Summary

The combination of azathioprine and trimethoprim can lead to significant bone marrow suppression and increased hematologic toxicity. This interaction occurs through trimethoprim's inhibition of folate metabolism, which potentiates azathioprine's myelosuppressive effects.

Introduction

Azathioprine is an immunosuppressive medication belonging to the purine analog class, commonly used to prevent organ transplant rejection and treat autoimmune conditions such as inflammatory bowel disease and rheumatoid arthritis. Trimethoprim is an antibiotic that belongs to the dihydrofolate reductase inhibitor class, frequently used alone or in combination with sulfamethoxazole to treat bacterial infections, particularly urinary tract infections and Pneumocystis jirovecii pneumonia.

Mechanism of Interaction

The interaction between azathioprine and trimethoprim occurs through complementary mechanisms that affect cellular metabolism. Azathioprine is metabolized to 6-mercaptopurine, which interferes with purine synthesis and DNA replication, leading to bone marrow suppression. Trimethoprim inhibits dihydrofolate reductase, blocking the conversion of dihydrofolate to tetrahydrofolate, which is essential for DNA synthesis and cellular division. When used together, trimethoprim's folate antagonism compounds azathioprine's antiproliferative effects, resulting in enhanced myelosuppression and increased risk of severe hematologic toxicity.

Risks and Symptoms

The primary clinical risk of combining azathioprine and trimethoprim is severe bone marrow suppression, manifesting as leukopenia, thrombocytopenia, and anemia. Patients may experience increased susceptibility to infections due to neutropenia, bleeding complications from thrombocytopenia, and fatigue or weakness from anemia. The interaction is considered clinically significant and can lead to life-threatening hematologic complications, particularly in elderly patients or those with pre-existing bone marrow dysfunction. Additional risks include delayed wound healing, increased risk of opportunistic infections, and potential for megaloblastic anemia due to folate deficiency.

Management and Precautions

When this combination cannot be avoided, close monitoring is essential with complete blood counts performed weekly initially, then every 2-4 weeks during concurrent therapy. Consider dose reduction of azathioprine by 25-50% when initiating trimethoprim. Folate supplementation (5-10mg daily) should be considered to mitigate folate antagonism effects. Patients should be educated about signs of bone marrow suppression including unusual bleeding, bruising, fever, or signs of infection. Alternative antibiotics such as nitrofurantoin for urinary tract infections or fluoroquinolones should be considered when clinically appropriate. If severe hematologic toxicity develops, both medications should be discontinued immediately and supportive care initiated.

Azathioprine interactions with food and lifestyle

Azathioprine should be taken with food to reduce gastrointestinal side effects such as nausea and stomach upset. Alcohol consumption should be limited or avoided while taking azathioprine, as both the medication and alcohol can affect liver function, potentially increasing the risk of liver toxicity. Patients should also avoid live vaccines while on azathioprine due to its immunosuppressive effects, which can reduce the body's ability to respond to vaccines and increase infection risk. Sun exposure should be minimized and protective measures (sunscreen, protective clothing) should be used, as azathioprine increases the risk of skin cancer and photosensitivity reactions.

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.