Trimethoprim Combinations

Trimethoprim is a diaminopyrimidine that inhibits bacterial dihydrofolate reductase. It is used alone for urinary infection and prophylaxis and combined with sulfamethoxazole as co-trimoxazole, which has a bactericidal synergistic effect and broad activity including Pneumocystis jirovecii, Toxoplasma, Nocardia, Stenotrophomonas maltophilia, Shigella, Isospora and many staphylococci. Co-trimoxazole prophylaxis is a cornerstone of care for people living with HIV in East Africa.

Mechanism. Trimethoprim blocks conversion of dihydrofolate to tetrahydrofolate; sulfamethoxazole blocks an earlier step (dihydropteroate synthase). The combination prevents thymidine and purine synthesis. Human DHFR has about 10,000 times lower affinity for trimethoprim.

Pharmacokinetics. About 90 to 100 percent oral bioavailability, wide tissue penetration including prostate, CSF and lung; half-life 8 to 11 hours; renal elimination; trimethoprim blocks tubular secretion of creatinine and raises serum creatinine without lowering true GFR.

Resistance. Plasmid dfr genes and sul genes; resistance is high in E. coli, Klebsiella, Salmonella and Shigella in many East African isolates, which limits empirical use for urinary and enteric infection.

• Trimethoprim alone: 200 mg orally every 12 hours for cystitis; 100 mg at night for prophylaxis.
• Co-trimoxazole: each 960 mg tablet contains trimethoprim 160 mg and sulfamethoxazole 800 mg; a single-strength tablet is 480 mg.
• Trimethoprim-sulfamethoxazole IV: for severe infection and PCP.
• Related combinations: pyrimethamine with a sulphonamide for toxoplasmosis and malaria.

Adult regimens (normal renal function).

• Cystitis, susceptible: co-trimoxazole 960 mg every 12 hours for 3 days; trimethoprim 200 mg every 12 hours for 3 days.
• Pneumocystis pneumonia, treatment: trimethoprim 15 to 20 mg/kg daily (sulfamethoxazole 75 to 100 mg/kg) in 3 or 4 divided doses, orally or IV, for 21 days. Add prednisolone if the arterial oxygen tension is under 9.3 kPa (70 mmHg) or oxygen saturation under 92 percent on air: 40 mg every 12 hours for 5 days, then 40 mg daily for 5 days, then 20 mg daily for 11 days.
• Prophylaxis (PCP and toxoplasmosis) in people with HIV or other immunosuppression: 960 mg daily (or 480 mg daily, or 960 mg three times weekly).
• MRSA skin infection, mild: 960 mg every 12 hours for 5 to 7 days.
• Nocardiosis: trimethoprim 10 to 15 mg/kg daily in 2 to 4 divided doses; Stenotrophomonas infection: 8 to 12 mg/kg daily of the trimethoprim component with a second agent in severe disease.
• Melioidosis eradication: 960 mg to 1.92 g every 12 hours for 12 weeks.
• Children: treatment of common infections 4 mg/kg of trimethoprim every 12 hours; PCP prophylaxis 5 mg/kg of trimethoprim once daily.

Selection. First line for PCP and toxoplasmosis prophylaxis, nocardiosis and Stenotrophomonas infection; alternative for MRSA skin infection and for urinary infection where local resistance is under 20 percent; step-down for ESBL urinary infection when susceptible.

Contraindications. Sulphonamide or trimethoprim hypersensitivity; severe hepatic impairment; megaloblastic anaemia from folate deficiency; infants under 6 weeks (HIV-exposed infant prophylaxis starts at 4 to 6 weeks of age); concurrent methotrexate (severe marrow suppression).

Serious effects. Hyperkalaemia (especially with ACE inhibitors, ARBs, spironolactone, renal impairment, high dose); creatinine rise; hyponatraemia; marrow suppression and folate deficiency; Stevens-Johnson syndrome and toxic epidermal necrolysis; hypoglycaemia; aseptic meningitis; hepatotoxicity; haemolysis in G6PD deficiency.

Interactions. Methotrexate, azathioprine and mercaptopurine (marrow toxicity), warfarin (INR rise), phenytoin, digoxin, ciclosporin, ACE inhibitors, ARBs and spironolactone (hyperkalaemia), dapsone, sulphonylureas.

Monitoring. Full blood count, potassium and creatinine at baseline, at days 3 to 5 and weekly in high-dose therapy; folate supplementation for long courses; check for rash daily.

Special groups.

• Pregnancy: avoided in the first trimester (neural tube risk) and near term (kernicterus); if essential, give folic acid 5 mg daily. PCP in pregnancy is treated despite the risk.
• Breastfeeding: acceptable for healthy term infants; avoid in jaundice, G6PD deficiency or prematurity.
• Renal impairment: reduce dose by 50 percent at creatinine clearance 15 to 30 mL/min; avoid under 15 mL/min unless dialysis or monitoring is arranged.
• Older adults: higher risk of hyperkalaemia and marrow toxicity.
• Region: co-trimoxazole prophylaxis for HIV-exposed infants and people with HIV also reduces malaria and diarrhoea in endemic areas, so availability is protected in HIV programmes.