In vitro and in vivo activities of SCH 56592 (posaconazole), a new triazole antifungal agent, against Aspergillus and Candida

Abstract

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 microg/ml, and those of itraconazole ranged from </=0.008 to 1 microg/ml. The SCH 56592 MICs for Candida and Cryptococcus strains ranged from </=0. 004 to 16 microg/ml, and those of fluconazole ranged from </=0.062 to >64 microg/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.

FIG. 1

Effects of SCH (administered orally once daily) and ITC (administered orally three times daily) administered in a prophylactic regimen 1 day preinfection to 7 days postinfection on survival of immunocompromised mice infected (by 1 min of exposure to spores on day 0) with A. fumigatus ND152 by the pulmonary route. Total daily doses (in milligrams per kilogram) are indicated. Controls were administered MC or HPβCD.

FIG. 2

Effect of SCH and FLC (administered oral once daily) administered in a prophylactic regimen 1 day preinfection to 7 days postinfection on survival of immunocompromised mice systemically infected (with 5 × 10⁶ CFU/mouse on day 0) with C. albicans C284 (FLC R). Dose levels (in milligrams per kilogram) are indicated. Controls were administered sWFI.