescribing information and clinical studies
This monograph is for educational purposes only and does not replace clinical judgment. Always consult appropriate references and clinical guidelines for specific patient situations.