Trimethoprim Sulfamethoxazole

Trimethoprim sulfamethoxazole (co-trimoxazole) is a fixed combination that blocks two steps of bacterial folate synthesis. It is used for urinary infection, Pneumocystis jirovecii pneumonia and prophylaxis, toxoplasmosis prophylaxis, Nocardia, Stenotrophomonas, MRSA skin infection and prophylaxis in HIV infection. In East Africa it is central to HIV care.

Classification. Folate synthesis inhibitor combination (sulphonamide and diaminopyrimidine).

Mechanism. Sulfamethoxazole inhibits dihydropteroate synthase and trimethoprim inhibits dihydrofolate reductase; the combination is bactericidal and synergistic.

Spectrum. Enterobacterales (resistance common), Haemophilus, Staphylococcus aureus including many MRSA, Streptococcus pneumoniae (resistance rising), Nocardia, Stenotrophomonas maltophilia, Burkholderia pseudomallei, Listeria, Pneumocystis jirovecii, Toxoplasma gondii, Isospora and Cyclospora. Not active against Pseudomonas aeruginosa or anaerobes.

Pharmacokinetics. Oral bioavailability over 90%. Half-life 8 to 10 hours (trimethoprim) and 10 to 12 hours (sulfamethoxazole). Wide tissue and CSF penetration. Excreted mainly in urine; trimethoprim blocks tubular secretion of creatinine.

The usual tablet is 960 mg (trimethoprim 160 mg and sulfamethoxazole 800 mg, double strength). Single strength is 480 mg (80 mg and 400 mg). Doses are written as the combination tablet strength unless stated as trimethoprim.

Adults, oral.

• Uncomplicated cystitis: 960 mg every 12 hours for 3 days, only where local resistance is low.
• Pyelonephritis, prostatitis: 960 mg every 12 hours for 7 to 14 days (prostatitis 28 days).
• Pneumocystis pneumonia, treatment: trimethoprim 15 to 20 mg/kg/day in 3 to 4 divided doses (oral or IV) for 21 days. Mild to moderate disease can use 960 mg two tablets three times daily. Add prednisolone in moderate to severe disease (hypoxia).
• Pneumocystis prophylaxis, HIV and immunosuppression: 960 mg once daily (or 480 mg once daily, or 960 mg three times weekly) while the CD4 count is under 200 cells/microlitre or immune suppression continues.
• Toxoplasma prophylaxis: 960 mg once daily.
• MRSA skin and soft tissue infection: 960 mg every 12 hours for 5 to 10 days.
• Nocardia infection: trimethoprim 5 to 10 mg/kg/day in 2 to 4 divided doses for at least 6 to 12 months depending on site, often with a second drug in severe disease.
• Stenotrophomonas maltophilia: trimethoprim 8 to 12 mg/kg/day IV or oral in 2 to 3 divided doses.
• Cholera, travellers diarrhoea (where susceptible): 960 mg every 12 hours for 3 days.
• Cotrimoxazole prophylaxis in HIV (all stages in many programmes): 960 mg once daily.

Children.

• Treatment: trimethoprim 4 mg/kg every 12 hours (maximum 160 mg a dose).
• Oral by age: 6 weeks to 5 months 120 mg every 12 hours; 6 months to 5 years 240 mg every 12 hours; 6 to 11 years 480 mg every 12 hours; 12 years and over 960 mg every 12 hours.
• Pneumocystis treatment: trimethoprim 15 to 20 mg/kg/day in 3 to 4 doses for 21 days.
• HIV prophylaxis: trimethoprim 5 mg/kg once daily. Alternatively use 960 mg dosing by weight bands once daily: under 5 kg 120 mg, 5 to 15 kg 240 mg, 15 to 30 kg 480 mg, over 30 kg 960 mg.
• Start from 4 to 6 weeks of age in HIV-exposed infants and continue until infection is excluded.

Alternatives. Nitrofurantoin, fosfomycin, doxycycline, linezolid, atovaquone, dapsone with pyrimethamine, pentamidine.

Contraindications. Sulphonamide or trimethoprim hypersensitivity; severe renal impairment without monitoring; megaloblastic anaemia from folate deficiency; blood dyscrasias; acute porphyria; severe hepatic failure. Also infants under 6 weeks (kernicterus), except for prophylaxis in HIV-exposed infants from 4 to 6 weeks where programmes direct.

Adverse effects. Nausea, vomiting, rash, photosensitivity, raised creatinine without true fall in filtration, hyperkalaemia. Serious: Stevens-Johnson syndrome and toxic epidermal necrolysis (early weeks of therapy, higher in HIV), bone marrow suppression (neutropenia, thrombocytopenia, megaloblastic anaemia), haemolysis in glucose 6-phosphate dehydrogenase deficiency, hepatotoxicity, aseptic meningitis, hypoglycaemia, hyponatraemia, acute kidney injury, Clostridioides difficile infection.

Interactions.

• ACE inhibitors, angiotensin receptor blockers, spironolactone and potassium supplements (severe hyperkalaemia).
• Warfarin (INR rise), phenytoin, methotrexate (marrow suppression), ciclosporin, digoxin, sulphonylureas (hypoglycaemia), dapsone, lamivudine, procainamide.
• Zidovudine or other marrow-suppressing drugs add to cytopenias.

Common prescribing errors. Missing hyperkalaemia in older adults on ACE inhibitors, no creatinine adjustment, prolonged high-dose courses without blood counts, and treating a rash as minor.

Special groups.

• Pregnancy: avoid in the first trimester where possible (folate antagonism and neural tube defects). Give folic acid 5 mg daily if it must be used. Folic acid can reduce Pneumocystis treatment effect, and folinic acid should be avoided in that treatment.
• Avoid near term (neonatal haemolysis and kernicterus). Prophylaxis in HIV is continued in pregnancy where indicated.
• Breastfeeding: acceptable for healthy full-term infants; avoid in jaundiced, premature or G6PD-deficient infants.
• Older adults: higher risk of hyperkalaemia, marrow suppression and acute kidney injury.
• Kidney impairment: creatinine clearance 15 to 30 mL/min half the usual dose; under 15 mL/min avoid, or use half the dose with levels in specialist care. Haemodialysis: dose after each session.
• Liver impairment: avoid in severe disease; monitor.
• Region: widely used for HIV, Pneumocystis and toxoplasmosis prophylaxis and for opportunistic infection in East Africa, with a protective effect against malaria and some bacterial infections in HIV. Resistance is common in urinary Escherichia coli, Salmonella, Shigella and pneumococci.

Preparation. Give oral tablets with food and plenty of fluid. For IV, dilute each 5 mL ampoule (80 mg trimethoprim) in 125 mL of 5% glucose (75 mL if fluid-restricted) and infuse over 60 to 90 minutes. Do not refrigerate or mix with other drugs.

Baseline and monitoring.

• Baseline: creatinine, potassium, full blood count, liver tests, G6PD status where available, pregnancy status, medication review.
• During treatment: creatinine and potassium within the first week, and weekly in high doses or kidney impairment. Full blood count weekly in courses over 2 weeks. Ask about rash and fever.

Stop rules. Stop for any rash with fever, mucosal involvement or blistering, jaundice, severe neutropenia or thrombocytopenia, potassium over 6 mmol/L, or acute kidney injury.

Referral and escalation. Refer for severe cutaneous reaction, marrow suppression, Pneumocystis pneumonia with hypoxia, and Nocardia or Stenotrophomonas infection.