Abstract
ABSTRACTPC945 is a novel triazole optimized for lung delivery, and the objective of this study is to determine the effects of intranasally dosed PC945 on Aspergillus fumigatus infection and associated biomarkers in immunocompromised mice. PC945, posaconazole, or voriconazole was administered intranasally once daily on days 0 to 3 (early intervention) or days 1 to 3 (late intervention) postinfection in temporarily neutropenic A/J mice infected intranasally with A. fumigatus, and bronchoalveolar lavage fluid (BALF) and serum were collected on day 3. The effects of extended prophylaxis treatment (daily from days −7 to +3 or days −7 to 0) were also compared with those of the shorter treatment regimens (days −1 to +3 or days −1 and 0). Early and late interventions with PC945 (2.8 to 350 μg/mouse; approximately 0.11 to ∼14 mg/kg of body weight) were found to inhibit lung fungal loads and to decrease the concentrations of galactomannan (GM) in both BALF and serum as well as several biomarkers in BALF (interferon gamma [IFN-γ], interleukin-17 [IL-17], and malondialdehyde) and serum (tumor necrosis factor alpha [TNF-α] and IL-6) in a dose-dependent manner and were >3- and >47-fold more potent than intranasally dosed posaconazole and voriconazole, respectively. Furthermore, extended prophylaxis with low-dose PC945 (0.56 μg/mouse; 0.022 mg/kg) was found to inhibit fungal loads and to decrease the concentrations biomarkers more potently than did the shorter treatment regimens. Thus, PC945 dosed intranasally once daily showed potent antifungal effects, and the effects of PC945 accumulated upon repeat dosing and were persistent. Therefore, PC945 has the potential to be a novel inhaled therapy for the treatment of A. fumigatus infection in humans.
Highlights
PC945 is a novel triazole optimized for lung delivery, and the objective of this study is to determine the effects of intranasally dosed PC945 on Aspergillus fumigatus infection and associated biomarkers in immunocompromised mice
According to the CLSI test, MIC values of PC945, posaconazole, and voriconazole were 0.031, 0.031, and 0.50 mg/liter, respectively. In both tests, the ATCC 13073 strain was highly susceptible to PC945, which was equal to posaconazole and 5.3- and 16-fold more potent than voriconazole according to EUCAST and CLSI tests, respectively
A suspension of PC945 in isotonic saline (2.8, 14, 70, or 350 g/mouse; equivalent to 0.11, 0.56, 2.8, or 14 mg/kg of body weight, respectively) was dosed by intranasal injection once daily on days 0, 1, 2, and 3 postinfection. This “early-intervention” regimen was found to strongly inhibit fungal loads in the lung (CFU), with a 50% infective dose (ID50) value of 2.66 g/mouse (0.13 mg/kg) (Fig. 2A and 3A and Table 1; see Table S1 in the supplemental material), and to decrease GM concentrations in both bronchoalveolar lavage fluid (BALF) and serum in a dose-dependent manner (ID50s of Ͻ2.8 g/mouse [Ͻ0.14 mg/kg] for both), as 85% inhibition was observed at 2.8 g/ mouse (Fig. 2B and C and 3B and C, Table 1, and Table S1)
Summary
PC945 is a novel triazole optimized for lung delivery, and the objective of this study is to determine the effects of intranasally dosed PC945 on Aspergillus fumigatus infection and associated biomarkers in immunocompromised mice. Extended prophylaxis with low-dose PC945 (0.56 g/mouse; 0.022 mg/kg) was found to inhibit fungal loads and to decrease the concentrations biomarkers more potently than did the shorter treatment regimens. Inhaled amphotericin is well tolerated in lung transplant patients and does not interact with immunosuppressive drugs, it has been reported to cause bronchospasm in severe asthmatics [14]. A dry-power formulation of voriconazole for the treatment of respiratory fungal infection was developed [17] Both voriconazole and amphotericin have very short durations of action in the lungs (short lung residence times) and require high doses and frequent administration
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