Nitroimidazoles

Nitroimidazoles (metronidazole, tinidazole, secnidazole, ornidazole) are bactericidal and antiprotozoal agents active against anaerobic bacteria and protozoa (Entamoeba histolytica, Giardia, Trichomonas vaginalis). They are the first-line drugs for anaerobic infection in combination with other agents, amoebiasis, giardiasis, trichomoniasis and bacterial vaginosis. Pretomanid and delamanid are nitroimidazoles used in tuberculosis, with separate indications.

Mechanism. The nitro group is reduced inside anaerobic cells to short-lived radicals that damage DNA and cause cell death. Aerobes cannot reduce the drug and are unaffected. Killing is concentration-dependent.

Pharmacokinetics. Metronidazole: oral bioavailability near 100 percent; half-life 8 hours; wide distribution including CSF, brain abscess, bone and abscess cavities; hepatic metabolism with active hydroxy metabolite. Tinidazole: half-life 12 to 14 hours; allows single-dose regimens. Secnidazole has a half-life of about 17 hours.

Spectrum. Bacteroides fragilis, other Gram-negative anaerobes, Fusobacterium, Clostridium (including C. difficile and C. tetani), Gram-positive anaerobic cocci; Helicobacter pylori (resistance common); the protozoa Entamoeba histolytica, Giardia and Trichomonas. Inactive against aerobes, Actinomyces, Cutibacterium and microaerophilic streptococci.

• Metronidazole: oral, IV, rectal, topical, vaginal; first-line; shorter half-life.
• Tinidazole and secnidazole: longer half-lives and single-dose regimens for giardiasis, trichomoniasis, vaginosis and amoebiasis.
• Ornidazole: similar to tinidazole; available in some regions.

Adult regimens (normal renal function).

• Anaerobic infection, intra-abdominal sepsis, pelvic infection: metronidazole 500 mg IV or orally every 8 hours, with Gram-negative cover as needed. Brain abscess 500 mg every 8 hours IV for weeks. Tetanus: 500 mg IV every 6 hours for 7 to 10 days.
• Clostridioides difficile infection (non-severe, where vancomycin or fidaxomicin are unavailable): 500 mg orally every 8 hours for 10 days; fulminant disease: 500 mg IV every 8 hours with high-dose oral vancomycin.
• Amoebic colitis and liver abscess: metronidazole 750 mg orally every 8 hours (or 500 mg IV every 8 hours) for 7 to 10 days, followed by a luminal agent (paromomycin 25 to 35 mg/kg daily in three divided doses for 7 days). Tinidazole 2 g orally once daily for 3 days (colitis) or 5 days (liver abscess).
• Giardiasis: tinidazole 2 g once, or metronidazole 250 mg every 8 hours for 5 to 7 days.
• Trichomoniasis: metronidazole 500 mg every 12 hours for 7 days (preferred for women), or 2 g once (men); partner treatment is essential.
• Bacterial vaginosis: metronidazole 500 mg every 12 hours for 7 days.
• Helicobacter pylori: 400 to 500 mg every 8 to 12 hours within combination regimens where resistance is not high.
• Children: 7.5 mg/kg every 8 hours (maximum 500 mg each dose); amoebiasis 30 to 50 mg/kg daily in three divided doses.

Selection. Add to a beta-lactam, aminoglycoside or cephalosporin whenever anaerobes are likely and the first agent lacks anaerobic cover. Avoid adding it to a carbapenem, piperacillin-tazobactam or a combination that already covers anaerobes.

Contraindications. Hypersensitivity to nitroimidazoles; first trimester caution in some regions.

Serious and common effects. Metallic taste, nausea; peripheral neuropathy and cerebellar or encephalopathic toxicity with prolonged courses (usually over 4 weeks or cumulative doses over 42 g), which may be reversible but sometimes persists; seizures; disulfiram-like reaction (alcohol is avoided during treatment and for 48 to 72 hours after); QT prolongation; dark urine; hepatotoxicity in Cockayne syndrome.

Interactions. Warfarin (marked INR rise), lithium (raised levels), busulfan, fluorouracil, ciclosporin, phenytoin and phenobarbital (lower metronidazole levels), cimetidine.

Monitoring. INR in warfarin users; neurological symptoms in courses over 2 weeks; full blood count in prolonged therapy.

Special groups. Pregnancy: acceptable in all trimesters when indicated. Breastfeeding: after a single 2 g dose, avoid breastfeeding for 12 to 24 hours; shorter courses are compatible with infant monitoring. Hepatic impairment (Child-Pugh C): halve the dose. Renal impairment: no adjustment, but dose after haemodialysis. Older adults: monitor for neurotoxicity. Region: amoebiasis, giardiasis and trichomoniasis are common in East Africa, and tetanus remains a cause of death where immunisation is incomplete.