<i>In Vitro</i> and <i>In Vivo</i> Antifungal Profile of a Novel and Long-Acting Inhaled Azole, PC945, on Aspergillus fumigatus Infection

Abstract

The profile of PC945, a novel triazole antifungal designed for administration via inhalation, was assessed in a range of <i>in vitro</i> and <i>in vivo</i> studies. PC945 was characterized as a potent, tightly binding inhibitor of <i>Aspergillus fumigatus</i> sterol 14α-demethylase (CYP51A and CYP51B) activity (50% inhibitory concentrations [IC₅₀s], 0.23 μM and 0.22 μM, respectively) with characteristic type II azole binding spectra. Against 96 clinically isolated <i>A. fumigatus</i> strains, the MIC values of PC945 ranged from 0.032 to >8 μg/ml, while those of voriconazole ranged from 0.064 to 4 μg/ml. Spectrophotometric analysis of the effects of PC945 against itraconazole-susceptible and -resistant <i>A. fumigatus</i> growth yielded IC₅₀ (determined based on optical density [OD]) values of 0.0012 to 0.034 μg/ml, whereas voriconazole (0.019 to >1 μg/ml) was less effective than PC945. PC945 was effective against a broad spectrum of pathogenic fungi (with MICs ranging from 0.0078 to 2 μg/ml), including <i>Aspergillus terreus</i>, <i>Trichophyton rubrum</i>, <i>Candida albicans</i>, <i>Candida glabrata</i>, <i>Candida krusei</i>, <i>Cryptococcus gattii</i>, <i>Cryptococcus neoformans</i>, and <i>Rhizopus oryzae</i> (1 or 2 isolates each). In addition, when <i>A. fumigatus</i> hyphae or human bronchial cells were treated with PC945 and then washed, PC945 was found to be absorbed quickly into both target and nontarget cells and to produce persistent antifungal effects. Among temporarily neutropenic immunocompromised mice infected with <i>A. fumigatus</i> intranasally, 50% of the animals survived until day 7 when treated intranasally with PC945 at 0.56 μg/mouse, while posaconazole showed similar effects (44%) at 14 μg/mouse. This profile affirms that topical treatment with PC945 should provide potent antifungal activity in the lung.