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Understanding Echinocandin Resistance in the Emerging Pathogen Candida auris.

Abstract

Candida auris has simultaneously emerged on five continents as a fungal pathogen causing nosocomial outbreaks. The challenges in the treatment of C. auris infections are the variable antifungal susceptibility profiles among clinical isolates and the development of resistance to single or multiple classes of available antifungal drugs. Here, the in vitro susceptibility to echinocandin antifungal drugs was determined and FKS1 sequencing was performed on 106 C. auris clinical isolates. Four isolates were identified to be resistant to all tested echinocandins (MIC ≥ 4 mg/liter) and harbored an S639F mutation in FKS1 hot spot region 1. All remaining isolates were FKS1 wild type (WT) and echinocandin susceptible, with micafungin being the most potent echinocandin (MIC50 = 0.125 mg/liter). Antifungal susceptibility testing with caspofungin was challenging due to the fact that all FKS1 WT isolates exhibited an Eagle effect (also known as the paradoxical growth effect), which occurred at various intensities. To assess whether the Eagle effect resulted in pharmacodynamic resistance, 8 representative isolates were evaluated for their in vivo drug response in a murine model of invasive candidiasis. All isolates were susceptible to caspofungin at a human therapeutic dose, except for those harboring the S639F mutation. The data suggest that only isolates carrying mutations in FKS1 are echinocandin resistant and that routine in vitro testing of C. auris isolates for susceptibility to caspofungin by the broth microdilution method should be viewed cautiously or avoided.

Authors+Show Affiliations

Public Health Research Institute, Rutgers Biomedical and Health Sciences, Newark, New Jersey, USA milena.kordalewska@rutgers.edu perlinds@njms.rutgers.edu.Public Health Research Institute, Rutgers Biomedical and Health Sciences, Newark, New Jersey, USA.Public Health Research Institute, Rutgers Biomedical and Health Sciences, Newark, New Jersey, USA.Medical and Experimental Mycology Group, Corporación para Investigaciones Biológicas (CIB), Medellín, Colombia. Hospital General de Medellin Luz Castro de Gutiérrez ESE, Medellín, Colombia.Department of Medical Mycology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India.Public Health Research Institute, Rutgers Biomedical and Health Sciences, Newark, New Jersey, USA.Public Health Research Institute, Rutgers Biomedical and Health Sciences, Newark, New Jersey, USA milena.kordalewska@rutgers.edu perlinds@njms.rutgers.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29632013

Citation

Kordalewska, Milena, et al. "Understanding Echinocandin Resistance in the Emerging Pathogen Candida Auris." Antimicrobial Agents and Chemotherapy, vol. 62, no. 6, 2018.
Kordalewska M, Lee A, Park S, et al. Understanding Echinocandin Resistance in the Emerging Pathogen Candida auris. Antimicrob Agents Chemother. 2018;62(6).
Kordalewska, M., Lee, A., Park, S., Berrio, I., Chowdhary, A., Zhao, Y., & Perlin, D. S. (2018). Understanding Echinocandin Resistance in the Emerging Pathogen Candida auris. Antimicrobial Agents and Chemotherapy, 62(6), doi:10.1128/AAC.00238-18.
Kordalewska M, et al. Understanding Echinocandin Resistance in the Emerging Pathogen Candida Auris. Antimicrob Agents Chemother. 2018;62(6) PubMed PMID: 29632013.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Understanding Echinocandin Resistance in the Emerging Pathogen Candida auris. AU - Kordalewska,Milena, AU - Lee,Annie, AU - Park,Steven, AU - Berrio,Indira, AU - Chowdhary,Anuradha, AU - Zhao,Yanan, AU - Perlin,David S, Y1 - 2018/05/25/ PY - 2018/02/06/received PY - 2018/03/31/accepted PY - 2018/4/11/pubmed PY - 2019/8/20/medline PY - 2018/4/11/entrez KW - Candida KW - Candida auris KW - anidulafungin KW - antifungal resistance KW - antifungal susceptibility testing KW - caspofungin KW - echinocandins KW - micafungin KW - susceptibility JF - Antimicrobial agents and chemotherapy JO - Antimicrob. Agents Chemother. VL - 62 IS - 6 N2 - Candida auris has simultaneously emerged on five continents as a fungal pathogen causing nosocomial outbreaks. The challenges in the treatment of C. auris infections are the variable antifungal susceptibility profiles among clinical isolates and the development of resistance to single or multiple classes of available antifungal drugs. Here, the in vitro susceptibility to echinocandin antifungal drugs was determined and FKS1 sequencing was performed on 106 C. auris clinical isolates. Four isolates were identified to be resistant to all tested echinocandins (MIC ≥ 4 mg/liter) and harbored an S639F mutation in FKS1 hot spot region 1. All remaining isolates were FKS1 wild type (WT) and echinocandin susceptible, with micafungin being the most potent echinocandin (MIC50 = 0.125 mg/liter). Antifungal susceptibility testing with caspofungin was challenging due to the fact that all FKS1 WT isolates exhibited an Eagle effect (also known as the paradoxical growth effect), which occurred at various intensities. To assess whether the Eagle effect resulted in pharmacodynamic resistance, 8 representative isolates were evaluated for their in vivo drug response in a murine model of invasive candidiasis. All isolates were susceptible to caspofungin at a human therapeutic dose, except for those harboring the S639F mutation. The data suggest that only isolates carrying mutations in FKS1 are echinocandin resistant and that routine in vitro testing of C. auris isolates for susceptibility to caspofungin by the broth microdilution method should be viewed cautiously or avoided. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/29632013/Understanding_Echinocandin_Resistance_in_the_Emerging_Pathogen_Candida_auris_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&pmid=29632013 DB - PRIME DP - Unbound Medicine ER -