An ongoing Candida auris outbreak in the New York metropolitan area is the largest recorded to date in North America. Laboratory surveillance revealed NY C. auris isolates are resistant to fluconazole, with variable resistance to other currently used broad-spectrum antifungal drugs, and that several isolates are panresistant. Thus, there is an urgent need for new drugs with a novel mechanism of action to combat the resistance challenge. Manogepix (MGX) is a first-in-class agent that targets the fungal Gwt1 enzyme. The prodrug fosmanogepix is currently in phase 2 clinical development for the treatment of fungal infections. We evaluated the susceptibility of 200 New York C. auris isolates to MGX and 10 comparator drugs using CLSI methodology. MGX demonstrated lower MICs than comparators (MIC₅₀ and MIC₉₀, 0.03 mg/liter; range, 0.004 to 0.06 mg/liter). The local epidemiological cutoff value (ECV) for MGX indicated all C. auris isolates were within the population of wild-type (WT) strains; 0.06 mg/liter defines the upper limit of wild type (UL-WT). MGX was 8- to 32-fold more active than the echinocandins, 16- to 64-fold more active than the azoles, and 64-fold more active than amphotericin B. No differences were found in the MGX or comparators’ MIC₅₀, MIC₉₀, or geometric mean (GM) values when subsets of clinical, surveillance, and environmental isolates were evaluated. The range of MGX MIC values for six C. auris panresistant isolates was 0.008 to 0.015 mg/liter, and the median and mode MIC values were 0.015 mg/liter, demonstrating that MGX retains activity against these isolates. These data support further clinical evaluation of fosmanogepix for the treatment of C. auris infections, including highly resistant isolates.

中文翻译：

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评价manogepix对来自纽约疫情的多药耐药和泛耐药性假丝酵母的体外活性。

纽约大都会地区正在进行的念珠菌暴发是迄今为止北美地区最大的记录。实验室监测显示，纽约分离株耳孢菌对氟康唑有抗药性，对其他目前使用的广谱抗真菌药也有不同的抗药性，并且几种分离株具有泛抗性。因此，迫切需要具有新颖的作用机制以对抗耐药性挑战的新药。Manogepix（MGX）是针对真菌Gwt1酶的一流药物。fosmanogepix前药目前处于2期临床研究中，用于治疗真菌感染。我们评估了200个纽约C. auris的敏感性使用CLSI方法分离出MGX和10种比较药物。MGX表现出比比较低的MIC（MIC ₅₀和MIC ₉₀，0.03毫克/升;范围内，0.004〜0.06毫克/升）。MGX的局部流行病学临界值（ECV）表明所有金黄色葡萄球菌的分离物都在野生型（WT）菌株的种群内。0.06 mg / L定义了野生型（UL-WT）的上限。MGX的活性比棘轮and蛋白高8至32倍，活性比唑类高16至64倍，活性比两性霉素B高64倍。在MGX或对照品的MIC ₅₀，MIC中未发现差异₉₀或当评估临床，监测和环境分离株的子集时的几何平均值（GM）值。六MGX MIC值的范围C.耳panresistant分离为0.008〜0.015毫克/升，并且平均和模式MIC值分别为0.015毫克/升，这表明MGX保留针对这些菌株的活性。这些数据支持fosmanogepix的进一步临床评价用于治疗C.耳感染，包括高抗菌株。