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.
Highlights
Candida auris is a multi-drug resistant fungal pathogen, responsible for several cases of invasive fungemia since 2009, that has become a global public concern [1,2]
Echinocandins alone had a negligible concentration of 0.5 mg/L was limited against the six isolates of C. auris, as no fungicidal nor effect, even at the highest tested concentrations
In contrast to the poor results of the monotherapies, fungin led to a sustained fungistatic effect, and the fungicidal endpoint was reached the combination of 0.5 mg/L of amphotericin B with anidulafungin or caspofungin led against isolates C. auris CJ94, C. auris CJ99, C. auris CJ100, and C. auris CJ102
Summary
Candida auris is a multi-drug resistant fungal pathogen, responsible for several cases of invasive fungemia since 2009, that has become a global public concern [1,2]. In contrast to what has been observed for other species of Candida, where resistance to antifungal drugs are exceptions, in the case of C. auris, both intrinsic and acquired resistance are the norm [3,4]. C. auris shows high rates of resistance to fluconazole and other azoles, along with a reduced susceptibility to amphotericin B and echinocandins that complicate the therapeutic approaches for candidiasis caused by this species [5,6]. Crossand multi-resistance has been found in 18–41% of C. auris isolates and approximately 4%. Of them are resistant to the three main classes antifungal drugs: polyenes, azoles, and echinocandins [7,8]. It has been evidenced that echinocandins are not fungicidal against C. auris clinical isolates representing the four identified main clades [9,10].
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