Background: PC1244 is a novel potent and long acting antifungal triazole designed for inhalation treatment of pulmonary aspergillosis and other difficult-to-treat fungi. In this study the antifungal activities of PC1244 were assessed by performing susceptibility testing against well-characterized azole-resistant Aspergillus fumigatus isolates.
Methods: In-vitro antifungalsusceptibility of PC1244 (0.016 – 8 µg/ml) was tested, in comparison with voriconazole (0.031 – 16 µg/ml) and posaconazole (0.016 – 8 µg/ml), against TR34/L98H (n=36), TR46/Y121F/T289A (n=12), M220 (n=6), G54 (n=5), TR92/ Y121F/T289A (n=1), G432C (n=1) and P216S (n=1) A. fumigatus mutants originated from India and the Netherlands using CLSI broth microdilution. The antifungal susceptibility data obtained were further compared with MIC values of wild-type A. fumigatus strains (n=3), including a quality control strain (ATCC204305). Antifungal drugs were dissolved in DMSO and applied to wells in microdilution plates at a final concentration of 1% DMSO.
Results: The MIC values of voriconazole and posaconazole against quality control ATCC204305 were 1 µg/mL and 0.25 µg/mL, respectively, and that of PC1244 was 0.25 µg/mL. The median MIC values of PC1244 against TR34/L98H, TR46/Y121F/T289A, G54, M220 and wild type were1 µg/mL, 1 µg/mL, 1 µg/mL, 1 µg/mL and 0.25 µg/mL, respectively. PC1244 was much more potent than voriconazole (MICs: 8 µg/mL, >16 µg/mL, 1 µg/mL, >16 µg/mL, 1 µg/mL) and comparable to posaconazole (MICs: 1 µg/mL, 1 µg/mL, 1 µg/mL, 1 µg/mL, 0.25 µg/mL)against TR34/L98H, TR46/Y121F/T289A, G54, M220 and wild type, respectively. Single mutant isolates carrying TR92/ Y121F/T289A, G432C and P216S mutations exhibited MIC values of 1 µg/mL, 1 µg/mL and 0.5 µg/mL for PC1244, >16 µg/mL, >16 µg/mL and 1 µg/mL for voriconazole and 1 µg/mL, 1 µg/mL and 0.5 µg/mL for posaconazole. Overall, the geometric mean MIC [median, range] of 59 isolates was 0.92 µg/mL [1, 0.125->8] for PC1244, 16 µg/mL [16, 0.5->16] for voriconazole and 1.1 µg/mL [1, 0.5->8] for posaconazole.
Conclusion: PC1244 demonstrated more potent activities against A. fumigatus with well characterised cyp51A mutations than voriconazole. PC1244, therefore, has the potential to become a novel approach for the topical treatment of pulmonary aspergillosis.
Full conference title:
- AAA 8th (2018)