Posaconazole is the broadest-spectrum member of the azole family, with activity against most species of Candida and Aspergillus. It is the first azole with significant activity against the agents of mucormycosis. It is currently licensed for salvage therapy in invasive aspergillosis, as well as prophylaxis of fungal infections during induction chemotherapy for leukemia, and for allogeneic bone marrow transplant patients with graft-versushost disease.
Isavuconazonium sulfate is a prodrug of the newest triazole, isavuconazole; 186 mg of the water-soluble prodrug is equivalent to 100 mg of isavuconazole. It is available as highly bioavailable oral capsules and an intravenous formulation. Following a 2-day loading dose of 372 mg administered every 8 hours, isavuconazonium sulfate is given as a single 372-mg daily dose. Food does not significantly impact the oral absorption of isavuconazonium sulfate. Measurement of isavuconazole levels has not been demonstrated to be of benefit. Coadministration with strong 3A4 inhibitors (eg, ritonavir) or inducers (eg, rifampin) is not recommended.
Isavuconazole has an antifungal spectrum similar to that of posaconazole. It is currently licensed for the treatment of invasive aspergillosis and invasive mucormycosis. Data from published clinical trials are limited. Preliminary evidence indicates that it is better tolerated than voriconazole.
Echinocandins are the newest class of antifungal agents to be developed. They are large cyclic peptides linked to a long-chain fatty acid. Caspofungin, micafungin, and anidulafungin are the only licensed agents in this category of antifungals, although other drugs are under active investigation. These agents are active against Candida and Aspergillus, but not C neoformans or the agents of zygomycosis and mucormycosis.
Echinocandins are available only in intravenous formulations. Caspofungin is administered as a single loading dose of 70 mg, followed by a daily dose of 50 mg. Caspofungin is water soluble and highly protein-bound. The half-life is 9–11 hours, and the metabolites are excreted by the kidneys and gastrointestinal tract. Dosage adjustments are required only in the presence of severe hepatic insufficiency. Micafungin displays similar properties with a half-life of 11–15 hours and is used at a dose of 150 mg/d for treatment of esophageal candidiasis, 100 mg/d for treatment of candidemia, and 50 mg/d for prophylaxis of fungal infections.
Anidulafungin has a half-life of 24–48 hours. For esophageal candidiasis, it is administered intravenously at 100 mg on the first day and 50 mg/d thereafter for 14 days. For candidemia, a loading dose of 200 mg is recommended with 100 mg/d thereafter for at least 14 days after the last positive blood culture.
Mechanism of Action
Echinocandins act at the level of the fungal cell wall by inhibiting the synthesis of β(1–3)-glucan (Figure 48–1). This results in disruption of the fungal cell wall and cell death.