azathioprine and trimethoprim

Trimethoprim inhibits thiopurine methyltransferase (TPMT), the enzyme responsible for inactivating azathioprine's active metabolite 6-mercaptopurine. This inhibition reduces its metabolism, leading to elevated concentrations of active thioguanine nucleotides. Additionally, both drugs can independently cause bone marrow suppression, and their effects may be additive.

Co-administration increases the risk of severe bone marrow suppression, manifesting as leucopenia, thrombocytopenia, and anaemia. Pancytopenia has been reported, potentially leading to serious infections or bleeding. The effect is more pronounced in patients with low baseline TPMT activity.

Avoid 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.

Based on case reports, observational studies, and known pharmacology. The interaction is well documented in drug interaction databases and clinical literature.