Center for Medical Mycology, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, Ohio, USA.
Amplyx Pharmaceuticals, San Diego, California, USA.
Antimicrob Agents Chemother. 2018 Feb 23;62(3). doi: 10.1128/AAC.02319-17. Print 2018 Mar.
is an emerging multidrug-resistant yeast that has been responsible for invasive infections associated with high morbidity and mortality. strains often demonstrate high fluconazole and amphotericin B MIC values, and some strains are resistant to all three major antifungal classes. We evaluated the susceptibility of 16 clinical strains, isolated from a wide geographical area, to 10 antifungal agents, including APX001A, a novel agent that inhibits the fungal protein Gwt1 (glycosylphosphatidylinositol-anchored wall transfer protein 1). APX001A demonstrated significantly lower MIC and MIC values (0.004 and 0.031 μg/ml, respectively) than all other agents tested. The efficacy of the prodrug APX001 was evaluated in an immunocompromised murine model of disseminated infection. Significant efficacy (80 to 100% survival) was observed in all three APX001 treatment groups versus 50% survival for the anidulafungin treatment group. In addition, APX001 showed a significant log reduction in CFU counts in kidney, lung, and brain tissue (1.03 to 1.83) versus the vehicle control. Anidulafungin also showed a significant log reduction in CFU in the kidneys and lungs (1.5 and 1.62, respectively) but did not impact brain CFU. These data support further clinical evaluation of this new antifungal agent.
是一种新兴的多药耐药酵母，已导致与高发病率和死亡率相关的侵袭性感染。 菌株通常表现出高氟康唑和两性霉素 B MIC 值，并且一些菌株对所有三种主要抗真菌药物都具有耐药性。我们评估了来自广泛地理区域的 16 株临床分离株对 10 种抗真菌药物的敏感性，包括抑制真菌蛋白 Gwt1（糖基磷脂酰肌醇锚定壁转移蛋白 1）的新型药物 APX001A。APX001A 的 MIC 和 MIC 值（分别为 0.004 和 0.031 μg/ml）明显低于所有其他测试药物。在免疫功能低下的播散性 感染的小鼠模型中评估了前药 APX001 的疗效。在所有三个 APX001 治疗组中均观察到 80%至 100%的生存效果，而安尼度芬组的生存率为 50%。此外，APX001 在肾脏、肺和脑组织中的 CFU 计数方面表现出显著的对数减少（1.03 至 1.83），而与载体对照组相比。安尼度芬在肾脏和肺部的 CFU 中也显示出显著的对数减少（分别为 1.5 和 1.62），但不影响大脑 CFU。这些数据支持进一步评估这种新型抗真菌药物的临床应用。
