Tracking the origin and evolution of multidrug resistance in Candida auris
Authors: Nicolas Papon, Dominique Sanglard
Journal: The Lancet Microbe (2020)

For 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.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 (0) Google Scholar 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.2O'Brien B Liang J Chaturvedi S Jacobs JL Chaturvedi V Pan-resistant Candida auris: New York subcluster susceptible to antifungal combinations.Lancet Microbe. 2020; 1: e193-e194Summary Full Text Full Text PDF Scopus (5) Google Scholar To unravel the genetic determinant(s) of resistance towards the available antifungals (triazoles, polyenes, and echinocandins), a comparative genomic approach was taken. First, pan-resistant isolates emerged as a subclade of C auris clade I. Strains from this prevalent clade in the USA are known to be mostly resistant to azoles and polyenes but are usually still susceptible to echinocandins.3Chow 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-e03369Crossref PubMed Scopus (62) Google Scholar Interrestingly, Chaturvedi's group found a point mutation located within a hotspot in the gene encoding the main targets of echinocandins4Kordalewska M Lee A Park S et al.Understanding echinocandin resistance in the emerging pathogen Candida auris.Antimicrob Agents Chemother. 2018; 62: e00238-e00248Crossref PubMed Scopus (102) Google Scholar and, importantly, data also revealed an amino acid substitution in the target of azoles5Healey KR Kordalewska M Jiménez Ortigosa C et al.Limited ERG11 mutations identified in isolates of Candida auris directly contribute to reduced azole susceptibility.Antimicrob Agents Chemother. 2018; 62: e01427-e01428Crossref PubMed Scopus (79) Google Scholar (appendix). These mutations thus stand out as genetic determinants associated with echinocandin and azole resistance in the C auris pan-resistant subclade in New York hospitals. Even the molecular basis for amphotericin B resistance in C auris remained obscure; this enlightening article fits the continuing efforts to decipher the origin and evolution of pan-resistance in C auris3Chow 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-e03369Crossref PubMed Scopus (62) Google Scholar, 6Muñoz JF Gade L Chow NA et al.Genomic insights into multidrug-resistance, mating and virulence in Candida auris and related emerging species.Nat Commun. 2018; 95346Crossref PubMed Scopus (138) Google Scholar (appendix). Interrestingly, Chaturvedi and colleagues addressed antifungal combinations on their collected multiresistant C auris strains. The authors showed that flucytosine combined with either a triazole, amphotericin B, or echinocandin were fungicidal on these isolates. Further in vivo studies should be done to address the relevance of this interesting therapeutic option. The use of flucytosine in monotherapy is usually compromised by resistance acquisition via mutations in genes involved in the pyrimidine salvage pathway7Hope WW Tabernero L Denning DW Anderson MJ Molecular mechanisms of primary resistance to flucytosine in Candida albicans.Antimicrob Agents Chemother. 2004; 48: 4377-4386Crossref PubMed Scopus (96) Google Scholar (appendix). It would be thus advisable to test the capacity of C auris pan-resistant strains to develop flucytosine resistance in vitro, to evaluate fitness costs of these additional mutations, and to address the molecular basis for hypothetical flucytosine resistance.8Kannan A Asner SA Trachsel E Kelly S Parker J Sanglard D Comparative genomics for the elucidation of multidrug resistance in Candida lusitaniae.MBio. 2019; 10: e02512-e02519Crossref PubMed Scopus (10) Google Scholar Even if flucytosine side-effects were to complicate the suggested antifungal combinations, it is important to emphasise that flucytosine combined therapy, like that used to treat the cerebral forms of cryptococcosis, could constitute in the near future a salvage therapeutic option to bypass pan-resistance in C auris. We declare no competing interests. Download .pdf (.39 MB) Help with pdf files Supplementary appendix Pan-resistant Candida auris: New York subcluster susceptible to antifungal combinationsRecently we reported the emergence of pan-resistance in Candida auris from New York.1 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.2 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. Full-Text PDF Open Access