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Manogepix (APX001A) In Vitro Activity against Candida auris: Head-to-Head Comparison of EUCAST and CLSI MICs.
Antimicrobial Agents and Chemotherapy ( IF 4.9 ) Pub Date : 2020-09-21 , DOI: 10.1128/aac.00656-20
Maiken Cavling Arendrup 1, 2, 3 , Anuradha Chowdhary 4 , Karin Meinike Jørgensen 5 , Joseph Meletiadis 6, 7
Affiliation  

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.

中文翻译:

Manogepix(APX001A)对耳假丝酵母的体外活性:EUCAST和CLSI MIC的头对头比较。

Fosmanogepix是新型抗真菌剂中的新型前药。Manogepix是活性部分。我们评估了manogepix的CLSI和EUCAST MICs以及八种比较品对假丝酵母的比较。对于122个进行manogepix的CLSI M27-A3药敏试验C.耳分离株和相比CLSI和manogepix EUCAST的MIC和八个比较。计算每种化合物的差异和一致性。确定了manogepix的野生型上限(WT-UL;野生型分布结束的上限MIC)以及与其他药物的MIC的相关性。Manogepix MIC(CLSI / EUCAST [mg / L])和WT-UL如下:MIC 50 s,0.008 / 0.016; 麦克风90s,0.03 / 0.03;范围0.001至0.25 / 0.001至0.125; WT-UL分别为97.5%和99%,分别为0.03 / 0.125和0.06 / 0.125。manogepix CLSI / EUCAST MIC分布分别跨越9/8稀释液。所有唑类,特别是氟康唑,均具有显着相关性(r = 0.22至0.74,P<0.05)。≤0.004的EUCAST manogepix MIC的分离株比剩余的具有更高manogepix MIC的分离株的fluconazole CLSI / EUCAST MIC低7.6- / 10.2倍。对于manogepix和fluconazole,在CLSI和EUCAST结果之间观察到最高的基本一致性,稀释度的中位数差异为-1至0 2倍,90%绝对差异为1,且90%至92%和98至100%一致性在±之内1和±2稀释。在艾伐康唑和阿尼芬净中,在±1和±2稀释度内的最低一致性(44%至50%和69%至76%)。对CLSI和EUCAST manogepix MIC值之间的相关性C.耳是优异的。发现了不同的MIC,这些与氟康唑的MIC相关,这表明C. auris种群是低度manogepix MIC升高的野生型分离株和非野生型分离株的混合物,可能涉及外排泵表达。然而,manogepix反对最有力的代理人C.耳在此体外研究。
更新日期:2020-09-21
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