Which antibiotic should be avoided with methotrexate to reduce the risk of myelosuppression?

• A. Amoxicillin
• B. Doxycycline
• C. Trimethoprim
• D. Azithromycin

Answer: (C)

The key idea is that combining methotrexate with drugs that have antifolate activity can amplify bone marrow suppression. Methotrexate already blocks the folate pathway, reducing DNA synthesis in rapidly dividing cells like those in the bone marrow. An antibiotic that adds antifolate effects to this situation will heighten the risk of myelosuppression.

Trimethoprim is the one to avoid because it also inhibits dihydrofolate reductase, and at higher exposures can affect human cells as well as bacterial ones. When used with methotrexate, this dual antifolate action can markedly increase suppression of bone marrow, leading to neutropenia, anemia, and thrombocytopenia. Therefore, it’s preferred to choose an antibiotic without this antifolate interaction, or monitor very closely if combination is necessary.

The other options—amoxicillin, doxycycline, and azithromycin—do not have the same antifolate effects that compound methotrexate toxicity, so they are considered safer choices in this context, though individual patient factors and monitoring remain important.