米替福新作为一种新兴真菌耳念珠菌治疗的替代策略。

Miltefosine as an alternative strategy in the treatment of the emerging fungus Candida auris.

机构信息

Laboratory of Antifungal Chemotherapy, Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.

Special Laboratory of Mycology, Federal University of São Paulo, São Paulo, Brazil.

出版信息

Int J Antimicrob Agents. 2020 Aug;56(2):106049. doi: 10.1016/j.ijantimicag.2020.106049. Epub 2020 Jun 13.

DOI:10.1016/j.ijantimicag.2020.106049

PMID:32544569

Abstract

OBJECTIVES

Candida auris (C. auris) is an emerging fungal species that is able to develop multidrug resistance and outbreaks of invasive infections worldwide with high mortality rates. To increase the treatment options for C. auris infection this study assessed the efficacy of miltefosine (MFS), that has demonstrated a broad-spectrum antifungal action in vitro. This study aimed to: (i) evaluate the in vitro antifungal activity of MFS against C. auris clinical isolates in the planktonic and biofilm lifestyles; and (ii) compare the activity of MFS in its free form and encapsulated in alginate nanoparticles (MFS-AN) in Galleria mellonella larvae infected by C. auris.

METHODS

The antifungal susceptibility test was performed using broth microdilution method and the in vivo treatment in Galleria mellonella larval infection model.

RESULTS

MFS exhibited in vitro inhibitory effects at MICs ranging 1-4 µg/mL and fungicidal activity against planktonic cells of C. auris clinical isolates. MFS antibiofilm activity was observed during biofilm formation (0.25-4 µg/mL) and on pre-formed biofilms (16-32 µg/mL). Moreover, the dispersed cells from C. auris biofilms had a similar susceptibility to those obtained for planktonic cells. Treatment with free MFS or MFS-AN resulted in significant improvements in the survival and morbidity rates of Galleria mellonella larvae infected by C. auris. In addition, reduction of fungal burden (0.5-1 log CFU/g) and granuloma formation were observed when compared with the untreated group.

CONCLUSIONS

The findings suggest that both the free MFS and MFS-AN have potential for the treatment of fungal infections caused by the emerging C. auris.

摘要

目的

耳念珠菌（C. auris）是一种新兴的真菌物种，能够在全球范围内产生多药耐药性并爆发侵袭性感染，死亡率很高。为了增加对耳念珠菌感染的治疗选择，本研究评估了米替福新（MFS）的疗效，该药物在体外具有广谱抗真菌作用。本研究旨在：（i）评估 MFS 对浮游和生物膜生活方式的耳念珠菌临床分离株的体外抗真菌活性；（ii）比较游离形式和包封在海藻酸钠纳米颗粒中的 MFS（MFS-AN）在感染耳念珠菌的金蝇幼虫中的活性。

方法

使用肉汤微量稀释法进行抗真菌药敏试验，并在金蝇幼虫感染模型中进行体内治疗。

结果

MFS 在 MIC 范围为 1-4 µg/mL 时表现出体外抑制作用，并对耳念珠菌临床分离株的浮游细胞具有杀菌活性。在生物膜形成过程中（0.25-4 µg/mL）和形成预生物膜时（16-32 µg/mL）观察到 MFS 抗生物膜活性。此外，从耳念珠菌生物膜中分散的细胞对浮游细胞的敏感性相似。用游离 MFS 或 MFS-AN 治疗可显著提高感染耳念珠菌的金蝇幼虫的存活率和发病率。此外，与未治疗组相比，观察到真菌负荷减少（0.5-1 log CFU/g）和肉芽肿形成减少。