In vitro interaction of fluconazole and trimethoprim-sulfamethoxazole against Candida auris using ETEST and checkerboard methods

Abstract

Candida auris was discovered in 2009 and has rapidly emerged as a serious public health threat with cases reported in over 20 countries worldwide. As of May 8, 2020, the Centers for Disease Control and Prevention reported a total of 1122 US cases. C. auris is often multidrug resistant, leaving few options for treatment. Sulfonamides are known to inhibit a bacterial enzyme involved in folate synthesis and may also inhibit yeast organisms by a similar mechanism. The combination of trimethoprim and sulfamethoxazole is more commonly used than either drug alone. The objective of this study was to evaluate the combination of fluconazole and trimethoprim-sulfamethoxazole against C. auris Minimum inhibitory concentrations (MICs) of fluconazole and trimethoprim-sulfamethoxazole were determined by ETEST and broth microdilution for 11 Cauris strains. Fluconazole MICs (µg/mL) were 4->256 by ETEST and 2->256 by broth microdilution (73% resistant); trimethoprim-sulfamethoxazole MICs were >32 by ETEST and 32->128 by broth microdilution (no interpretive guidelines for C. auris). Using our MIC: MIC ETEST method and a checkerboard method, we investigated the interaction of fluconazole and trimethoprim-sulfamethoxazole against all isolates. These interactions were analyzed by calculating the summation fractional inhibitory concentration with synergyof ≤0.5, additivity of >0.5-1.0, indifference of >1-4, and antagonism of >4. The combination of fluconazole and trimethoprim-sulfamethoxazole revealed synergy with three (27%) and additivity with one (9%) isolate. Indifference was found for the remaining seven (64%) isolates. With the checkerboard method, synergy was seen in 1/11 (9%) isolates with fluconazole (½ MIC) plus trimethoprim-sulfamethoxazole (1/64 MIC); additivity, in 7/11 (64%) isolates with fluconazole (1/8 MIC-1×MIC) plus trimethoprim-sulfamethoxazole (1/128 MIC-½ MIC); and indifference in 3/11 (27%) isolates. Regardless, in vitro interactions may or may not correlate with clinical outcomes. Synergy testing with additional drug combinations and isolates should be performed.

Keywords: antibacterial agents; research.