In Vitro Activity and In Vivo Efficacy in a Murine Model of Rezafungin, Anidulafungin, Caspofungin, and Micafungin Against the Fifth Clade of Candida (Candidozyma) auris

Full abstract

Read the full abstract

Objectives: The aim of our study was to investigate the in vitro activity and in vivo efficacy of rezafungin, anidulafungin, caspofungin and micafungin against Candida auris isolates belonging to clade V. Methods: Five clinical isolates were evaluated (IFRC2087, IFRC4050, MRL40, TMML616 and TMML617). Echinocandin MICs, according to CLSI M27-Ed4, and killing activities were determined in RPMI-1640. In the survival and fungal tissue burden experiments (heart, kidney and brain), neutropenic mice were infected intravenously (1 × 107 CFU/mouse). Treatment was initiated 24 h post-infection with intraperitoneal dosing of 20 mg/kg of rezafungin on days 1, 3 and 6 or once-daily dosing for 6 days with 3 mg/kg of caspofungin, 5 mg/kg of micafungin or 5 mg/kg of anidulafungin. Results: MIC ranges of rezafungin, anidulafungin, caspofungin, and micafungin were 0.06–0.25, ≤0.03–0.12, 0.12–0.5 and ≤0.03–0.12 mg/L, respectively. Growth in RPMI-1640 showed pseudohypha in all five isolates both at 30 °C and 37 °C, but hyphae were never observed. In contrast, echinocandin-treated yeasts at 37 °C showed small and large aggregates of blastoconidia at both 0.25 and 16 mg/L echinocandin concentrations. The four echinocandins at ≥1 mg/L were fungicidal only against isolate MRL40. All echinocandin regimens improved the survival in mice infected with isolates MRL40 and IFRC4050 (p-values were ≤0.0002 and 0.0006, respectively), but only rezafungin was effective against isolate TMML617 (p = 0.0049). All four echinocandins induced more than 4 log mean CFU/gram decreases in the kidneys and hearts of mice infected with isolate MRL40 (p < 0.001 for all echinocandins). Rezafungin and caspofungin significantly decreased the fungal kidney and heart burdens in mice infected with isolate TMML617. Against IFRC4050, rezafungin, anidulafungin and caspofungin significantly decreased the fungal burdens in the kidneys (p < 0.05) and hearts (p < 0.05–0.01). The fungal brain tissue burdens were always higher than 105 CFU/gram. Histopathology showed large aggregates of pseudohyphae in the hearts, kidneys and brains in control mice. In echinocandin-treated mice, only blastoconidia were observed. Conclusions: In vitro activity and in vivo efficacy of the four echinocandins against the fifth clade of C. auris was echinocandin- and isolate-specific. Pseudohyphae production was common in controls, but not in echinocandin-treated mice. Rezafungin activity was comparable to or better than the three previously approved echinocandins.