Metronidazole

Metronidazole is a nitroimidazole with activity against anaerobic bacteria and protozoa, used for intra-abdominal, pelvic and brain abscess, Clostridioides difficile infection (alternative), bacterial vaginosis, trichomoniasis, amoebiasis and giardiasis. It is cheap and widely available.

Classification. Nitroimidazole.

Mechanism. The nitro group is reduced inside anaerobic organisms, producing free radicals that break DNA; bactericidal and antiprotozoal.

Spectrum. Bacteroides, Fusobacterium, Clostridium (including Clostridioides difficile), Prevotella, Peptostreptococcus, Gardnerella, Helicobacter pylori (resistance common), Trichomonas vaginalis, Entamoeba histolytica and Giardia lamblia. Not active against aerobes or Actinomyces, Propionibacterium or Lactobacillus.

Pharmacokinetics. Oral bioavailability over 90%. Half-life 8 hours. Protein binding under 20%. Good penetration into abscess, brain and CSF. Hepatic metabolism with active metabolites.

Maximum 4 g daily.

Adults, oral or IV. 400 to 500 mg every 8 hours (IV 500 mg every 8 hours over 20 minutes).

• Anaerobic and intra-abdominal infection: 500 mg every 8 hours for 5 to 7 days after source control (up to 10 days).
• Brain abscess, pelvic abscess: 500 mg IV every 8 hours with an appropriate partner agent, for 6 to 8 weeks in brain abscess.
• Pelvic inflammatory disease: 400 to 500 mg every 12 hours for 14 days with ceftriaxone and doxycycline.
• Invasive amoebiasis (colitis, liver abscess): 750 mg every 8 hours (or 500 mg to 800 mg every 8 hours) for 7 to 10 days. Follow with a luminal agent such as paromomycin or diloxanide.
• Giardiasis: 2 g once daily for 3 days, or 400 mg every 8 hours for 5 days.
• Bacterial vaginosis: 400 to 500 mg every 12 hours for 7 days.
• Trichomoniasis: 2 g as a single dose, or 500 mg every 12 hours for 7 days (preferred in women).
• Clostridioides difficile infection, non-severe (alternative when vancomycin and fidaxomicin are unavailable): 500 mg every 8 hours for 10 days.
• Helicobacter pylori bismuth quadruple therapy: 500 mg every 8 hours for 14 days with tetracycline, bismuth and a proton pump inhibitor.
• Surgical prophylaxis: 500 mg IV once within 60 minutes before incision.
• Periodontal and dental infection: 200 to 400 mg every 8 hours for 3 to 7 days.

Children.

• 7.5 mg/kg every 8 hours (maximum 500 mg a dose)
• Invasive amoebiasis: 35 to 50 mg/kg/day in 3 divided doses for 7 to 10 days
• Giardiasis: 15 mg/kg/day in 3 divided doses for 5 to 7 days
• Neonates: 15 mg/kg loading dose then 7.5 mg/kg every 12 hours (preterm) or every 8 hours (term)

Alternatives. Tinidazole, secnidazole, clindamycin, meropenem, piperacillin tazobactam, vancomycin, fidaxomicin.

Contraindications. Nitroimidazole hypersensitivity; Cockayne syndrome; alcohol ingestion during and for 48 hours after treatment (disulfiram-like reaction).

Adverse effects. Metallic taste, nausea, vomiting, abdominal pain, dark urine, headache, oral thrush. Serious: peripheral neuropathy (cumulative dose, usually over 4 weeks), encephalopathy and cerebellar toxicity, seizures, aseptic meningitis, hepatotoxicity, QT prolongation, pancreatitis, severe skin reactions, Clostridioides difficile infection.

Interactions. Alcohol (disulfiram-like); warfarin (INR rise); lithium (toxicity); phenytoin and phenobarbital (lower metronidazole levels); busulfan and fluorouracil (toxicity); disulfiram (psychosis); ciclosporin and tacrolimus (levels rise); QT-prolonging drugs; cimetidine.

Common prescribing errors. Alcohol during treatment, prolonged courses without neuropathy review, using it as the only agent in mixed aerobic infection, and no luminal agent after invasive amoebiasis.

Special groups.

• Pregnancy: acceptable when indicated, including in the first trimester for trichomoniasis or bacterial vaginosis when treatment is needed.
• Breastfeeding: acceptable. A high single dose (2 g) can be followed by pumping and discarding milk for 12 to 24 hours.
• Older adults: usual dose; monitor for neurotoxicity.
• Kidney impairment: no adjustment. Haemodialysis removes the drug, so give the dose after dialysis.
• Liver impairment: Child-Pugh C reduce to 500 mg once daily (or one third of the usual dose). Mild to moderate disease needs no adjustment.
• Region: widely used and inexpensive in East Africa for amoebiasis, giardiasis and anaerobic infection.

Preparation. Oral with or after food to reduce nausea. IV: ready solution 5 mg/mL infused over 20 to 60 minutes; do not mix with other drugs.

Baseline and monitoring. - Baseline: medication review (alcohol, lithium, warfarin), neurological history, liver tests in prolonged courses. - During treatment: neuropathy and cerebellar symptoms in courses over 2 weeks; liver tests in prolonged courses; INR in warfarin users.

Stop rules. Stop for new paraesthesia or numbness, ataxia, confusion, seizures, severe rash, jaundice or aseptic meningitis.

Referral and escalation. Refer for brain abscess, liver abscess not responding at 72 hours, neurotoxicity and treatment failure.