No abstract

C andida auris, a globally emerging human fungal pathogen, has arisen as a public health concern worldwide because of its ability to cause nosocomial outbreaks and its resistance to multiple antifungal drugs (1, 2). C. auris is resistant to fluconazole in up to 90% of isolates and exhibits reduced susceptibility to other azoles (3, 4); resistance to amphotericin B and 5-flucytosine has also been reported (5-7). Echinocandin resistance is relatively rare, and this drug class has been chosen as the first line of choice to treat C. auris infections; however, reduced susceptibility to echinocandins has been increasingly reported (6, 8, 9). Thus, in the absence of new antifungal drugs currently available to treat the disease, alternative antifungal regimens are urgently sought. Miltefosine, a type of alkyl-phospholipid analogue, is a clinically licensed antileishmanial drug. The drug was found to possess in vitro antifungal activity against a pan-antifungal drug-resistant fungus, Lomentospora prolificans, but demonstrated different in vitro and in vivo activities against Cryptococcus neoformans (10-12). In this study, we examined the in vitro antifungal susceptibility of miltefosine alone or in combination with fluconazole or amphotericin B against 12 C. auris clinical isolates, which included 10 from the CDC and FDA Antibiotic Resistance (AR) Bank and 2 from the Johns Hopkins Hospital (representing 4 different geographic clades). The MICs were determined using the broth microdilution method or the broth checkerboard method from the CLSI M27-A4 document (13). The endpoints were defined as at least 50% inhibition of growth for azoles alone and in combination with miltefosine and as 100% inhibition of growth for amphotericin B alone and in combination with miltefosine. The endpoint for miltefosine alone was read at 50% and 100% inhibition, respectively. Drug synergy testing (repeated three times) was assessed by calculating the fractional inhibitory concentration index (FICI) as follows: FICI Յ 0.5 for synergism, 0.5 Ͻ FICI Ͻ 4 for indifference, and FICI Ͼ 4 for antagonism (14). The minimum fungicidal concentrations (MFCs) were defined as the lowest concentration that eliminated 99.9% of the colonies formed on the plates as previously described (15). Strains of Candida parapsilosis ATCC 22019 and Candida krusei ATCC 6258 were used as controls. Eleven isolates (11/12) were fluconazole resistant (MIC 90 , 256 g/ml), and seven isolates (7/12) had a high MIC for voriconazole (MIC 90 , 4 g/ml) (Table 1), according to the tentative MIC breakpoints recommended by the U.S. Centers for Disease Control and Prevention (https://www.cdc.gov/fungal/candida-auris/c-auris-antifungal.html). Three isolates (3/12) were resistant to amphotericin B (2 g/ml) and fluconazole (128 to 256 g/ml). All isolates were susceptible to micafungin (data not Citation Wu Y, Totten M, Memon W, Ying C, Zhang SX. 2020. In vitro antifungal susceptibility of the emerging multidrugresistant pathogen Candida auris to miltefosine alone and in combination with amp...