In Vitro Interaction and Killing-Kinetics of Amphotericin B Combined with Anidulafungin or Caspofungin against Candida auris

Abstract

Treatment of invasive infections caused by Candida auris is challenging due to the limited therapeutic options. The combination of antifungal drugs may be an interesting and feasible approach to be investigated. The aim of this study was to examine the in vitro activity of amphotericin B in combination with anidulafungin or caspofungin against C. auris. In vitro static time–kill curve experiments were conducted for 48 h with different combinations of amphotericin B with anidulafungin or caspofungin against six blood isolates of C. auris. The antifungal activity of 0.5 mg/L of amphotericin B was limited against the six isolates of C. auris. Similarly, echinocandins alone had a negligible effect, even at the highest tested concentrations. By contrast, 1 mg/L of amphotericin B showed fungistatic activity. Synergy was rapidly achieved (8 h) with 0.5 mg/L of amphotericin B plus 2 mg/L of anidulafungin or caspofungin. These combinations lead to a sustained fungistatic effect, and the fungicidal endpoint was reached against some C. auris isolates. Additionally, ≥0.5 mg/L of either of the two echinocandins with 1 mg/L of amphotericin B resulted in fungicidal effect against all C. auris isolates. In conclusion, combinations of amphotericin B with anidulafungin or caspofungin provided greater killing with a lower dose requirement for amphotericin B compared to monotherapy, with synergistic and/or fungicidal outcomes.

Small molecules for combating multidrug-resistant superbug Candida auris infections

“… Drug Antifungal drug FICI Isolate a Ref. Antifungal drug Micafungin Voriconazole 0.15–0.5 10/10 56 Anidulafungin Isavuconazole 0.25–0.38 11/36 38 Voriconazole 0.25–0.38 5/36 38 Amphotericin B Caspofungin ND b 6/6 100 Anidulafungin ND 6/6 100 Non-antifungal drug Sulfamethoxazole Fluconazole 0.156 1/1 101 Voriconazole 0.09–0.5 3/8 101 Itraconazole 0.186–0.373 3/4 101 Lopinavir Itraconazole 0.04–0.09 10/10 58 Voriconazole 0.19–0.31 6/10 58 Fluconazole 0.13–0.31 3/10 58 Aprepitant Itraconazole 0.14–0.31 8/10 102 Pitavastatin Fluconazole 0.25–0.5 5/5 103 Ospemifene Itraconazole 0.14–0.27 5/5 104 …”

“…In a time–kill curve assay against six C. auris isolates, monotherapy with echinocandins (anidulafungin and caspofungin) was ineffective, while high concentrations of amphotericin B (≥1 μg/mL) only showed fungistatic activity 100 . When used in combination, higher fungal killing activity was observed 100 . Lower doses of amphotericin B (0.5 mg/L) and anidulafungin or caspofungin (2 mg/L) achieved rapid synergism with potent fungicidal activity 100 .…”

“…When used in combination, higher fungal killing activity was observed 100 . Lower doses of amphotericin B (0.5 mg/L) and anidulafungin or caspofungin (2 mg/L) achieved rapid synergism with potent fungicidal activity 100 .…”

Heightened efficacy of anidulafungin when used in combination with manogepix or 5-flucytosine againstCandida auris in vitro

“…Thus far, nine studies have examined antifungal drug combinations against C. auris. The majority of these studies focussed on combinations of azoles with echinocandins (20,23,24,38), while a smaller number have evaluated polyene-echinocandin interactions (21,22) or combinations with 5-flucytosine (25)(26)(27). These studies reported mainly synergistic (including partial synergy) or indifferent interactions, with inter-strain variability observed for some combinations.…”

Synergism between the Antidepressant Sertraline and Caspofungin as an Approach to Minimise the Virulence and Resistance in the Dermatophyte Trichophyton rubrum

“…There are few studies demonstrating the CASP effect with other antifungal agents. In most cases, the combination therapy of CASP with another agent is used for treating infections caused by the genus Candida [ 22 , 23 ]. In association with farnesol, CASP significantly inhibited the metabolic activity of Candida parapsilosis cells [ 24 ].…”