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. 2020 Sep 21;64(10):e00656-20.
doi: 10.1128/AAC.00656-20. Print 2020 Sep 21.

Manogepix (APX001A) In Vitro Activity against Candida auris: Head-to-Head Comparison of EUCAST and CLSI MICs

Affiliations

Manogepix (APX001A) In Vitro Activity against Candida auris: Head-to-Head Comparison of EUCAST and CLSI MICs

Maiken Cavling Arendrup et al. Antimicrob Agents Chemother. .

Abstract

Fosmanogepix is a novel prodrug in a new class of antifungal agents. Manogepix is the active moiety. We evaluated the CLSI and EUCAST MICs of manogepix and eight comparators against Candida auris CLSI M27-A3 susceptibility testing of manogepix was performed for 122 C. auris isolates and compared to CLSI and EUCAST MICs for manogepix and eight comparators. Differences and agreement were calculated for each compound. Wild-type upper limits (WT-ULs; the upper MIC where the wild-type distribution ends) for manogepix and correlations with other drugs' MICs were determined. Manogepix MICs (CLSI/EUCAST [mg/liter]) and WT-ULs were as follows: MIC50s, 0.008/0.016; MIC90s, 0.03/0.03; ranges, 0.001 to 0.25/0.001 to 0.125; 97.5% and 99% WT-ULs, 0.03/0.125 and 0.06/0.125, respectively. The manogepix CLSI/EUCAST MIC distributions spanned 9/8 dilutions, respectively. Significant correlation was found for all azoles, particularly fluconazole (r = 0.22 to 0.74, P < 0.05). Isolates with EUCAST manogepix MICs of ≤0.004 had 7.6-/10.2-fold-lower fluconazole CLSI/EUCAST MICs than the remaining isolates that had higher manogepix MICs. The highest essential agreement between CLSI and EUCAST results was observed for manogepix and fluconazole, with a median difference of -1 to 0 2-fold dilutions, 90th percentile absolute difference of 1, and 90 to 92% and 98 to 100% agreement within ±1 and ±2 dilutions. The lowest agreements within ±1 and ±2 dilutions were found for isavuconazole and anidulafungin (44 to 50% and 69 to 76%). The correlation between CLSI and EUCAST manogepix MICs against C. auris was excellent. Differential MICs were found, and these correlated with fluconazole MICs, suggesting that the C. auris population is a mix of wild-type isolates and non-wild-type isolates with low-grade manogepix MIC elevation, probably involving efflux pump expression. However, manogepix was the most potent agent against C. auris in this in vitro study.

Keywords: APX001; APX001A; CLSI; EUCAST; amphotericin B; antifungal susceptibility; candidemia; echinocandins; fluconazole; fosmanogepix; manogepix.

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Figures

FIG 1
FIG 1
Manogepix MICs (mg/liter) against 122 C. auris isolates determined by the CLSI (a) and EUCAST (b) reference methods. The ECOFFs (mg/liter) determined using ECOFFinder XL 2.0, including various proportions of the fitted population, are indicated for both methods in the embedded tables.
FIG 2
FIG 2
Comparison of fluconazole CLSI and EUCAST MICs for isolates with low (≤0.004 mg/liter) and high (0.008 to 0.125 mg/liter) EUCAST MIC profiles. Whiskers show 5th to 95th percentiles.
FIG 3
FIG 3
Correlations between manogepix MICs and MICs of the other drugs with the EUCAST methodology. Correlation coefficients are shown.

References

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