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Objectives Rezafungin (CD101) is a new long-acting echinocandin allowing weekly dosing, currently undergoing phase-II clinical trials for invasive candidiasis. The aim of this study was to assess rezafungin's in vitro activity against the most frequent Candida species following the EUCAST methodology. Methods The susceptibility of 2018 clinical Candida isolates was determined at four European laboratories. In parallel, six control strains were repeatedly tested. Wild-type upper limits (WT-ULs), defined as the MIC value where the wild-type distribution ends, were determined following the principles for EUCAST ECOFF-setting. Results The lowest rezafungin MICs (geometric MIC (GM-MIC), MIC range (mg/L)) were observed for C. albicans (0.016, 0.002–0.125) and the highest for C. parapsilosis (1.657, 0.063->4). MICs for the remaining species were in between these values (GM-MICs 0.048–0.055). Visual and statistical WT-ULs were identical for C. glabrata (0.125), C. krusei (0.125), C. parapsilosis (4), and C. tropicalis (0.25). If adopting these WT-ULs for classification into WT and non-WT populations, 1/413 C. glabrata , 1/402 C. krusei , 1/398 C. parapsilosis , and 1/402 C. tropicalis isolates were categorized as non-WT, all of which derived from Laboratory 1. For C. albicans unexplained laboratory variation was observed (WT-UL: 0.063–0.125 in Laboratories 1 and 2 versus 0.016 in Laboratories 3 and 4). A similar systematic difference was observed comparing the MICs for the three C. albicans QC strains, specifically, obtained in Laboratories 1and 2 with those in Laboratories 3 and 4. Discussion Rezafungin displayed species-specific activity similar to other echinocandins. Interlaboratory variation was observed for the most susceptible species C. albicans clinical and QC strains, an observation that warrants further investigation. [ABSTRACT FROM AUTHOR]

Abstract: The CLSI established clinical breakpoints (CBPs) for caspofungin (CSF), micafungin (MCF) and anidulafungin (ANF) versus Candida. The same CBP (susceptible (S): MIC≤2mcg/ml; non-S: MIC>2mcg/ml) was applied to all echinocandins and species. More data now allow reassessment of these CBPs. We examined cases of echinocandin failure where both MICs and fks mutations were assessed; wild type (WT) MICs and epidemiological cutoff values (ECVs) for a large Candida collection; molecular analysis of fks hotspots for Candida with known MICs; and pharmacokinetic and pharmacodynamic (PK/PD) data. We applied these findings to propose new species-specific CBPs for echinocandins and Candida. Of 18 candidiasis cases refractory to echinocandins and with fks mutations, 28% (CSF), 58% (ANF) and 66% (MCF) had MICs in the S category using CBP of ≤2mcg/ml, while 0–8% would be S using CBP of ≤0.25mcg/ml. WT MIC distributions revealed ECV ranges of 0.03–0.25mcg/ml for all major species except C. parapsilosis (1–4mcg/ml) and C. guilliermondii (4–16mcg/ml). Among Candida tested for fks mutations, only 15.7–45.1% of 51 mutants were detected using the CBP for NS of >2mcg/ml. In contrast, a cutoff of >0.25mcg/ml for C. albicans, C. tropicalis, C. krusei, and C. dubliniensis detected 85.6% (MCF) to 95.2% (CSF) of 21 mutant strains. Likewise, a cutoff of >0.12mcg/ml for ANF and CSF and of >0.06mcg/ml for MCF detected 93% (ANF) to 97% (CSF, MCF) of 30 mutant strains of C. glabrata. These data, combined with PK/PD considerations, support CBPs of ≤0.25mcg/ml (S), 0.5mcg/ml (I), ≥1 (R) for CSF/MCF/ANF and C. albicans, C. tropicalis and C. krusei and ≤2mcg/ml (S), 4mcg/ml (I), and ≥8mcg/ml (R) for these agents and C. parapsilosis. The CBPs for ANF and CSF and C. glabrata are ≤0.12mcg/ml (S), 0.25mcg/ml (I), and ≥0.5mcg/ml (R), whereas those for MCF are ≤0.06mcg/ml (S), 0.12mcg/ml (I), and ≥0.25mcg/ml (R). New, species-specific CBPs for Candida and the echinocandins are more sensitive to detect emerging resistance associated with fks mutations, and better able to predict risk for clinical failure. [Copyright &y& Elsevier]

The Subcommittee on Antifungal Susceptibility Testing (AFST) of the ESCMID European Committee for Antimicrobial Susceptibility Testing (EUCAST) has determined breakpoints for isavuconazole and Aspergillus and for itraconazole and Candida spp., released a new document summarizing existing and new minimum inhibitory concentration ranges for quality control strains and revised the method documents for yeast and mould susceptibility testing. This technical note is based on the EUCAST isavuconazole and itraconazole rationale documents, version 1.0 of the routine and extended internal quality control for antifungal susceptibility testing as recommended by EUCAST, and the E.Def 7.3, E.Def 9.2 and E.Def 9.3 method documents ( http://www.eucast.org ). [ABSTRACT FROM AUTHOR]

Objectives Given the increasing number of antifungal drugs and the emergence of resistant Aspergillus isolates, objective, automated and high-throughput antifungal susceptibility testing is important. The EUCAST E.Def 9.3 reference method for MIC determination of Aspergillus species relies on visual reading. Spectrophotometric reading was not adopted because of concern that non-uniform filamentous growth might lead to unreliable and non-reproducible results. We therefore evaluated spectrophotometric reading for the determination of MICs of antifungal azoles against Aspergillus fumigatus . Methods Eighty-eight clinical isolates of A. fumigatus were tested against four medical azoles (posaconazole, voriconazole, itraconazole, isavuconazole) and one agricultural azole (tebuconazole) with EUCAST E.Def 9.3. The visually determined MICs (complete inhibition of growth) were compared with spectrophotometrically determined MICs and essential (±1 twofold dilution) and categorical (susceptible/intermediate/resistant or wild-type/non-wild-type) agreement was calculated. Spectrophotometric data were analysed with regression analysis using the E max model, and the effective concentration corresponding to 5% (EC 5 ) was estimated. Results Using the 5% cut-off, high essential (92%–97%) and categorical (93%–99%) agreement (<6% errors) was found between spectrophotometric and visual MICs. The EC 5 also correlated with the visually determined MICs with an essential agreement of 83%–96% and a categorical agreement of 90%–100% (<5% errors). Conclusions Spectrophotometric determination of MICs of antifungal drugs may increase objectivity, and allow automation and high-throughput of EUCAST E.Def 9.3 antifungal susceptibility testing of Aspergillus species. [ABSTRACT FROM AUTHOR]