Summary

Methotrexate and trimethoprim have a significant drug interaction due to their combined antifolate effects, which can lead to increased methotrexate toxicity. This interaction may result in severe bone marrow suppression, mucositis, and other serious adverse effects requiring careful monitoring and potential dose adjustments.

Introduction

Methotrexate is an antimetabolite and antifolate drug primarily used as a chemotherapy agent for various cancers and as an immunosuppressant for autoimmune conditions like rheumatoid arthritis and psoriasis. It belongs to the class of folate antagonists and works by inhibiting dihydrofolate reductase. Trimethoprim is an antibiotic commonly used to treat urinary tract infections and is often combined with sulfamethoxazole (co-trimoxazole). It also acts as a folate antagonist by inhibiting bacterial dihydrofolate reductase, though it has some activity against the human enzyme as well.

Mechanism of Interaction

The interaction between methotrexate and trimethoprim occurs through their shared mechanism as folate antagonists. Both drugs inhibit dihydrofolate reductase, the enzyme responsible for converting dihydrofolate to tetrahydrofolate, which is essential for DNA synthesis and cellular metabolism. When used together, their antifolate effects are additive, leading to more profound folate depletion. Additionally, trimethoprim may compete with methotrexate for renal tubular secretion, potentially reducing methotrexate clearance and increasing its plasma concentrations. This combination results in enhanced methotrexate toxicity beyond what would be expected from either drug alone.

Risks and Symptoms

The concurrent use of methotrexate and trimethoprim significantly increases the risk of methotrexate-related toxicities. Primary concerns include severe bone marrow suppression leading to pancytopenia (decreased white blood cells, red blood cells, and platelets), which can result in increased infection risk, anemia, and bleeding complications. Patients may also experience severe mucositis, gastrointestinal toxicity including nausea, vomiting, and diarrhea, hepatotoxicity, and nephrotoxicity. The interaction is particularly dangerous in elderly patients, those with renal impairment, or patients with folate deficiency. Even short courses of trimethoprim can precipitate serious methotrexate toxicity, and fatalities have been reported with this combination.

Management and Precautions

When this combination cannot be avoided, close monitoring is essential. Patients should have complete blood counts, liver function tests, and renal function assessed before starting treatment and monitored frequently (at least weekly initially). Consider reducing the methotrexate dose when trimethoprim is added, and ensure adequate folate supplementation is provided. Healthcare providers should educate patients about early signs of toxicity including fever, sore throat, unusual bleeding or bruising, mouth sores, and gastrointestinal symptoms. Alternative antibiotics should be considered when possible, such as nitrofurantoin for urinary tract infections. If trimethoprim must be used, consider temporary methotrexate discontinuation during the antibiotic course, especially for short-term treatments. Leucovorin (folinic acid) rescue may be necessary if severe toxicity develops.

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.