Ashutosh Singh1, Pradeep K Singh1, Theun de Groot2, Anil Kumar3, Purva Mathur4, Bansidhar Tarai5, Neelam Sachdeva6, Gargi Upadhyaya1, Smita Sarma7, Jacques F Meis2,8, Anuradha Chowdhary1. 1. Department of Medical Mycology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India. 2. Department of Medical Microbiology and Infectious Diseases, Canisius-Wilhelmina Hospital (CWZ), Nijmegen, The Netherlands. 3. Department of Microbiology, Amrita Institute of Medical Sciences and Research Center, Vishwa Vidyapeetham, Ponekkara, Cochin, India. 4. Department of Laboratory Medicine, Jai Prakash Narayan Apex Trauma Centre, All India Institute of Medical Sciences, New Delhi, India. 5. Department of Microbiology, Max Hospital, New Delhi, India. 6. Department of Microbiology, Rajiv Gandhi Cancer Institute & Research Center, Delhi, India. 7. Department of Microbiology, Medanta-The Medcity, Gurgaon, Haryana, India. 8. Centre of Expertise in Mycology Radboudumc/CWZ, Nijmegen, The Netherlands.
Abstract
OBJECTIVES: The emergence of fluconazole resistance in Candida parapsilosis healthcare-associated infections has recently been increasingly reported. Antifungal susceptibility profiles and mechanisms of fluconazole resistance in C. parapsilosis (n = 199) from nine hospitals in India collected over a period of 3 years were studied. Further, clonal transmission of fluconazole-resistant isolates in different hospitals was investigated. METHODS: Antifungal susceptibility testing of five azoles, amphotericin B and 5-flucytosine was performed by the CLSI microbroth dilution method. The azole target ERG11 gene was sequenced, and the significance of a novel ERG11 mutation in C. parapsilosis was determined using a gap-repair cloning approach in Saccharomyces cerevisiae. In addition, microsatellite analysis was performed to determine the clonal lineage of C. parapsilosis-resistant strains circulating among different hospitals. RESULTS: A total of 64 (32%) C. parapsilosis isolates were non-susceptible to fluconazole, which included resistant (n = 55; MIC >4 mg/L) and susceptible dose-dependent (n = 9) isolates. Of these 64 non-susceptible isolates, a novel K143R amino acid substitution was noted in 92%, and the remaining five isolates had the Y132F substitution. Elevated azole MICs (≥16-fold) were detected in S. cerevisiae upon expression of C. parapsilosis ERG11 alleles carrying Y132F or K143R substitutions. Two major clusters of non-susceptible isolates were circulating in seven Indian hospitals. CONCLUSIONS: We report a novel K143R amino acid substitution in ERG11p causing fluconazole resistance in C. parapsilosis. Fluconazole-non-susceptible C. parapsilosis isolates carrying the novel K143R amino acid substitution should be identified in clinical microbiology laboratories to prevent further clonal transmission.
OBJECTIVES: The emergence of fluconazole resistance in Candida parapsilosis healthcare-associated infections has recently been increasingly reported. Antifungal susceptibility profiles and mechanisms of fluconazole resistance in C. parapsilosis (n = 199) from nine hospitals in India collected over a period of 3 years were studied. Further, clonal transmission of fluconazole-resistant isolates in different hospitals was investigated. METHODS: Antifungal susceptibility testing of five azoles, amphotericin B and 5-flucytosine was performed by the CLSI microbroth dilution method. The azole target ERG11 gene was sequenced, and the significance of a novel ERG11 mutation in C. parapsilosis was determined using a gap-repair cloning approach in Saccharomyces cerevisiae. In addition, microsatellite analysis was performed to determine the clonal lineage of C. parapsilosis-resistant strains circulating among different hospitals. RESULTS: A total of 64 (32%) C. parapsilosis isolates were non-susceptible to fluconazole, which included resistant (n = 55; MIC >4 mg/L) and susceptible dose-dependent (n = 9) isolates. Of these 64 non-susceptible isolates, a novel K143R amino acid substitution was noted in 92%, and the remaining five isolates had the Y132F substitution. Elevated azole MICs (≥16-fold) were detected in S. cerevisiae upon expression of C. parapsilosis ERG11 alleles carrying Y132F or K143R substitutions. Two major clusters of non-susceptible isolates were circulating in seven Indian hospitals. CONCLUSIONS: We report a novel K143R amino acid substitution in ERG11p causing fluconazole resistance in C. parapsilosis. Fluconazole-non-susceptible C. parapsilosis isolates carrying the novel K143R amino acid substitution should be identified in clinical microbiology laboratories to prevent further clonal transmission.
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