Effects Of Pc945, A Novel Antifungal Agent Optimised For Lung Delivery, On Candida Albicans Lung Infection In Mice

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. is involved in pathogenesis of respiratory diseases such as bronchiectasis, asthma and COPD. Here the aim is to establish a Candida albicans lung infection model in mice, and investigate the effects of PC945, a novel antifungal triazole optimised for lung delivery. Candida albicans (MYA4901) was administered intranasally to immunocompromised temporarily neutropenic A/J mice, pre-treated with hydrocortisone and cyclophosphamide. In this model, 71 % of mice were dead 5 days post inoculation. High levels of fungal burden in lung (6.55 ± 0.20 Log CFU/g of lung) and inflammatory markers CXCL1 in BALF (5.3 ± 1.1 ng/mL) were observed on day 5. Histology revealed significant inflammation and acute lung injury. PC945 saline suspension, when treated intranasally once daily, starting a day after candida inoculation, improved survival rates and inhibited lung fungal burden as well as BALF CXCL1 in a dose-dependent manner (0.56, 2.8 and 14 µg/mouse). Thus, Candida albicans, when inoculated intranasally, induced acute lung injury/death, and intranasally dosed PC945 showed potent antifungal effects. Therefore, PC945 has the potential to be a novel inhaled therapy for the treatment of C. albicans infection/colonization in humans.