voriconazole
Summary
Voriconazole is a second-generation triazole antifungal that inhibits fungal cytochrome P450-dependent 14α-demethylase, blocking ergosterol synthesis. It is the first-line treatment for invasive aspergillosis and is also used for candidiasis and other invasive fungal infections. Key adverse effects include visual disturbances, hepatotoxicity, and photosensitivity/skin reactions.
Detail
Mechanism: Voriconazole inhibits lanosterol 14α-demethylase (a CYP450 enzyme), preventing conversion of lanosterol to ergosterol, an essential component of the fungal cell membrane. This disrupts membrane integrity and fungal growth, similar to other azoles (fluconazole, itraconazole, posaconazole, isavuconazole), but voriconazole has broader activity against molds, particularly Aspergillus species.
Clinical use: Voriconazole is the drug of choice for invasive aspergillosis, and is also used for serious infections caused by Candida (including some fluconazole-resistant strains), Fusarium, and Scedosporium. It has poor activity against Mucorales (zygomycetes), unlike isavuconazole or posaconazole.
Pharmacokinetics: Well absorbed orally, metabolized by CYP2C19, CYP2C9, and CYP3A4 - subject to significant genetic polymorphism affecting metabolism (CYP2C19 poor vs. rapid metabolizers), leading to variable drug levels. Therapeutic drug monitoring is often required.
Adverse effects: - Visual disturbances (blurred vision, photopsia, altered color perception) - common but transient - Hepatotoxicity (elevated LFTs, rare severe liver injury) - Skin reactions including photosensitivity and rare Stevens-Johnson syndrome/toxic epidermal necrolysis - QT prolongation - Hallucinations/CNS effects - Periostitis (with prolonged use, due to fluoride accumulation)
Drug interactions: Significant CYP450 inhibitor (multiple isoenzymes), leading to many drug interactions (e.g., increases levels of warfarin, cyclosporine, tacrolimus, sirolimus - contraindicated with sirolimus). Also substrate of these enzymes, so its own levels are affected by inducers/inhibitors.
Contraindications: Avoid with drugs that significantly prolong QT interval, and with rifampin/rifabutin (induces metabolism, reduces voriconazole levels).
High-yield board points: Remember voriconazole = go-to for Aspergillus (compare to amphotericin B as second-line), and its unique side effects of visual changes and photosensitivity/skin cancer risk with long-term use.
Sources
- First Aid for the USMLE Step 1
- Katzung's Basic and Clinical Pharmacology
- UpToDate: Voriconazole drug information
- Mandell's Principles and Practice of Infectious Diseases
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