SCH 56592 (posaconazole), a new triazole antifungal agent, was tested in vitro, and its activity was compared to that of itraconazole against 39 Aspergillus strains and to that of fluconazole against 275 Candida and 9 Cryptococcus strains. The SCH 56592 MICs for Aspergillus ranged from <0.002 to 0.5 g/ml, and those of itraconazole ranged from <0.008 to 1 g/ml. The SCH 56592 MICs for Candida and Cryptococcus strains ranged from <0.004 to 16 g/ml, and those of fluconazole ranged from <0.062 to >64 g/ml. SCH 56592 showed excellent activity against Aspergillus fumigatus and Aspergillus flavus in a pulmonary mouse infection model. When administered therapeutically, the 50% protective doses (PD 50 s) of SCH 56592 ranged from 3.6 to 29.9 mg/kg of body weight, while the PD 50 s of SCH 56592 administered prophylactically ranged from 0.9 to 9.0 mg/kg; itraconazole administered prophylactically was ineffective (PD 50 s, >75 mg/kg). SCH 56592 was also very efficacious against fluconazole-susceptible, -susceptible dose-dependent, or -resistant Candida albicans strains in immunocompetent or immunocompromised mouse models of systemic infection. The PD 50 s of SCH 56592 administered therapeutically ranged from 0.04 to 15.6 mg/kg, while the PD 50 s of SCH 56592 administered prophylactically ranged from 1.5 to 19.4 mg/kg. SCH 56592 has excellent potential for therapy against serious Aspergillus or Candida infections.Of the estimated 100,000 known species of fungi, only about 180 have been shown to cause disease in humans, and only about 10% of these are encountered in most clinical settings (8). However, fungal infections have substantially increased over the past two decades, and invasive forms are important causes of morbidity and mortality (2, 16). The major increase in fungal infections is related to increased numbers of immunocompromised patients including those with human immunodeficiency virus infection-AIDS or cancer and bone marrow or solid organ transplant recipients, who are at risk of developing invasive fungal infections (5,7,12,16). Disseminated candidiasis, pulmonary aspergillosis, and mycoses caused by emerging opportunistic fungi are the most common of these serious mycoses (7,16,38). As a result, there is a developing consensus that prophylactic therapy should be used for these high-risk patients (12). Fluconazole (FLC) is used for prevention of fungal infections in some of these patients, but it is not active against Aspergillus or other filamentous fungi. However, there is great concern about the development of resistant Candida due to prophylactic use of FLC (4,10,15,18,23,35,37). Clearly, alternative antifungal agents are needed for both therapeutic and prophylactic use. SCH 56592 (SCH; posaconazole) is a new triazole antifungal agent with broad-spectrum activity against fungi including strains of Aspergillus and Candida resistant to FLC (9,11,19,24,30,33). This report describes the in vitro activity of SCH against Aspergillus and Candida and its efficacy in clinically relevant experimental infection models ...