Summary

Erythromycin significantly increases sirolimus blood levels by inhibiting CYP3A4 metabolism, potentially leading to sirolimus toxicity. This major drug interaction requires careful monitoring and possible dose adjustments when these medications are used together.

Introduction

Sirolimus (rapamycin) is an immunosuppressive medication primarily used to prevent organ transplant rejection and treat certain cancers. It belongs to the mTOR inhibitor class of drugs. Erythromycin is a macrolide antibiotic commonly prescribed to treat bacterial infections, particularly respiratory tract infections, skin infections, and as an alternative for patients allergic to penicillin. Both medications are metabolized through the cytochrome P450 system, which creates the potential for significant drug interactions.

Mechanism of Interaction

The interaction between sirolimus and erythromycin occurs through competitive inhibition of the CYP3A4 enzyme system. Sirolimus is extensively metabolized by CYP3A4 in the liver and intestinal wall. Erythromycin is a potent CYP3A4 inhibitor that blocks this metabolic pathway, significantly reducing sirolimus clearance. This inhibition can increase sirolimus plasma concentrations by 2-5 fold, leading to prolonged drug exposure and increased risk of dose-related adverse effects. The interaction affects both hepatic metabolism and intestinal first-pass metabolism of sirolimus.

Risks and Symptoms

The primary clinical risk is sirolimus toxicity due to elevated blood levels. Potential adverse effects include severe immunosuppression leading to increased infection risk, delayed wound healing, bone marrow suppression with thrombocytopenia and anemia, hyperlipidemia, nephrotoxicity, and hepatotoxicity. In transplant patients, while increased immunosuppression might seem beneficial, excessive levels can lead to over-immunosuppression and life-threatening infections. The interaction is classified as major due to the significant increase in sirolimus exposure and the narrow therapeutic window of sirolimus.

Management and Precautions

When concurrent use is necessary, sirolimus dose reduction of 50-75% may be required, with close monitoring of sirolimus trough levels. Baseline sirolimus levels should be obtained before starting erythromycin. Monitor sirolimus levels 3-5 days after initiating erythromycin and adjust doses accordingly. Consider alternative antibiotics such as azithromycin (weaker CYP3A4 inhibitor) or non-macrolide antibiotics when possible. Monitor for signs of sirolimus toxicity including complete blood count, liver function tests, and renal function. After discontinuing erythromycin, sirolimus levels should be monitored as concentrations may decrease, requiring dose adjustments back toward baseline. Healthcare providers should always verify current drug interaction databases and consult clinical pharmacists for specific dosing recommendations.

Sirolimus interactions with food and lifestyle

Sirolimus should be taken consistently either with or without food, as food can significantly affect absorption. High-fat meals can increase sirolimus blood levels by up to 35%, while taking it on an empty stomach may reduce absorption. Patients should avoid grapefruit and grapefruit juice, as they contain compounds that inhibit CYP3A4 enzymes and can significantly increase sirolimus blood levels, potentially leading to toxicity. St. John's wort should be avoided as it can decrease sirolimus levels by inducing CYP3A4 metabolism, potentially reducing the drug's effectiveness. Patients should limit sun exposure and use sunscreen, as sirolimus increases photosensitivity and skin cancer risk. Live vaccines should be avoided due to sirolimus's immunosuppressive effects.

Erythromycin interactions with food and lifestyle

Erythromycin should be taken on an empty stomach (1 hour before or 2 hours after meals) for optimal absorption, as food can significantly reduce the drug's bioavailability. However, if gastrointestinal upset occurs, it may be taken with food to minimize stomach irritation, though this may reduce effectiveness. Alcohol consumption should be avoided or limited while taking erythromycin, as it may increase the risk of gastrointestinal side effects and potentially reduce the antibiotic's effectiveness. Patients should also avoid taking erythromycin with dairy products or calcium-fortified foods within 2 hours of dosing, as calcium can interfere with absorption.