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, which creates the potential for a clinically significant drug interaction when used concurrently.

Mechanism of Interaction

The interaction between methotrexate and trimethoprim occurs through their complementary effects on the folate pathway. Methotrexate inhibits dihydrofolate reductase, preventing the conversion of dihydrofolate to tetrahydrofolate, which is essential for DNA synthesis and cellular metabolism. Trimethoprim also inhibits dihydrofolate reductase, though it has greater selectivity for bacterial enzymes. When used together, these medications create an additive antifolate effect that can overwhelm the body's folate reserves and significantly increase the risk of methotrexate-related toxicity.

Risks and Symptoms

The primary risks of combining methotrexate and trimethoprim include severe bone marrow suppression leading to pancytopenia (decreased white blood cells, red blood cells, and platelets), increased risk of infection, bleeding complications, and severe anemia. Additional risks include gastrointestinal toxicity with nausea, vomiting, diarrhea, and mucositis. Hepatotoxicity may also be enhanced, and there is an increased risk of megaloblastic anemia. The interaction is considered clinically significant and can be life-threatening, particularly in elderly patients or those with compromised renal function.

Management and Precautions

Management of this interaction requires careful monitoring and potential dose adjustments. If concurrent use is necessary, complete blood counts should be monitored more frequently (weekly initially), along with liver function tests and renal function. Consider reducing the methotrexate dose or temporarily discontinuing it during trimethoprim therapy. Folate supplementation (leucovorin rescue) may be considered in high-risk situations. Alternative antibiotics should be used when possible to avoid this interaction. Patients should be educated about signs of toxicity including unusual bleeding, bruising, fever, sore throat, or severe fatigue, and instructed to seek immediate medical attention if these 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.