Background: Candida auris is an emerging drug-resistant pathogen associated with nosocomial outbreaks and high mortality rates. Based on in vitro susceptibility data, echinocandins have been recommended as first-line treatment.
Objectives: To assess the in vitro killing dynamics and in vivo efficacies of single and double drug regimens against C. auris.
Methods: We performed time-kill analyses of fluconazole, caspofungin, and amphotericin B, alone and in combination with flucytosine, on 5 clinical C. auris strains. FUN-1 viability staining was used to visualize and quantitate spatial differences in drug response within C. auris yeast cell aggregates. In vivo efficacies of caspofungin and amphotericin B were determined in cyclophosphamide-treated mice infected intravenously with C. auris yeast cells.
Results: Time-kill analyses showed fungistatic activity of fluconazole and flucytosine and fungicidal activity of amphotericin B. Surprisingly, caspofungin exhibited only mild fungistatic activity, despite low echinocandin MICs. Flucytosine enhanced amphotericin B activity but was only additive in combination with caspofungin. FUN-1 viability staining of C. auris aggregates after caspofungin exposure demonstrated loss of viability of peripheral cells, relative resistance of aggregate cores, and the appearance of persister cells. Amphotericin B increased the survival of neutropenic mice with hematogenic C. auris infection (50% versus 0% for untreated controls, P=0.03), whereas caspofungin had no effect on survival rates.
Conclusions: C. auris exhibits tolerance to caspofungin, which may be due to its aggregative properties. Our findings suggest that, pending clinical data, amphotericin B should be considered as primary treatment of C. auris infections.
