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Methotrexate and co-trimoxazole and trimethoprim

Authoring team

Co-trimoxazole is a combination antibiotic containing trimethoprim and sulfamethoxazole.

 

Methotrexate toxicity

  • taking methotrexate with trimethoprim or co-trimoxazole can increase the risk of bone marrow suppression
    • mechanism is not fully understood but may be due to additive antifolate effects
  • the sulfamethoxazole component of co-trimoxazole can also increase the amount of free plasma methotrexate, through competitive plasma protein binding or decreased renal clearance
  • the interaction may be delayed and has occurred in people who have taken co-trimoxazole after recently stopping methotrexate

Suggested management options (1):

  • avoid prescribing co-trimoxazole or trimethoprim with methotrexate, due to the risk of severe bone marrow suppression. Consult your local microbiologist to consider alternative antibiotics
  • if concurrent use cannot be avoided:
    • counsel the person to report signs of myelosuppression, such as sore throat, mouth ulcers, fever or chills, unexplained bruising or bleeding, and shortness of breath
    • monitor the full blood count (FBC) frequently to detect any signs of bone marrow suppression
    • consider the additional FBC monitoring, above routine monitoring (https://www.sps.nhs.uk/monitorings/methotrexate-monitoring/), for at least 2 months*

*the suggested 2-month monitoring period is based on a case report of bone marrow hypoplasia

  • this adverse effect occurred over 2 months after completion of a 10-day course of co-trimoxazole in combination with methotrexate

Reference:

  1. NHS Specialist Pharmacy Service (June 30th 2025). Managing interactions with methotrexate.

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The content herein is provided for informational purposes and does not replace the need to apply professional clinical judgement when diagnosing or treating any medical condition. A licensed medical practitioner should be consulted for diagnosis and treatment of any and all medical conditions.

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