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In vitro interaction of fluconazole and trimethoprim-sulfamethoxazole against Candida auris using ETEST and
Heather R Davis1, Deborah S Ashcraft1, George A Pankey2
1Infectious Disease Translational Research, Ochsner Clinic Foundation, New Orleans, Louisiana, USA.
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.
Insights
This study investigated the combination of fluconazole and trimethoprim-sulfamethoxazole against the multidrug-resistant fungus Candida auris. The combination showed synergy or additivity in some cases, but further research is needed.
Area of Science:
- Medical Mycology
- Infectious Diseases
- Antimicrobial Resistance
Background:
- Candida auris is a multidrug-resistant yeast that emerged globally in 2009, posing a significant public health threat.
- As of May 2020, over 1100 cases were reported in the US, with limited treatment options due to frequent drug resistance.
Purpose of the Study:
- To evaluate the in vitro efficacy of combining fluconazole with trimethoprim-sulfamethoxazole against Candida auris.
- To determine the synergistic, additive, or indifferent interactions between these two antimicrobial agents.
Main Methods:
- Minimum inhibitory concentrations (MICs) for fluconazole and trimethoprim-sulfamethoxazole were determined for 11 Candida auris strains using ETEST and broth microdilution.
- Drug interactions were assessed using the MIC:MIC ETEST and checkerboard methods, analyzing synergy, additivity, indifference, and antagonism.
Main Results:
- Fluconazole exhibited high resistance rates (73%), while trimethoprim-sulfamethoxazole showed no established interpretive guidelines for C. auris.
- The combination demonstrated synergy in 27% of isolates and additivity in 9% using the summation fractional inhibitory concentration method.
- Checkerboard analysis revealed synergy in 9% and additivity in 64% of isolates, with indifference observed in the remaining strains.
Conclusions:
- The combination of fluconazole and trimethoprim-sulfamethoxazole shows potential for synergistic or additive effects against some Candida auris isolates in vitro.
- Clinical outcomes may not directly correlate with in vitro findings, necessitating further investigation.
- Additional studies exploring drug combinations and a broader range of isolates are recommended.
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