Candida species (spp.) are frequently detected in fungal cultures of respiratory secretions, and there is growing evidence that Candida spp. are involved in the pathogenesis of respiratory diseases. The aim of this study is to investigate in vivo effects of a novel antifungal triazole, PC945, optimized for topical delivery, in Candida albicans pulmonary infection murine model as well as to evaluate in vitro antifungal profiles of PC945 with an extended collection of Candida spp. In temporarily neutropenic, immunocompromised mice, intranasal inoculation with C. albicans (529L) caused significant pulmonary inflammation and minor acute lung injury as well as high local Candida burden. PC945 saline suspension, dosed intranasally once daily, starting one day post Candida inoculation, dosedependently (0.56~14 µg/mouse) improved survival rate and inhibited fungal load in the lung on Day 5 post inoculation as well as lung inflammation. 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.
Candida, Lung, Intranasal, Antifungal, Acute lung injury, Triazole, Mice, Prophylaxis