Abstract
We report low MIC50 of Ibrexafungerp (SCY-078) for 102 Candida auris clinical and surveillance isolates from outbreak in New York. The group included C. auris with a variable resistance to antifungal drugs. Five pan-resistant C. auris isolates were susceptible to Ibrexafungerp with low MIC50 range of 0.12-1 µg/ml.
Introduction
Since its discovery in 2009, Candida auris has become a major concern as an emerging drug resistant, healthcare-related infection around the globe (1, 2). Beginning in 2013, the New York metropolitan area has suffered from a large, sustained outbreak of C. auris in hospitals and healthcare facilities (3). The latest NY data from 540 C. auris clinical isolates, C. auris isolates recovered from 11,035 patient surveillance specimens, and 3,672 environmental surveillance samples suggests the predominance of the South Asia Clade I with variable multidrug-resistance (4). There is a pressing public health need to test additional antifungal drugs for their efficacy against drug resistant C. auris.
Ibrexafungerp (formerly SCY-078), is an orally bioavailable, semi-synthetic modified compound of enfumafungin, a triterpene glycoside natural product (5, 6). Ibrexafungerp laboratory testing showed broad activity against Candida species including fluconazole-resistant C. albicans, and C. auris (7-9). We report in vitro activity of Ibrexafungerp against 102 C. auris isolates from NY comprising clinical and surveillance cases. The C. auris selection included variable resistance (resistance to one drug in one or two classes of antifungal drug) multidrug-resistant (resistance to two or more drugs between two classes of antifungal drugs) or pan-resistant (resistance to two or more azoles, all echinocandins, and amphotericin B).
Materials and Methods
A recent publication from our laboratory includes details about the processing, identification, and characterization of C. auris from the NY outbreak (4). Broth micro-dilution antifungal susceptibility testing was performed per Clinical and Laboratory Standards Institute reference method M27-A3 as described by Berkow et al. (7). Amphotericin B MIC100 was tested using E-test strips (bioMerieux USA, St. Louis, MO). We used CDC guidelines to assess antifungal resistance patterns in C. auris as breakpoints are not available for this pathogen (https://www.cdc.gov/fungal/candida-auris/c-auris-antifungal.html). We also used EUCAST recommendations as a surrogate breakpoint to determine resistance pattern to various antifungals (http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/AFST/Clinical_breakpoints/Antifungal_breakpoints_v_9.0_180212.pdf).
Results and Discussion
Ibrexafungerp MIC50 readings for 102 C. auris isolates are summarized in Tables 1-3. For 97 C. auris isolates with a variable resistance to antifungal drugs, Ibrexafungerp MIC50 range was 0.06-0.5 µg/ml, median and mode were 0.5 µg/ml, respectively (Table 1-2). All five pan-resistant C. auris isolates were susceptible to Ibrexafungerp with low MIC50 range of 0.12-1 (Table 3). Notably, Ibrexafungerp MIC50 range against our collection is well within the serum achievable concentrations reported from preclinical pharmacokinetics and pharmacodynamic studies, and murine models of disseminated candidiasis (10). Our laboratory findings expand earlier reports on in vitro efficacy of Ibrexafungerp against C. auris resistant to amphotericin B, flucytosine, itraconazole and isavuconazole (7, 9). The near universal fluconazole resistance, and unusually high resistance to azoles, echinocandins, polyene, and nucleoside inhibitors is a noticeable feature of C. auris isolates in the NY outbreak (3, 4). The exact mechanisms behind the observed resistance pattern remain unknown; with the exception of few isolates, all NY C. auris isolates belonged to South Asia clade, which is reported to have high drug-resistance (2). Our findings support enhanced evaluations of Ibrexafungerp including expanded clinical studies to better understand its therapeutic potential for C. auris.
ACKNOWLEDGEMENTS
We thank Brittany O’Brien and Jiali Liang for their contributions to antifungal susceptibility testing at the Mycology Laboratory, Wadsworth Center; Thomas Chen, SCNYNEXIS, Inc., is thanked for the editorial comments. Stephen A. Barat, Katyna Borroto-Esoda, and David Angulo are employed by SCYNEXIS, Inc., the manufacturer of Ibrexafungerp.