Summary

The combination of methotrexate and trimethoprim creates a significant drug interaction due to their synergistic antifolate effects. This interaction can lead to increased methotrexate toxicity, including severe bone marrow suppression and other serious adverse effects.

Introduction

Methotrexate is a folate antagonist medication primarily used as an immunosuppressant for autoimmune conditions like rheumatoid arthritis and psoriasis, and as a chemotherapy agent for various cancers. Trimethoprim is an antibiotic commonly used to treat urinary tract infections and is often combined with sulfamethoxazole in the formulation known as co-trimoxazole or Bactrim. Both medications interfere with folate metabolism through different mechanisms, making their concurrent use potentially dangerous.

Mechanism of Interaction

Both methotrexate and trimethoprim are antifolate agents that disrupt folate metabolism through complementary pathways. Methotrexate inhibits dihydrofolate reductase, preventing the conversion of dihydrofolate to tetrahydrofolate, which is essential for DNA synthesis and cellular division. Trimethoprim also inhibits dihydrofolate reductase, though with greater selectivity for bacterial enzymes. When used together, these drugs create additive antifolate effects, significantly depleting cellular folate stores and enhancing methotrexate's cytotoxic effects beyond therapeutic levels.

Risks and Symptoms

The primary risk of combining methotrexate and trimethoprim is severe methotrexate toxicity, which can manifest as life-threatening bone marrow suppression leading to pancytopenia (decreased white blood cells, red blood cells, and platelets). Additional serious risks include severe mucositis, gastrointestinal toxicity with nausea and diarrhea, hepatotoxicity, and increased susceptibility to infections due to immunosuppression. The interaction is considered clinically significant and can occur even with low-dose methotrexate therapy commonly used for rheumatoid arthritis.

Management and Precautions

If concurrent use cannot be avoided, close monitoring is essential including frequent complete blood counts, liver function tests, and assessment for signs of toxicity. Consider temporary discontinuation of methotrexate during trimethoprim therapy when possible. Leucovorin (folinic acid) rescue may be necessary if toxicity develops. Alternative antibiotics should be strongly considered for patients on methotrexate therapy. Healthcare providers should maintain heightened vigilance for early signs of toxicity including unusual fatigue, bleeding, bruising, mouth sores, or signs of infection. Patients should be educated about these warning signs and instructed to seek immediate medical attention if they occur.

Methotrexate interactions with food and lifestyle

Alcohol consumption should be avoided or strictly limited while taking methotrexate due to increased risk of liver toxicity and hepatotoxicity. Both methotrexate and alcohol can cause liver damage, and their combination significantly increases this risk. Patients should also maintain adequate hydration and avoid excessive sun exposure, as methotrexate can increase photosensitivity. Folic acid supplementation is commonly recommended to reduce certain side effects, though this should be discussed with a healthcare provider as timing and dosing are important.

Trimethoprim interactions with food and lifestyle

Trimethoprim should be taken with adequate fluid intake to prevent kidney stone formation. Alcohol consumption should be limited as it may increase the risk of side effects and reduce the effectiveness of the antibiotic. Patients should maintain adequate folate intake through diet, as trimethoprim can interfere with folate metabolism, though routine folate supplementation is typically not required for short-term use.