Efficacy of the combination of amphotericin B and echinocandins against Candida auris in vitro and in the Caenorhabditis elegans host model

Abstract

The multidrug-resistant Candida auris is a global health emergency, being responsible for outbreaks of invasive candidiasis worldwide. Limited effective therapeutic options make it difficult to treat this emerging pathogen. In this context, combinations of different antifungal drugs are considered a promising therapeutic alternative. The aim of this work was to analyze the antifungal activity of combinations of amphotericin B and echinocandins against five clinical blood isolates of C. auris. One of these isolates showed an aggregative phenotype already described in C. auris species, forming large aggregates of cells that are very difficult to disintegrate. First, the in vitro activity of these drugs was evaluated both in monotherapy and in combination, and results showed synergistic interactions between amphotericin B and echinocandins in most cases, although higher minimum inhibitory concentration (MIC) values were observed against the aggregative isolate compared to non-aggregative counterparts. The most promising drug combinations were then selected for in vivo activity evaluation using a Caenorhabditis elegans model of candidiasis and by determination of survival rates. The combination of amphotericin B and caspofungin showed the strongest protective effect during C. elegans infection with C. auris blood isolates, achieving up to 99% C. elegans survival. Although the MIC values for micafungin were low in vitro, these drug concentrations had no effect in vivo, and the combination of amphotericin B and micafungin was the least effective. The results of this study showed that the combination amphotericin B and echinocandins might be a promising therapeutic approach for the treatment of invasive candidiasis caused by C. auris. Moreover, the nematode C. elegans is a suitable alternative model for screening of new therapeutic agents capable of overcoming multidrug-resistant C. auris infections.