Trimethoprim

Trimethoprim alone is a folate antagonist used for urinary tract infection and for prophylaxis against recurrent cystitis. It is also used in some prostatitis and respiratory infection. Resistance is common, so culture or local resistance data should decide use.

Classification. Diaminopyrimidine folate antagonist.

Mechanism. Inhibits bacterial dihydrofolate reductase; bacteriostatic when used alone.

Spectrum. Escherichia coli, Proteus mirabilis, Klebsiella (variable), Staphylococcus saprophyticus, Haemophilus and some Streptococcus pneumoniae. Not active against Pseudomonas, enterococci or anaerobes.

Pharmacokinetics. Oral bioavailability over 90%. Half-life 8 to 11 hours (longer in renal impairment). High prostatic and urinary levels. Mainly excreted unchanged in urine.

Maximum 400 mg daily.

Adults, oral. - Uncomplicated cystitis: 200 mg every 12 hours for 3 days. - Prostatitis: 200 mg every 12 hours for 28 days. - Prophylaxis of recurrent urinary infection: 100 mg at night, reviewed after 6 months. - Acute exacerbation of chronic bronchitis (alternative): 200 mg every 12 hours for 5 to 7 days.

Children. 4 mg/kg every 12 hours (maximum 200 mg a dose) for 3 to 7 days; prophylaxis 2 mg/kg once at night (maximum 100 mg). Not advised under 6 weeks.

Alternatives. Nitrofurantoin, fosfomycin, pivmecillinam, cephalexin, trimethoprim sulfamethoxazole.

Contraindications. Trimethoprim hypersensitivity; blood dyscrasias; severe renal impairment without monitoring; acute porphyria; first-trimester pregnancy where possible.

Adverse effects. Nausea, vomiting, rash, itching, raised creatinine without a true fall in filtration, hyperkalaemia. Serious: marrow suppression (neutropenia, thrombocytopenia, megaloblastic anaemia), severe skin reactions, aseptic meningitis, hepatotoxicity.

Interactions. ACE inhibitors, angiotensin receptor blockers, spironolactone and potassium supplements (hyperkalaemia); methotrexate (marrow suppression); phenytoin, digoxin, ciclosporin, warfarin and sulphonylureas; dapsone and lamivudine.

Common prescribing errors. Missing hyperkalaemia in older adults on ACE inhibitors, continuing beyond 3 days in simple cystitis, and long prophylaxis without a blood count.

Special groups. - Pregnancy: avoid in the first trimester (folate antagonism; give folic acid 5 mg daily if it must be used). Avoid with other folate antagonists. Breastfeeding: compatible. - Older adults: higher risk of hyperkalaemia and marrow suppression. - Kidney impairment: creatinine clearance 15 to 30 mL/min usual dose for 3 days, then half dose; under 15 mL/min 100 mg every 12 hours or avoid. - Liver impairment: use with caution. - Region: widely available in East Africa; resistance in urinary Escherichia coli is high in many settings.

Administration. Oral tablets with water, with or without food.

Baseline and monitoring. - Baseline: creatinine, potassium in at-risk patients, pregnancy status, medication review. - During treatment: full blood count and potassium in prolonged courses and in older or renally impaired patients.

Stop rules. Stop for rash, mucosal reaction, unexplained bruising or sore throat, or potassium over 6 mmol/L.

Referral and escalation. Refer for recurrent urinary infection, treatment failure, and marrow suppression.