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Identification and Elimination of Antifungal Tolerance in Candida auris
Samira Rasouli Koohi1, Shamanth A Shankarnarayan1, Clare Maristela Galon1
1Department of Physics, University of Alberta, Edmonton, AB T6G 2R3, Canada.
Abstract:
Antimicrobial resistance is a global health crisis to which pathogenic fungi make a substantial contribution. The human fungal pathogen C. auris is of particular concern due to its rapid spread across the world and its evolution of multidrug resistance. Fluconazole failure in C. auris has been recently attributed to antifungal "tolerance". Tolerance is a phenomenon whereby a slow-growing subpopulation of tolerant cells, which are genetically identical to susceptible cells, emerges during drug treatment. We use microbroth dilution and disk diffusion assays, together with image analysis, to investigate antifungal tolerance in C. auris to all three classes of antifungal drugs used to treat invasive candidiasis. We find that (1) C. auris is tolerant to several common fungistatic and fungicidal drugs, which in some cases can be detected after 24 h, as well as after 48 h, of antifungal drug exposure; (2) the tolerant phenotype reverts to the susceptible phenotype in C. auris; and (3) combining azole, polyene, and echinocandin antifungal drugs with the adjuvant chloroquine in some cases reduces or eliminates tolerance and resistance in patient-derived C. auris isolates. These results suggest that tolerance contributes to treatment failure in C. auris infections for a broad range of antifungal drugs, and that antifungal adjuvants may improve treatment outcomes for patients infected with antifungal-tolerant or antifungal-resistant fungal pathogens.
Insights
Antifungal tolerance in Candida auris, a multidrug-resistant fungus, contributes to treatment failure. Combining antifungals with chloroquine may overcome this tolerance and resistance.
Area of Science:
- Medical Mycology
- Antimicrobial Resistance
- Infectious Diseases
Background:
- Antimicrobial resistance is a global health crisis, with pathogenic fungi posing a significant threat.
- Candida auris is a concerning multidrug-resistant fungal pathogen with rapid global spread.
- Antifungal tolerance, a phenomenon where a subpopulation of genetically identical cells exhibits reduced susceptibility, contributes to treatment failure.
Purpose of the Study:
- To investigate antifungal tolerance in Candida auris across all three major antifungal drug classes.
- To determine if the tolerant phenotype in C. auris is reversible.
- To evaluate the potential of antifungal adjuvants, like chloroquine, in overcoming tolerance and resistance.
Main Methods:
- Microbroth dilution assays
- Disk diffusion assays
- Image analysis
- Assessment of antifungal tolerance and resistance in C. auris isolates
Main Results:
- Candida auris exhibits tolerance to common fungistatic and fungicidal drugs, detectable at 24 and 48 hours.
- The tolerant phenotype in C. auris was observed to revert to a susceptible state.
- Combination therapy with azoles, polyenes, echinocandins, and chloroquine reduced or eliminated tolerance and resistance in patient-derived isolates.
Conclusions:
- Antifungal tolerance is a key factor in treatment failure for a wide range of antifungal drugs against C. auris infections.
- Antifungal adjuvants, such as chloroquine, show promise in improving treatment outcomes for invasive fungal infections.
- Further research into combination therapies may lead to more effective strategies against tolerant and resistant fungal pathogens.
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