International Evaluation of MIC Distributions and Epidemiological Cutoff Value (ECV) Definitions for Fusarium Species Identified by Molecular Methods for the CLSI Broth Microdilution Method.

The CLSI epidemiological cutoff values (ECVs) of antifungal agents are available for various Candida spp., Aspergillus spp., and the Mucorales. However, those categorical endpoints have not been established for Fusarium spp., mostly due to the difficulties associated with collecting sufficient CLSI MICs for clinical isolates identified according to the currently recommended molecular DNA-PCR-based identification methodologies. CLSI MIC distributions were established for 53 Fusarium dimerum species complex (SC), 10 F. fujikuroi, 82 F. proliferatum, 20 F. incarnatum-F. equiseti SC, 226 F. oxysporum SC, 608 F. solani SC, and 151 F. verticillioides isolates originating in 17 laboratories (in Argentina, Australia, Brazil, Canada, Europe, Mexico, and the United States). According to the CLSI guidelines for ECV setting, ECVs encompassing ≥97.5% of pooled statistically modeled MIC distributions were as follows: for amphotericin B, 4 µg/ml (F. verticillioides) and 8 µg/ml (F. oxysporum SC and F. solani SC); for posaconazole, 2 µg/ml (F. verticillioides), 8 µg/ml (F. oxysporum SC), and 32 µg/ml (F. solani SC); for voriconazole, 4 µg/ml (F. verticillioides), 16 µg/ml (F. oxysporum SC), and 32 µg/ml (F. solani SC); and for itraconazole, 32 µg/ml (F. oxysporum SC and F. solani SC). Insufficient data precluded ECV definition for the other species. Although these ECVs could aid in detecting non-wild-type isolates with reduced susceptibility to the agents evaluated, the relationship between molecular mechanisms of resistance (gene mutations) and MICs still needs to be investigated for Fusarium spp.

Multicenter evaluation of MIC distributions for epidemiologic cutoff value 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 isolates. 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, those for M. circinelloides were 1 and 2 µg/ml, those for R. arrhizus were 2 and 4 µg/ml, and those for R. microsporus were 2 and 2 µg/ml, respectively; posaconazole ECVs for L. corymbifera were 1 and 2, those for M. circinelloides were 4 and 4, those for R. arrhizus were 1 and 2, and those for R. microsporus were 1 and 2, respectively; both itraconazole ECVs for R. arrhizus were 2 µg/ml. ECVs may aid in detecting emerging resistance or isolates with reduced susceptibility (non-WT MICs) to the agents evaluated.