Trimethoprim Should Be Avoided in Patients Taking Methotrexate
The answer is (b) - Trimethoprim. Concurrent use of trimethoprim (including trimethoprim-sulfamethoxazole) with methotrexate should be avoided due to the risk of severe, potentially fatal bone marrow toxicity.
Mechanism of Interaction
Trimethoprim creates a dangerous interaction with methotrexate through multiple mechanisms:
- Decreased protein binding: Trimethoprim and sulfonamides displace methotrexate from serum albumin, leading to increased free (active) methotrexate levels 1
- Reduced renal elimination: These agents decrease renal tubular excretion of methotrexate, causing drug accumulation 1
- Synergistic antifolate effect: Both drugs inhibit folate metabolism through different pathways, creating additive toxicity 2, 3
Clinical Evidence of Toxicity
The combination has been documented to cause severe, life-threatening complications:
- Severe pancytopenia (including fatal cases) has been reported even after brief exposure 2, 3, 4
- Mucocutaneous ulceration, leukopenia, and renal insufficiency occur with this combination 2
- One case report documented fatal pancytopenia followed by pneumonia and septic shock in a 74-year-old woman on methotrexate who received trimethoprim-sulfamethoxazole for a urinary tract infection 4
- The literature describes this as an "extremely serious and life-threatening combination" 3
Guideline Recommendations
Avoid co-trimoxazole, trimethoprim, and other antifolate drugs in patients taking methotrexate due to risk of bone marrow suppression 5. The Journal of the American Academy of Dermatology explicitly lists trimethoprim/sulfamethoxazole among medications that may increase methotrexate toxicity 1.
Important Clinical Caveat
Low-dose trimethoprim-sulfamethoxazole may be used for Pneumocystis jirovecii pneumonia prophylaxis in patients receiving immunosuppressive therapy, but this requires careful consideration and should not be confused with therapeutic dosing 1. When used prophylactically at low doses in the oncology setting with high-dose methotrexate, some recent evidence suggests minimal interaction 6, but this does NOT apply to the rheumatology setting with chronic low-dose methotrexate where the interaction is well-established and dangerous.
Why Other Options Are Incorrect
- Erythromycin (a): Not listed as a major interacting drug with methotrexate 1
- Sumatriptan (c): No documented interaction with methotrexate
- Lansoprazole (d): While proton pump inhibitors may theoretically reduce renal elimination of methotrexate, this is not an absolute contraindication and requires monitoring rather than avoidance 7
- Sodium valproate (e): Not listed as a contraindicated medication with methotrexate