A multicenter evaluation of MIC distributions for ECV definition to detect amphotericin B, posaconazole and itraconazole resistance among the most clinically relevant species of Mucorales

Clinical breakpoints (CBPs) have not been established for the Mucorales and any antifungal agent. In lieu of CBPs, epidemiologic cutoff values (ECVs) are proposed for amphotericin B, posaconazole and itraconazole and four Mucorales species. Wild type (WT) MIC distributions (organisms in a species/drug combination with no detectable acquired resistance mechanisms) were defined with available pooled CLSI MICs from 14 laboratories (Argentina, Australia, Canada, Europe, India, Mexico, and the United States) as follows: 10 Apophysomyces variabilis, 32 Cunninghamella bertholletiae, 136 Lichtheimia corymbifera, 10 Mucor indicus, 123 M. circinelloides, 19 M. ramosissimus, 349 Rhizopus arrhizus, 146 R. microsporus, 33 Rhizomucor pusillus, and 36 Syncephalastrum racemosum. CLSI broth microdilution MICs were aggregated for the analyses. ECVs comprising ≥95% and ≥97.5% of the modeled populations were as follows: amphotericin B ECVs for L. corymbifera were 1 and 2 μg/ml, for M. circinelloides 1 and 2 μg/ml, for R. arrhizus 2 and 4 μg/ml, and for R. microsporus 2 and 2 μg/ml, respectively; posaconazole ECVs for L. corymbifera were 1 and 2, for M. circinelloides 4 and 4, for R. arrhizus 1 and 2, and for R. microsporus 1 and 2, respectively; both itraconazole ECVs for R. arrhizus were 2 μg/ml. ECVs may aid in detecting emerging resistance or those isolates with reduced susceptibility (non-WT-MICs) to the agents evaluated.