In Vivo Efficacy of Rezafungin, Anidulafungin, Caspofungin, and Micafungin against Four Candida auris Clades in a Neutropenic Mouse Bloodstream Infection Model

Abstract

Objectives: Rezafungin is the first new drug approved to treat candidaemia and invasive candidiasis in more than 10 years. However, data are scant on the in vivo efficacy of rezafungin and the other three approved echinocandins against different Candida auris clades.

Methods: This study involved 10 isolates representing 4 C. auris clades: South Asian (n = 2), East Asian (n = 2), South African (n = 2), and South American (n = 4, including 2 environmental isolates). In the lethality experiment and fungal tissue burden experiment (kidney, heart, and brain), cyclophosphamide-treated BALB/c male mice were intravenously infected (10⁷ and 8 × 10⁶ colony-forming units [CFU]/mouse, respectively). A 20 mg/kg dose of rezafungin was administered on days 1, 3, and 6. Alternatively, beginning 24 h post-infection, mice received 3 mg/kg of caspofungin, 5 mg/kg of micafungin, or 5 mg/kg of anidulafungin once daily for 6 days.

Results: Regardless of isolate and clade, all echinocandin regimens improved survival after 21 days (p = 0.0041 to p < 0.0001). All echinocandins frequently produced >3-log mean CFU/g decreases in the fungal kidney and heart burdens, although some of these decreases were not statistically significant. Rezafungin, regardless of clade, produced 3-5 and 2-4 log CFU/g decreases in the kidney and heart burdens, respectively. Echinocandins did not inhibit fungal growth in the brain. Histopathological examination performed on day 7 showed no fungal cells in the heart and kidneys of rezafungin-treated mice and to a lesser extent, caspofungin-treated mice, regardless of the clinical isolate. All echinocandin-treated mice showed medium and/or large foci of fungal cells in their cerebrum or cerebellum.

Conclusions: Regardless of the C. auris clade, rezafungin activity in vivo was comparable to or improved over that of the three previously approved echinocandins.

Keywords: Candida auris; echinocandins; murine model.

Figure 1

Survival of neutropaenic echinocandin-treated and control BALB/c mice infected with isolates from the four Candida auris clades: isolates 27 and 196 (South Asian clade), isolates CBS 12372 {12372} and CBS 12373 {12373} (East Asian clade), isolates 2 and 204 (South African clade), and isolates I-24 and I-156 (South American clade). Two environmental isolates from the South American clade were also tested: CDC B-13108 {13108} and CDC B-13112 {13112}. The infectious dose was 10⁷ CFU/mouse. A 20 mg/kg dose of rezafungin (REZA) was administered on days 1, 3, and 6. Additionally, beginning 24 h post-infection, the mice received 3 mg/kg of caspofungin (CAS) (Cancidas^®), 5 mg/kg of micafungin (MCF) (Mycamine^®), and 5 mg/kg of anidulafungin (ANF) (Eraxis^®) once daily for 6 days. After 21 days, survival rates were compared using the Kaplan–Meier log rank test.

Figure 2

Fungal kidney, heart, and brain burdens were determined on days 1 and 7 with clinical isolates from the South Asian clade (isolate 196), East Asian clade (isolate CBS 12372), South African clade (isolate 2), and South American clade (isolate I-156). One environmental isolate from the South American clade was also tested (isolate CDC B-13112). The infectious dose was 8 × 10⁶ CFU/mouse. A 20 mg/kg dose of rezafungin (REZA) was administered on days 1, 3, and 6. Additionally, beginning 24 h post-infection, the mice received 3 mg/kg of caspofungin (CAS) (Cancidas^®), 5 mg/kg of micafungin (MCF) (Mycamine^®), and 5 mg/kg of anidulafungin (ANF) (Eraxis^®) once daily for 6 days. The bars represent the medians. The level of statistical significance is indicated as * p < 0.05, ** p < 0.01, and *** p < 0.001.

Figure 2

Fungal kidney, heart, and brain burdens were determined on days 1 and 7 with clinical isolates from the South Asian clade (isolate 196), East Asian clade (isolate CBS 12372), South African clade (isolate 2), and South American clade (isolate I-156). One environmental isolate from the South American clade was also tested (isolate CDC B-13112). The infectious dose was 8 × 10⁶ CFU/mouse. A 20 mg/kg dose of rezafungin (REZA) was administered on days 1, 3, and 6. Additionally, beginning 24 h post-infection, the mice received 3 mg/kg of caspofungin (CAS) (Cancidas^®), 5 mg/kg of micafungin (MCF) (Mycamine^®), and 5 mg/kg of anidulafungin (ANF) (Eraxis^®) once daily for 6 days. The bars represent the medians. The level of statistical significance is indicated as * p < 0.05, ** p < 0.01, and *** p < 0.001.

Figure 3

Histopathological findings of the heart, kidney, and cerebrum with periodic acid–Schiff staining in mice infected with isolate CDC B-13112 from the South American clade. A 20 mg/kg dose of rezafungin (REZA) was administered on days 1, 3, and 6. Additionally, beginning 24 h post-infection, the mice received 3 mg/kg of caspofungin (CAS) (Cancidas^®), 5 mg/kg of micafungin (MCF) (Mycamine^®), and 5 mg/kg of anidulafungin (ANF) (Eraxis^®) once daily for 6 days. Fungal lesions are indicated by yellow arrows. In the control mice, C. auris produced large aggregates in the heart and kidneys and one large aggregate in the brain. In anidulafungin- and micafungin-treated mice, two and one large aggregates, respectively, with numerous blastoconidia and budding yeast cells were detected in the heart. The size of the lesions in caspofungin-treated mice was similar to that in anidulafungin- and micafungin-treated mice, but the number of fungal cells was significantly lower. The smallest fungal lesions were detected in rezafungin-treated mice. Anidulafungin-, caspofungin-, and rezafungin-treated mice showed small fungal lesions in their brain tissue, but the lesions in micafungin-treated mice were similar to those in the control mice. In the kidneys in caspofungin- and rezafungin-treated mice, fungal cells were not seen, but small lesions were noted in anidulafungin- and micafungin-treated mice. Magnification, ×100.