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Drug Reference

trimethoprim

dihydrofolate reductase inhibitor· Brands: Proloprim, Monotrim, TrimpexIVPO

Mechanism of action
Trimethoprim inhibits bacterial dihydrofolate reductase, the enzyme that converts dihydrofolate to tetrahydrofolate. This blocks the synthesis of tetrahydrofolate, which is essential for the production of thymidine and purines, thereby inhibiting DNA replication and bacterial growth. It is bacteriostatic at therapeutic concentrations but may be bactericidal in combination with sulfamethoxazole.
Pharmacokinetics
Trimethoprim is well absorbed after oral administration with a bioavailability of approximately 90%. It is widely distributed throughout body tissues and fluids, including cerebrospinal fluid, saliva, and prostatic fluid. It is metabolised in the liver to a small extent, with about 20% of the parent drug being metabolised. The elimination half-life is approximately 8 to 11 hours. Excretion is mainly renal, with 50 to 60% of an oral dose excreted unchanged in urine. In patients with renal impairment, the dose should be reduced.
Indications & dosing

Acute uncomplicated UTI (cystitis) in adults

For acute uncomplicated lower urinary tract infection, usually for 3 days.

  • adult · PO: 200 mg twice daily · For acute uncomplicated lower urinary tract infection, usually for 3 days.

Recurrent UTI prophylaxis in adults

Prophylaxis of recurrent urinary tract infections, typically taken at night.

  • adult · PO: 100 mg once daily · Prophylaxis of recurrent urinary tract infections, typically taken at night.

Lower respiratory tract infection

For susceptible infections, e.g., acute exacerbations of chronic bronchitis.

  • adult · PO: 200 mg twice daily · For susceptible infections, e.g., acute exacerbations of chronic bronchitis.
Contraindications & precautions
  • Hypersensitivity to trimethoprim · Includes previous drug-induced blood dyscrasias or rash.
  • Severe renal impairment (eGFR <15 mL/min) · Dose adjustment and monitoring may allow use under specialist guidance.
  • Megaloblastic anaemia due to folate deficiency · Trimethoprim is a folate antagonist; may worsen anaemia.
  • Pregnancy (especially first trimester) · Folate antagonism risk of neural tube defects; use alternative if possible.
  • Monitor renal function and reduce dose in renal impairment; avoid in severe renal failure unless specialist supervision.
  • Use effective contraception and avoid in pregnancy, especially the first trimester; consider folate supplementation if treatment is essential.
  • Caution in patients with folate deficiency, the elderly, and those taking methotrexate or other folate antagonists.
  • Monitor serum potassium in patients at risk of hyperkalaemia, particularly those on potassium-sparing diuretics or ACE inhibitors/ARBs.
  • Caution in porphyria.
Adverse effects
  • Nausea
  • Diarrhoea
  • Vomiting
  • Rash
  • Hyperkalaemiaserious
  • Thrombocytopenia, leucopenia, or pancytopeniaserious
  • Stevens-Johnson syndrome or toxic epidermal necrolysisserious
Interactions
  • warfarinmajorAvoid co-prescription if an alternative antibiotic is suitable. If the combination is unavoidable, monitor INR more frequently (e.g., before starting, then 3–5 days later, and as needed), and consider a prophylactic warfarin dose reduction. Advise the patient to report signs of bleeding.
  • methotrexatemajorAvoid co-prescription where possible, especially with high-dose methotrexate. If combined use is essential, closely monitor full blood counts, renal function and serum methotrexate levels. Consider prophylactic folic acid, ensure adequate hydration, and adjust doses accordingly. Consult specialist advice for each individual case.
  • spironolactonemajorAvoid co-prescription if possible. If the combination is necessary, monitor serum potassium and renal function at baseline and within 5 to 7 days after starting therapy, and periodically thereafter. Advise patients to avoid potassium supplements and salt substitutes. Consider alternative antibiotics without potassium-sparing effects.
  • lisinoprilmajorAvoid empiric combination in high-risk patients. If co-prescription is necessary, check baseline serum potassium and renal function, recheck within 1–2 weeks after starting therapy, and periodically thereafter. Advise patients to avoid potassium supplements and salt substitutes. If hyperkalaemia develops, stop the offending drug(s), treat accordingly, and consider switching trimethoprim to an alternative antibiotic (e.g. nitrofurantoin for uncomplicated UTI) where clinically appropriate.
  • azathioprinemajorAvoid concurrent use unless absolutely necessary. If co-prescribed, consider alternative antibiotics with a more favourable profile. If no alternative is feasible, reduce the azathioprine dose, monitor full blood count closely (weekly for the first month, then at least twice monthly), and advise patients to report symptoms of infection or bleeding. Consider TPMT genotyping if not already done.
Renal & hepatic adjustment
  • eGFR 60+: No dose adjustment required.
  • eGFR 30–59: No dose adjustment usually required; monitor renal function and serum potassium.
  • eGFR 15–29: Reduce dose to half the usual dose (e.g., for acute uncomplicated UTI, use 100 mg once daily instead of 200 mg twice daily).
  • eGFR 0–14: Avoid; use an alternative antibiotic. If unavoidable, reduce dose to half the usual dose and monitor closely for toxicity. (avoid)
Monitoring, pregnancy & toxicity
  • Serum creatinine/eGFR · Baseline and periodically during treatment
  • Serum potassium · Baseline and periodically, especially in patients with renal impairment or on potassium-sparing drugs
  • Full blood count · Baseline and periodically with prolonged therapy or high doses
  • Serum folate · Consider in patients on long-term therapy or those at risk of folate deficiency
  • Pregnancy: Trimethoprim should be avoided in the first trimester of pregnancy because of the risk of neural tube defects. If use is unavoidable, folate supplementation should be considered. In the second and third trimesters, use only if the potential benefit outweighs the risk. Alternative antibiotics should be considered where appropriate.
  • Toxicity: Nausea, vomiting, and diarrhoea · Supportive care; ensure adequate hydration; consider antiemetics if symptoms are severe.
  • Toxicity: Hyperkalaemia · Monitor serum potassium; discontinue trimethoprim if potassium rises significantly; consider potassium-lowering therapy and manage underlying causes.
  • Toxicity: Hypersensitivity reactions (e.g., rash, pruritus, fever) · Discontinue the drug; if severe, treat as an allergic reaction and provide symptomatic management.
  • Toxicity: Bone marrow suppression (e.g., megaloblastic anaemia, cytopenias) and overdose · Discontinue the drug; administer folic acid or folinic acid (leucovorin) to counteract folate antagonism; monitor blood counts and provide supportive care.
Clinical notes
Trimethoprim is commonly used for the treatment and prophylaxis of uncomplicated urinary tract infections. It is also effective against respiratory tract infections such as otitis media and exacerbations of chronic bronchitis. Resistance is emerging, so local susceptibility patterns should be considered. It is contraindicated in patients with folate deficiency and should be used with caution in the elderly or those with renal impairment. Monitor for hyperkalaemia, especially in patients taking potassium-sparing diuretics or with renal dysfunction. Trimethoprim may potentiate the anticoagulant effect of warfarin and enhance the toxicity of phenytoin and methotrexate. It is not recommended in the first trimester of pregnancy.

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BNF; local formulary