Rarely, more severe effects have been reported. Sulfonamide-like skin reactions, including exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have occurred. Disturbances of liver enzyme values and cholestatic jaundice have been associated with trimethoprim. Rises in serum creatinine and blood-urea nitrogen have been reported although it is unclear whether this represents genuine renal dysfunction or inhibition of tubular secretion of creatinine. Photosensitivity has been reported. Fever is not uncommon but occasionally hypersensitivity reactions may be severe and manifest as anaphylaxis. Cases of aseptic meningitis have also been reported.

Trimethoprim may cause a depression of haematopoiesis due to interference of the drug in the metabolism of folic acid, particularly when given over a prolonged period or in high doses. This may manifest as megaloblastic anaemia, or as thrombocytopenia and leucopenia; methaemoglobinaemia has also been seen. Calcium folinate 5 to 15mg daily by mouth may be given to counter this effect. Trimethoprim is teratogenic in animals.

Hyperkalaemia. Trimethoprim has been reported to induce hyperkalaemia , particularly in HIV-infected patients being treated for Pneumocystis carinii pneumonia or in the elderly. The hyperkalaemia may be due to amiloride-like potassium-sparing properties of trimethoprim, and may be potentiated by ACE inhibitors.

Precautions

Trimethoprim should not be given to patients with a history of hypersensitivity to the drug, and it should be discontinued if a skin rash appears. Care is necessary in administering trimethoprim to patients with impaired renal function to avoid accumulation and toxicity: it should not be given in severe renal impairment unless blood concentrations can be monitored. It should be used with caution in patients with severe hepatic damage as changes may occur in the absorption and metabolism of trimethoprim.

It is suggested that regular haematological examination should be made during prolonged courses of treatment; trimethoprim should not usually be given to patients with serious haematological disorders and particularly not in megaloblastic anaemia secondary to folate depletion. Caution should be taken in patients with actual, or possible, folate deficiency and administration of folinic acid should be considered. Trimethoprim should be avoided during pregnancy. Trimethoprim appears in breast milt and care is required when it is used in breast-feeding mothers. Elderly patients may be more susceptible to adverse effects and a lower dosage may be advisable.

Trimethoprim may interfere with some diagnostic tests, including serum-methotrexate assay where dihydrofolate reductase is used and the Jaffe reaction for creatinine.