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Methotrexate-Co-trimoxazole Interaction — RACP Adult Medicine MCQ

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ModerateClinical PharmacologyMethotrexate-Co-trimoxazole InteractionRACP Adult Medicine

A 70-year-old woman on methotrexate for rheumatoid arthritis develops oral ulcers, diarrhoea, and pancytopaenia 10 days after her weekly methotrexate dose. She recently started co-trimoxazole for a UTI. What is the mechanism of this severe methotrexate toxicity?

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Correct answer: E — Both B and C

Co-trimoxazole potentiates methotrexate toxicity through TWO mechanisms: (1) Trimethoprim is itself a dihydrofolate reductase inhibitor, creating ADDITIVE antifolate toxicity with methotrexate; AND (2) Trimethoprim and sulfamethoxazole reduce renal tubular secretion of methotrexate, increasing methotrexate plasma levels. This combination is potentially fatal and should be AVOIDED in all patients on methotrexate. Alternative antibiotics (e.g., cefalexin, amoxicillin) should be used for UTIs in patients on methotrexate. Other drugs that increase methotrexate toxicity include NSAIDs (reduced renal clearance), PPIs, and penicillins.

Reference: AMH – 2025 – Methotrexate Drug Interactions; eTG – 2025 – Rheumatology