In Vitro Activity and In Vivo Efficacy of Rezafungin, Anidulafungin, Caspofungin and Micafungin Against the Fifth Clade of Candida (Candidozyma) Auris

Objectives: The aim of our study was to investigate the in vitro activity and in vivo effica-cy of rezafungin, anidulafungin, caspofungin and micafungin against Candida auris iso-lates belonging to clade V. Methods: Five clinical isolates were evaluated (IFRC2087, IFRC4050, MRL40, TMML616 and TMML617). Echinocandin MICs and killing activities were determined in RPMI-1640. In the survival and fungal tissue burden experiments (heart, kidney and brain), neutro-penic mice were infected intravenously (107 CFU/mouse). Treatment was initiated 24 hours 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. The four echinocandins at ≥1 mg/L were fungicidal only against isolate MRL40. All echinocandin regimens im-proved 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 TML617 (P=0.0049). All four echinocandins induced more than 3 logs mean CFU/gram decreases in the kidneys and hearts of mice infected with the three isolates compared to control mice, some of which were not statistically significant. Fungal growth, regardless of the isolate tested, was poorly inhibited by echinocandins in the brain. Histopathology showed large aggregates of pseudohyphae in the hearts, kidneys and brains in control mice. In echinocandin treated mice only blastoconidia were found. Conclusions: In vitro activity and in vivo efficacy of the four echinocandins against the fifth clade of C. auris was echinocandin- and isolate-specific. Pseudohyphal production was common in controls, but not in echinocandin treated mice. Rezafungin activity was comparable to or better than the three previously approved echinocandins. Keywords: Candida auris, fifth clade, time-kill, neutropenic mouse model, pseudohypha production, rezafungin, echinocandins,