Micafungin and amphotericin B synergy against Candida auris

Abstract

We read with interest the Correspondence by Brittany O'Brien and colleagues1O'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 (8) Google Scholar 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.2Jeffery-Smith A Taori SK Schelenz S et al.Candida auris: a review of the literature.Clin Microbiol Rev. 2018; 31: e00029-e00037PubMed Google Scholar Current frontline treatment for C auris is monotherapy with an echinocandin, typically micafungin, but micafungin-resistant isolates have emerged.2Jeffery-Smith A Taori SK Schelenz S et al.Candida auris: a review of the literature.Clin Microbiol Rev. 2018; 31: e00029-e00037PubMed Google Scholar We studied ten C auris isolates from the US Food and Drug Administration and US Centers for Disease Control and Prevention Antibiotic Resistance Bank. Using liquid media-based assays, we identified the combination of micafungin and amphotericin B as having strong activity against C auris. The minimum inhibitory concentration of micafungin for each isolate was reduced by addition of amphotericin B, in a range up to 64-fold (figure A; appendix). Furthermore, this enhanced activity of micafungin and amphotericin B in combination was classified as synergistic in eight of ten isolates (figure B). In addition to these assays, we validated that the combination of micafungin and amphotericin B led to killing of all isolates when survival was measured by plating for colony-forming units (figure C). Taken together, these data show the robust activity of micafungin and amphotericin B against C auris. Since micafungin is recommended for empirical treatment of C auris infection, patients generally receive a regimen of micafungin before susceptibility testing results are available.3US Centers for Disease Control and PreventionTreatment and management of infections and colonization: recommendations for treatment of Candida auris infections.https://www.cdc.gov/fungal/candida-auris/c-auris-treatment.htmlDate: May 29, 2020Date accessed: October 29, 2020Google Scholar Therefore, we also tested if initial exposure to micafungin would alter the subsequent efficacy of the micafungin and amphotericin B combination. We tested five isolates that were most resistant to micafungin by first pretreating them with micafungin (figure A). As expected, micafungin alone did not reduce the number of colony-forming units (figure D). After overnight growth in micafungin, the combination of micafungin and amphotericin B was still effective against all micafungin-refractory pretreated isolates (figure D). These results suggest that combination treatment with micafungin and amphotericin B could be effective as a second-line regimen when C auris infection is not cleared by micafungin monotherapy. These data support and extend the findings of O’Brien and colleagues1O'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 (8) Google Scholar and highlight the potential of antifungal combinations to combat C auris. Flucytosine is toxic for some groups of patients, including those with bone marrow defects and pregnant women.4Fujii S Yabe K Kariwano-Kimura Y et al.Developmental toxicity of flucytosine following administration to pregnant rats at a specific time point of organogenesis.Congenit Anom (Kyoto). 2019; 59: 39-42Crossref PubMed Scopus (4) Google Scholar, 5Vermes A Guchelaar H-J Dankert J Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions.J Antimicrob Chemother. 2000; 46: 171-179Crossref PubMed Scopus (525) Google Scholar Our data suggest combination treatment with micafungin and amphotericin B might have clinical use against C auris and have some benefits compared with combinations including flucytosine. We declare no competing interests. We thank Jacob Choby for critical reading of this manuscript. DSW is supported by a Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Disease award. Download .pdf (.16 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

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