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