Voriconazole is available in intravenous and oral formulations. The recommended dosage is 400 mg/d. The drug is well absorbed orally, with a bioavailability exceeding 90%, and it exhibits less protein binding than itraconazole. Metabolism is predominantly hepatic. Voriconazole is a clinically relevant inhibitor of mammalian CYP3A4, and dose reduction of a number of medications is required when voriconazole is started. These include cyclosporine, tacrolimus, and HMG-CoA reductase inhibitors.
In September 2012, the U.S. Centers for Disease Control and Prevention (CDC) in Atlanta received reports of a number of cases of fungal meningitis in patients who had received injections with the corticosteroid methylprednisolone. An investigation revealed a multistate outbreak of septic arthritis, paraspinal infections, and meningitis due to environmental molds, with the black mold Exserohilum rostratum being the most commonly isolated species. The outbreak was traced to the injection of methylprednisolone that was contaminated during its preparation by a compounding pharmacy facility in New England. Methylprednisolone injections are commonly given to patients with joint or back arthritis, and in the affected cases the patients were not only inadvertently injected with spores of environmental molds, but the normal immune response to this infection was inhibited by the potent immunosuppressive effect of the corticosteroid. As of November 2013 more than 750 cases of fungal infection had been identified in 20 states, with over 60 deaths. Treatment of these infections was challenging, and the CDC recommended the use of intravenous voriconazole as first-line therapy, with the addition of liposomal amphotericin B in cases of severe infection.
Observed toxicities include rash and elevated hepatic enzymes. Visual disturbances are common, occurring in up to 30% of patients receiving intravenous voriconazole, and include blurring and changes in color vision or brightness. These visual changes usually occur immediately after a dose of voriconazole and resolve within 30 minutes. Photosensitivity dermatitis is commonly observed in patients receiving chronic oral therapy.
Voriconazole is similar to itraconazole in its spectrum of action, having excellent activity against Candida sp (including some fluconazole-resistant species such as Candida krusei) and the dimorphic fungi. Voriconazole is less toxic than amphotericin B and is the treatment of choice for invasive aspergillosis and some environmental molds (see Box: Iatrogenic Fungal Meningitis). Measurement of voriconazole levels may predict toxicity and clinical efficacy, especially in immunocompromised patients. Therapeutic trough levels should be between 1 and 5 mcg/mL.
Posaconazole was originally available only in a liquid oral formulation and is used at a dosage of 800 mg/d, divided into two or four doses. Absorption is improved when taken with meals high in fat. An intravenous form of posaconazole and a sustained acting tablet form with higher bioavailability are now available. Posaconazole is rapidly distributed to the tissues, resulting in high tissue levels but relatively low blood levels. Measurement of posaconazole levels is recommended in patients with serious invasive fungal infections (especially mold infections); steady-state posaconazole levels should be between 0.5 and 1.5 mcg/mL. Drug interactions with increased levels of CYP3A4 substrates such as tacrolimus and cyclosporine have been documented.