Summary

The combination of trimethoprim-sulfamethoxazole (TMP-SMX) and methotrexate represents a clinically significant drug interaction that can lead to increased methotrexate toxicity. Both medications interfere with folate metabolism through different mechanisms, creating an additive antifolate effect that can result in serious adverse reactions including bone marrow suppression and gastrointestinal toxicity.

Introduction

Trimethoprim-sulfamethoxazole (TMP-SMX), also known as co-trimoxazole or Bactrim, is a combination antibiotic consisting of trimethoprim and sulfamethoxazole used to treat various bacterial infections including urinary tract infections, pneumonia, and certain opportunistic infections. Methotrexate is an antimetabolite medication primarily used as a chemotherapy agent for various cancers and as an immunosuppressive drug for autoimmune conditions such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease. Both drugs belong to the class of antifolate agents, which interfere with folate metabolism essential for DNA synthesis and cellular function.

Mechanism of Interaction

The interaction between trimethoprim-sulfamethoxazole and methotrexate occurs through their shared antifolate properties, creating an additive effect on folate metabolism inhibition. Methotrexate competitively inhibits dihydrofolate reductase, preventing the conversion of dihydrofolate to tetrahydrofolate, which is essential for purine and thymidine synthesis. Trimethoprim also inhibits dihydrofolate reductase, while sulfamethoxazole blocks an earlier step in folate synthesis by inhibiting dihydropteroate synthase. When used together, these medications create a synergistic antifolate effect that can significantly impair cellular DNA synthesis and repair, leading to enhanced cytotoxicity beyond what would be expected from methotrexate alone.

Risks and Symptoms

The primary clinical risk of combining trimethoprim-sulfamethoxazole with methotrexate is severe methotrexate toxicity, which can manifest as life-threatening complications. Key risks include profound bone marrow suppression leading to pancytopenia (decreased white blood cells, red blood cells, and platelets), severe gastrointestinal toxicity with mucositis and diarrhea, hepatotoxicity, nephrotoxicity, and increased susceptibility to infections due to immunosuppression. The interaction is particularly concerning in elderly patients, those with renal impairment, or patients receiving high-dose methotrexate therapy. Even short courses of TMP-SMX can precipitate methotrexate toxicity, and the effects may persist for several days after discontinuation of the antibiotic.

Management and Precautions

Trimethoprim-Sulfamethoxazole interactions with food and lifestyle

Trimethoprim-sulfamethoxazole should be taken with adequate fluid intake to prevent kidney stone formation and crystalluria. Patients should maintain good hydration by drinking plenty of water throughout treatment. Alcohol consumption should be avoided or limited as it may increase the risk of side effects and reduce the medication's effectiveness. Sun exposure should be minimized and protective clothing/sunscreen used, as trimethoprim-sulfamethoxazole can increase photosensitivity and risk of severe sunburn. Folate-rich foods or supplements may be recommended by healthcare providers for patients on long-term therapy, as the medication can interfere with folate metabolism.

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.