Summary

Trimethoprim and methotrexate have a significant drug interaction due to their combined antifolate effects, which can lead to increased methotrexate toxicity. This interaction requires careful monitoring and potential dose adjustments to prevent serious adverse effects including bone marrow suppression and hepatotoxicity.

Introduction

Trimethoprim is an antibiotic belonging to the dihydrofolate reductase inhibitor class, commonly used to treat urinary tract infections and as part of combination therapy with sulfamethoxazole. Methotrexate is an antimetabolite and antifolate drug used in cancer chemotherapy and as a disease-modifying antirheumatic drug (DMARD) for autoimmune conditions like rheumatoid arthritis and psoriasis. Both medications interfere with folate metabolism, making their concurrent use potentially problematic.

Mechanism of Interaction

Both trimethoprim and methotrexate inhibit dihydrofolate reductase, an enzyme essential for converting dihydrofolate to tetrahydrofolate, which is necessary for DNA synthesis and cellular metabolism. Trimethoprim has a higher affinity for bacterial dihydrofolate reductase but also affects the human enzyme. When used together, these drugs create an additive antifolate effect, potentially leading to folate deficiency at the cellular level. This combined inhibition can result in enhanced methotrexate toxicity, as the body's ability to maintain adequate folate levels becomes severely compromised.

Risks and Symptoms

The primary risks of this drug interaction include increased methotrexate toxicity manifesting as bone marrow suppression (pancytopenia, thrombocytopenia, neutropenia), hepatotoxicity, gastrointestinal toxicity (mucositis, diarrhea), and potential renal toxicity. Patients may experience severe fatigue, increased infection risk, bleeding tendencies, and liver dysfunction. The interaction is particularly concerning in patients receiving high-dose methotrexate or those with pre-existing kidney or liver impairment. Fatal outcomes have been reported in severe cases of methotrexate toxicity when combined with trimethoprim-containing antibiotics.

Management and Precautions

When this combination cannot be avoided, close monitoring is essential including complete blood count, liver function tests, and renal function assessment before and during treatment. Consider reducing methotrexate dose or temporarily discontinuing it during trimethoprim therapy. Leucovorin (folinic acid) rescue may be necessary to counteract severe toxicity. Patients should be educated about early signs of toxicity including unusual fatigue, bruising, bleeding, mouth sores, or jaundice. Alternative antibiotics should be considered when possible. If concurrent use is necessary, the shortest effective duration of trimethoprim should be used, and patients require frequent clinical and laboratory monitoring throughout treatment.

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.

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.