ABSTRACT
The new antifungal derivative posaconazole was tested against three clinical isolates of Cryptococcus neoformans var. neoformans using a broth microdilution procedure performed according to the guidelines established by the NCCLS. Posaconazole MICs were 0.125, 0.25 and 1.0 mg/L for isolates 491, 2337 and 486, respectively. To investigate the in vivo activity of this new compound, we established an experimental model of systemic cryptococcosis in CD1 mice by iv injection of cells of each strain of C. neoformans. Low (3 mg/kg/day) and high (10 mg/kg/day) doses of posaconazole were compared with amphotericin B given at 0.3 mg/kg/day for 10 consecutive days. Survival studies showed that all treatment regimens were effective in prolonging the survival of mice infected with C. neoformans 486 (P < 0.001). Only posaconazole at 10 mg/kg and amphotericin B were effective in prolonging the survival in mice infected with C. neoformans 2337 (P from <0.01 to <0.001), while neither agent was effective in mice infected with C. neoformans 491. Tissue burden experiments performed 24 h after the end of therapy revealed that posaconazole at 10 mg/kg was effective at reducing the fungal burden in both lung and brain tissues of all three strains of C. neoformans. In particular, for C. neoformans 491 and 2337 posaconazole was superior to amphotericin B at reducing the fungal burden in the brain (P < 0.05). The efficacy of posaconazole was also confirmed by determining the capsular antigen serum levels of treated mice versus untreated mice. Our study underlines the excellent activity of posaconazole against this pathogenic yeast.
Subject(s)
Antifungal Agents/pharmacology , Cryptococcus neoformans/drug effects , Triazoles/pharmacology , Animals , Antifungal Agents/therapeutic use , Cryptococcosis/drug therapy , Cryptococcosis/microbiology , Cryptococcus neoformans/isolation & purification , Humans , Male , Mice , Microbial Sensitivity Tests/methods , Triazoles/therapeutic useABSTRACT
A broth macrodilution method following the recommendations established by the National Committee for Clinical Laboratory Standards was used to compare the in vitro activity of posaconazole (PCZ) with that of itraconazole (ITC) against 30 clinical isolates of dermatophytes belonging to six different species. In terms of MICs, PCZ showed an activity equal to that of ITC. MICs of PCZ at which 50% (MIC(50)) and 90% (MIC(90)) of the isolates were inhibited were 0.5 and > 4.0 microg/ml, respectively. The MIC(50) and MIC(90) of ITC were 1.0 and > 4.0 microg/ml, respectively. However, PCZ showed a more potent fungicidal activity than that of ITC against isolates belonging to the genus Microsporum (P = 0.03). PCZ merits further investigation as a potentially useful agent for treatment of dermatophytosis.
