Practical information on using folic acid antagonists: trimethoprim and sulfamethoxazole

For practical information on dapsone, a folic acid antagonist, see Practical information on using dapsone.

Trimethoprim and sulfamethoxazole (a sulfonamide) act by inhibiting bacterial folate production.

The combination of trimethoprim+sulfamethoxazole (cotrimoxazole) should be restricted to indications for which the combination is more effective than trimethoprim alone. This includes treatment and prophylaxis of Pneumocystis jirovecii pneumonia (PJP), and treatment of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA), Burkholderia pseudomallei, Listeria monocytogenes and Nocardia infections. For treatment and prophylaxis of some infections (eg uncomplicated urinary tract infection), trimethoprim alone is as effective as trimethoprim+sulfamethoxazole.

Avoid trimethoprim+sulfamethoxazole in neonates (up to 28 days old) because of the risk of kernicterus (precipitated by the displacement of bilirubin from albumin by sulfonamides).

Some patients are hypersensitive to sulfonamide antibiotics (see Trimethoprim+sulfamethoxazole hypersensitivity in adults).

Gastrointestinal toxicity with trimethoprim+sulfamethoxazole is common and dose dependent. Oral trimethoprim+sulfamethoxazole should be taken with food to minimise gastrointestinal adverse effects. If the dose is not tolerated, seek advice from an infectious diseases physician or clinical microbiologist – strategies may include using a lower dose more frequently, reducing the total daily dose, or switching to an alternative antibiotic. If gastrointestinal toxicity occurs during treatment, assess for other toxicities (eg neutropenia, hepatitis).

Because of its mechanism of action, trimethoprim can interfere with folate metabolism, and high doses or prolonged treatment may result in megaloblastic changes (eg macrocytic anaemia, mild thrombocytopenia, leucopenia). Monitor a full blood count during high-dose or prolonged treatment with trimethoprim or trimethoprim+sulfamethoxazole. Folate supplementation (as folic acid or folinic acid) may be considered during high-dose or prolonged treatment in certain circumstances, but in some patient groups this can be associated with treatment failure – consult treatment protocols or seek expert advice before starting folate supplementation during treatment with trimethoprim or trimethoprim+sulfamethoxazole.

Some indications (eg Pneumocysitis jirovecii pneumonia, Stenotrophomonas maltophilia pneumonia) may require high-dose oral trimethoprim+sulfamethoxazole therapy in adults (5+25 mg/kg per dose, with the dosing interval dependent on the indication). Calculated dose and number of tablets of trimethoprim+sulfamethoxazole to achieve a 5+25 mg/kg dose in adults includes a practical approach to the number of double-strength formulation (160+800 mg) tablets of trimethoprim+sulfamethoxazole required to achieve approximately 5+25 mg/kg per dose, while minimising tablet splitting.

Table 1. Calculated dose and number of tablets of trimethoprim+sulfamethoxazole to achieve a 5+25 mg/kg dose in adults

Patient weight

Dose that achieves approximately 5 mg/kg per dose [NB1] [NB2]

Number of double-strength (160+800 mg) tablets per dose

adult 36 to less than 50 kg

240+1200 mg

1.5 tablets

adult 50 to less than 65 kg

320+1600 mg

2 tablets

adult 65 to less than 80 kg

400+2000 mg

2.5 tablets

adult 80 kg or more

480+2400 mg

3 tablets

Note:

NB1: The doses in this table were calculated so that approximately 5 mg/kg trimethoprim per dose is achieved. Depending on the patient’s weight and to minimise tablet splitting, the dose ranges from 4.8 to 6.6 mg/kg per dose.

NB2: For the dosing interval, refer to the clinical topics. Trimethoprim+ sulfamethoxazole is usually administered every 8 or 12 hours, depending on the indication.

Trimethoprim inhibits tubular secretion of creatinine, which can elevate serum creatinine without any true decrease in glomerular filtration rate. Trimethoprim also inhibits tubular excretion of potassium and can cause hyperkalaemia. In patients at increased risk of hyperkalaemia (eg patients with impaired kidney function, patients who are taking a high dose of trimethoprim or other drugs that can cause hyperkalaemia), monitor serum potassium if the duration of trimethoprim therapy is more than 3 days.