Posaconazole MIC distributions for Aspergillus fumigatus SC by four methods: Impact of Cyp51A mutations on estimation of epidemiological cutoff values (ECVs/ECOFFs)

47 48 Estimating epidemiological cutoff endpoints (ECVs/ECOFFS) may be hindered by the 49 overlap of MICs for mutant and non-mutant strains (harboring or not harboring mutations, 50 respectively). Posaconazole MIC distributions for Aspergillus fumigatus SC were collected from 51 26 laboratories (Australia, Canada, Europe, India, South/North America, Taiwan) and published 52 studies. Distributions that fulfilled CLSI criteria were pooled and ECVs were estimated. The 53 sensitivity of three ECV analytical techniques (ECOFFinder, NRI, derivatization) to the inclusion 54 of MICs for mutants was examined for three susceptibility testing methods (CLSI, EUCAST, and 55 Etest®). The totals of posaconazole MICs for non-mutant (no known cyp51A mutations) and 56 mutant A. fumigatus isolates were: by CLSI, 2,223 and 274; by EUCAST, 556 and 52; by the 57 Etest®, 1,365 and 29 respectively; 381 SensititreTM YeastOneTM (SYO) MICs with unknown 58 mutational status were also evaluated. We observed an overlap in posaconazole MICs among 59 non-mutant and cyp51A mutants. At the commonly chosen percentage of the modeled wild-type 60 population (97.5%), almost all ECVs remained the same when the MICs for non-mutant and 61 mutant distributions were merged: ECOFFinder ECVs 0.5 μg/ml (CLSI) and 0.25 μg/ml 62 (EUCAST and Etest®); NRI ECVs: 0.5 μg/ml for all three methods. However, the 95% 63 ECOFFinder CLSI ECV for non-mutants was 0.25 μg/ml. The tentative SYO ECOFFinder ECV 64 was 0.06 μg/ml (data from 3/8 laboratories). Derivatization ECVs with or without mutant 65 inclusion were either 0.25 μg/ml (CLSI, EUCAST, Etest) or 0.06 μg/ml (SYO). It appears that 66 ECV analytical techniques may not be vulnerable to overlap between presumptive wild-type and 67 cyp51A mutants when up to 11.6% of the estimated wild-type population includes mutants. 68 on F ebuary 5, 2018 by U niverssbibliotheek U trcht httpaac.asm .rg/ D ow nladed fom