Pan-resistant Candida auris: New York subcluster susceptible to antifungal combinations

Abstract

Recently we reported the emergence of pan-resistance in Candida auris from New York.1Ostrowsky B Greenko J Adams E et al.Candida auris isolates resistant to three classes of antifungal medications - New York, 2019.MMWR Morb Mortal Wkly Rep. 2020; 69: 6-9Crossref PubMed Scopus (10) Google Scholar Since 2016, New York hospitals and health-care facilities have faced the highest number of clinical cases and surveillance cases of C auris in the USA.2Zhu Y O'Brien B Leach L et al.Laboratory analysis of an outbreak of Candida auris in New York from 2016 to 2018: impact and lessons learned.J Clin Microbiol. 2020; 58: e01503-e01519Crossref PubMed Scopus (32) Google Scholar Effective strategies for the prevention, control, and treatment of C auris are still being developed; however, the development of strategies could be complicated by the observed pan-resistance. A conceptual framework supports using drug combinations to combat the threat of antimicrobial resistance.3Tyers M Wright GD Drug combinations: a strategy to extend the life of antibiotics in the 21st century.Nat Rev Microbiol. 2019; 17: 141-155Crossref PubMed Scopus (224) Google Scholar Accordingly, we studied strains of pan-resistant C auris to find out whether they are susceptible to combinations of current antifungal drugs and what genetic features distinguish pan-resistant C auris found in New York. Details of the methods are in the appendix (pp 2–5). Four pan-resistant C auris strains were 100% inhibited in vitro by combinations of two antifungal drugs using fixed concentrations achievable in vivo. Expectedly, flucytosine combinations with either amphotericin B, azoles, or echinocandins were the most effective (figure, A; appendix pp 8, 12). Time-kill analysis showed that every two-drug combination caused a reduction in growth greater than 2 log10 relative to the same drugs used separately, which is suggestive of fungicidal action (figure, B; appendix pp 9, 13). These results are consistent with our recent publication on the efficacy of antifungal combinations for New York C auris strains with various multidrug-resistance patterns (appendix p 25). On the basis of a comparative genomic analysis we found four pan-resistant C auris strains with mutations in 11 gene targets associated with major antifungal drugs (appendix pp 18–24). These findings are similar to other reports4Rhodes J Abdolrasouli A Farrer RA et al.Genomic epidemiology of the UK outbreak of the emerging human fungal pathogen Candida auris.Emerg Microbes Infect. 2018; 7: 43Crossref PubMed Scopus (116) Google Scholar, 5Chow NA Muñoz JF Gade L et al.Tracing the evolutionary history and global expansion of Candida auris using population genomic analyses.MBio. 2020; 11: e03364-e03419Crossref PubMed Scopus (57) Google Scholar for drug-resistant C auris strains. All four pan-resistant strains constituted a distinct subcluster among New York strains (figure, C; appendix pp 16, 17). Two different non-synonymous mutations in the predicted sequence of the FKS1 protein were observed. C auris strains 19–4 and 19–61 showed FKS1 Ser635Pro, whereas C auris strains 19–42 and 19–43 showed FKS1 Ser635Tyr (appendix p 19). These mutations are in a known hotspot of FKS1, a glucan synthase gene, and the target of echinocandin antifungal drugs. Finally, pan-resistance appears to exact a fitness cost in at least two C auris strains (19–42 and 19–43), which showed an extended lag growth phase (appendix p 14) and high resistance to caspofungin (>16 mg/L). Further results are presented in the appendix (pp 2–25). Our findings suggest that pan-resistant C auris strains remain susceptible to antifungal combinations, which might help to expand the therapeutic options. Genetic analysis suggests that ongoing mutations occurring in response to antifungal drug pressure are the probable drivers of emerging pan-resistance seen in the New York C auris strains. We declare no competing interests. Download .pdf (3.83 MB) Help with pdf files Supplementary appendix Tracking the origin and evolution of multidrug resistance in Candida aurisFor some years now, New York hospitals have been confronted with the highest numbers of Candida auris infections in the USA. As might be expected, this has been accompanied by the emergence of pan-resistant strains in several patients after antifungal medications.1 In a striking new report published in The Lancet Microbe, Vishnu Chaturvedi's group not only provides insight into the genetic evolution of pan-resistance in C auris but also suggests that some new antifungal combinations could be envisaged to circumvent this phenomenon. Full-Text PDF Open AccessMicafungin and amphotericin B synergy against Candida aurisWe read with interest the Correspondence by Brittany O'Brien and colleagues1 on antifungal combinations including flucytosine that kill highly resistant Candida auris isolates. C auris is an emerging fungal pathogen that is frequently resistant to multiple classes of antifungals and is difficult to eradicate from hospitals because it can survive for extended periods on contaminated surfaces.2 Current frontline treatment for C auris is monotherapy with an echinocandin, typically micafungin, but micafungin-resistant isolates have emerged. Full-Text PDF Open Access

Topics & Concepts