A 42-year-old man with acute leukemia presents with fever and pulmonary infiltrates. Blood and respiratory cultures grow Aspergillus fumigatus. He has normal renal function and no prior antifungal exposure. Which agent is the drug of choice for invasive aspergillosis?

Explanation

## Drug of Choice for Invasive Aspergillosis **Key Point:** Voriconazole is the first-line agent for invasive aspergillosis (IA), including pulmonary and disseminated disease, in immunocompromised hosts. ### Why Voriconazole? 1. **Spectrum**: Broad-spectrum azole with superior activity against Aspergillus spp. (including A. fumigatus) compared to fluconazole and itraconazole. 2. **Mechanism**: Inhibits fungal CYP51 (lanosterol 14α-demethylase), disrupting ergosterol synthesis. 3. **Pharmacokinetics**: - Excellent CNS penetration (unlike fluconazole, which does not penetrate well). - Achieves high lung concentrations, critical for pulmonary IA. - Available in both IV and oral formulations. 4. **Evidence**: Randomized trials (e.g., EORTC-MSG trial) demonstrate superior efficacy and survival vs. amphotericin B deoxycholate in invasive aspergillosis. ### Comparison of Antifungals in Invasive Aspergillosis | Drug | Aspergillus Activity | CNS Penetration | Role in IA | Limitation | |------|----------------------|-----------------|-----------|------------| | **Voriconazole** | Excellent | Good | **First-line** | Hepatotoxicity, visual disturbances, drug interactions | | Fluconazole | Poor | Excellent | Not for IA | Inactive against Aspergillus | | Itraconazole | Moderate | Poor | Alternative (oral step-down) | Unpredictable absorption, variable levels | | Caspofungin | Good | Poor | Second-line/salvage | Echinocandin; inferior to voriconazole in IA | | Amphotericin B | Excellent | Moderate | Salvage/CNS disease | Nephrotoxic, obsolete as monotherapy | **Clinical Pearl:** Voriconazole is preferred over amphotericin B because it has superior efficacy, better CNS penetration, and lower nephrotoxicity. Caspofungin is reserved for patients intolerant to voriconazole or with refractory disease. **High-Yield:** Voriconazole requires therapeutic drug monitoring (target trough 1–5.5 mg/L) because of nonlinear pharmacokinetics and high inter-individual variability. Loading dose is 6 mg/kg IV twice daily × 1 day, then 4 mg/kg IV twice daily or 200 mg orally twice daily. **Mnemonic:** **VFIC** — Voriconazole for Fungal Invasive Candida/Aspergillus.