In Vitro and In Vivo Activities of Posaconazole against Coccidioides immitis

Abstract

Posaconazole (SCH 56592) was tested against 25 strains of Coccidioides immitis to determine their in vitro susceptibilities. The geometric mean 48-h MIC of posaconazole (POSA) was 0.5 g/ml, the MIC range was 0.25 to 1 g/ml, and the MIC at which 50% of the isolates tested are inhibited (MIC 50 ) and the MIC 90 were 0.5 and 1 g/ml, respectively. The geometric mean 48-h MIC of itraconazole (ITRA) was 0.23 g/ml, the MIC range was 0.125 to 0.5 g/ml, and the MIC 50 and MIC 90 were both 0.25 g/ml. Two strains of C. immitis were selected for in vivo studies on the basis of the POSA 48-h MICs for the isolates. POSA orally administered at 0.01, 0.1, 0.5, 1, 5, and 10 mg/kg of body weight/day was compared with ITRA administered at 10 and 30 mg/kg three times a day. The spleens and livers of mice that died or survived to day 50 were removed to measure the fungal burdens. Mice had >90% survival when they were treated with >0.5 mg of POSA per kg or 30 mg of ITRA per kg. Cultures of whole spleens and livers from mice treated with 10 mg of POSA per kg showed >70% sterilization. No sterilization of whole spleens and livers from mice treated with ITRA was seen. POSA displayed potent in vivo activity against the two strains of C. immitis tested.Amphotericin B remains the drug of choice for the treatment of coccidioidomycosis as well as other systemic mycoses. However, amphotericin B is often toxic and is sometimes ineffective (7). Triazoles have been found to be effective in the treatment of threatening human mycoses. Itraconazole (ITRA) and fluconazole are used for the treatment of patients with mild or moderate manifestations of coccidioidomycosis and following treatment with amphotericin B in patients with severe forms of coccidioidomycosis (8). Therapy can be completed with these antifungal agents, but the response rates are only 50 to 60% (2, 9).These unfavorable conditions have prompted a search for more effective alternatives with improved pharmacokinetic parameters and safety. Posaconazole (POSA; SCH 56592) is a broad-spectrum triazole whose activities against a variety of systemic and opportunistic fungal pathogens are under active evaluation (1,4,6,10,12,15,16,17,19). Lutz et al. (11) reported on the activity of POSA in a murine model of disseminated coccidioidomycosis. POSA exhibited greater in vivo activity than fluconazole and ITRA in both survival and tissue burden studies, with doses of 10 and 25 mg/kg of body weight curing high proportions of infected mice. Pharmacokinetic studies with POSA in mice, rats, rabbits, dogs, and monkeys showed that it has good oral bioavailability (14). The half-lives in mice, rats, and rabbits were 7 to 9 h. In contrast, the halflives in dogs and monkeys were 15 and 23 h, respectively.In this study, we determined the in vitro activities of POSA against isolates of Coccidioides immitis and then compared the lowest and highest MICs of POSA in vivo using a murine model. MATERIALS AND METHODSAntifungal agents. Powders of POSA and ITRA for in vitro use were obtained from Schering-Plough Res...

Recent Advances in Our Understanding of the Environmental, Epidemiological, Immunological, and Clinical Dimensions of Coccidioidomycosis

“…The potential efficacy of posaconazole for coccidioidomycosis was reported from a murine model in 2002 (198). Treatment with posaconazole at doses ranging from 0.5 to 10 mg/kg/day for 20 days, beginning at 2 days postinfection, resulted in 100% survival, compared to 0% with placebo.…”

Pharmacokinetics, Safety, and Tolerability of Oral Posaconazole Administered in Single and Multiple Doses in Healthy Adults

“…In the RSD study, blood samples (10 ml) were collected at 0 h (predosing) and at 0.5, 1, 1.5, 2, 3, 4, 5,6,8,10,12,16,24,36,48,72,96, and 120 h postdosing. In the RMD study, on day 1 and day 14, blood samples (6 ml) were collected at 0 h (predosing) and at 2,4,5,6,8,10,12,16,17,18,20,22, and 24 h after the administration of the morning dose. On day 14, additional 6-ml blood samples were collected at 36, 48, 72, 96, and 120 h after the administration of the morning dose.…”

“…Numerous in vitro studies demonstrate that posaconazole has a broad spectrum of activity against the majority of yeasts, filamentous fungi, and azole-resistant Candida species (1,3,14,18,19). In addition, posaconazole has excellent in vitro activity against rare and emerging opportunistic fungal pathogens (4,9,10,15,17), including the difficult-to-treat zygomycetes (21). In a neutropenic mouse model of zygomycosis, posaconazole was shown to significantly reduce the fungal burden in tissue and prolong the survival of mice (22).…”

Disposition of Posaconazole following Single-Dose Oral Administration in Healthy Subjects

“…Posaconazole has demonstrated in vitro activity against several commonly encountered pathogens, including Candida, Aspergillus, Cryptococcus, and Coccidioides species (1,7,12,13). In addition, its activity against several emerging pathogens, such as the filamentous fungus Scedosporium (3, 10), has been explored clinically.…”