Summary

Rifampin significantly reduces voriconazole plasma concentrations through CYP450 enzyme induction, potentially leading to treatment failure of fungal infections. This interaction is considered clinically significant and requires careful management or alternative therapy selection.

Introduction

Rifampin is a potent antibiotic belonging to the rifamycin class, primarily used to treat tuberculosis and other mycobacterial infections. It is also effective against certain gram-positive bacteria and is often used in combination therapy. Voriconazole is a second-generation triazole antifungal medication used to treat serious invasive fungal infections, including aspergillosis, candidemia, and other opportunistic mycoses. Both medications are commonly prescribed in clinical practice, making their potential interaction clinically relevant.

Mechanism of Interaction

Rifampin is a potent inducer of cytochrome P450 enzymes, particularly CYP3A4, CYP2C9, and CYP2C19. Voriconazole is extensively metabolized by these same CYP450 enzymes, with CYP2C19 and CYP3A4 being the primary pathways. When rifampin is co-administered with voriconazole, it significantly increases the hepatic metabolism of voriconazole, leading to substantially reduced plasma concentrations and area under the curve (AUC). Studies have shown that rifampin can decrease voriconazole AUC by up to 96%, effectively rendering the antifungal therapy ineffective.

Risks and Symptoms

The primary clinical risk of this interaction is therapeutic failure of voriconazole, which can have serious consequences in patients with life-threatening fungal infections. Reduced voriconazole concentrations may lead to inadequate antifungal coverage, allowing fungal infections to progress or become resistant. This is particularly concerning in immunocompromised patients, such as those with hematologic malignancies, solid organ transplants, or severe immunodeficiency, where fungal infections can be rapidly fatal. Additionally, subtherapeutic antifungal levels may contribute to the development of azole-resistant fungal strains, complicating future treatment options.

Management and Precautions

The co-administration of rifampin and voriconazole should generally be avoided due to the severity of this interaction. If both medications are clinically necessary, consider the following management strategies: 1) Use alternative antifungal agents such as amphotericin B, caspofungin, or micafungin that are not significantly affected by CYP450 induction. 2) Consider alternative anti-tuberculosis agents like rifabutin, which has less potent enzyme-inducing effects, though some interaction may still occur. 3) If no alternatives are available, significantly higher voriconazole doses may be required, but therapeutic drug monitoring is essential to ensure adequate levels while avoiding toxicity. 4) Monitor patients closely for signs of treatment failure or fungal infection progression. 5) Consult with infectious disease specialists and clinical pharmacists for individualized management plans.

Rifampin interactions with food and lifestyle

Rifampin should be taken on an empty stomach, at least 1 hour before or 2 hours after meals, as food can significantly reduce its absorption and effectiveness. Alcohol consumption should be avoided or limited while taking rifampin, as both rifampin and alcohol can cause liver toxicity, and the combination may increase the risk of hepatotoxicity. Patients should be counseled to take rifampin consistently either with or without food (preferably without) to maintain consistent blood levels.

Voriconazole interactions with food and lifestyle

Voriconazole should be taken on an empty stomach, at least 1 hour before or 2 hours after meals, as food significantly reduces absorption and bioavailability. High-fat meals can decrease voriconazole absorption by up to 22%. Patients should avoid grapefruit and grapefruit juice during treatment, as these can increase voriconazole blood levels and risk of toxicity. Alcohol consumption should be avoided or limited, as both voriconazole and alcohol are metabolized by the liver and concurrent use may increase the risk of liver toxicity. Patients should also avoid prolonged sun exposure and use adequate sun protection, as voriconazole can cause photosensitivity reactions and increase risk of skin cancer with long-term use.