Antifungal effects of PC945, a novel inhaled triazole, onCandida albicans-infected immunocompromised mice

Abstract

Although Candida spp. are frequently detected in fungal cultures of respiratory secretions, their presence is normally assumed to reflect benign colonization. However, there is growing evidence that Candida spp. are involved in the pathogenesis of respiratory diseases such as bronchiectasis and asthma. The aim of this study is to investigate the in vitro and in vivo effects of a novel antifungal triazole, PC945, optimised for topical delivery, against C. albicans. In temporarily neutropenic, immunocompromised mice, C. albicans (529L [ATCC®MYA4901™] strain), inoculated intranasally, induced acute lung injury and death, associated with higher fungal burden and cytokine induction in the lung. PC945 saline suspension, dosed intranasally once daily, starting one day post candida inoculation, dose-dependently (0.56 ~ 14 μg/mouse) improved survival rate and inhibited fungal load in the lung on Day 5 post inoculation. These effects by PC945 were 7 ~ 25-fold more potent than those of voriconazole, despite being of similar in vitro antifungal activity versus this strain. Furthermore, extended prophylaxis with low dose PC945 (0.56 μg/mouse) was found to inhibit fungal load more potently than the shorter treatment regimens, suggesting antifungal effects of PC945 accumulated on repeat dosing. In addition, antifungal susceptibility testing on 88 candida isolates (C. albicans, C. parapsilosis, C. tropicalis, C. lucitaniae, C. glabrata, C. guilliermondii) revealed that PC945 has potent effects on Candida species broadly. Thus, PC945 has the potential to be a novel topical therapy for the treatment of C. albicans pulmonary infection in humans.