Lancet子刊：耐药新基因mcr-1如何传播的

　　

　在国家自然科学基金项目（项目编号：81101285）等资助下，浙江大学俞云松教授研究团队与其领导的全国临床和微生物协作网，通过对携带mcr-1基因的质粒生物信息学分析，明确了mcr-1基因的传播机制，临床资料显示mcr-1阳性菌株目前没有对感染病人的预后造成影响。研究成果以“Prevalence of mcr-1 in Escherichia coli and Klebsiella pneumoniae recovered from blood stream infections in China: a multicentre longitudinal study”（中国血流感染大肠埃希菌和肺炎克雷伯菌mcr-1基因流行情况：多中心纵向研究）为题于2017年1月27日在国际著名医学科学期刊The Lancet·Infectious Diseases杂志上在线发表。论文链接：。

　　近年来，细菌耐药现象日渐严重，给抗感染治疗带来重大挑战，严重威胁人类健康，已成为重要的公共卫生问题。多黏菌素被认为是治疗多重耐药革兰氏阴性菌感染的最后一道防线，目前我国尚未批准用于临床。早在20世纪80年代多黏菌素已被广泛应用于动物养殖业，我国学者于2015年首先发现质粒介导的多黏菌素耐药新基因mcr-1，mcr-1基因在动物肠道大肠杆菌中携带率非常高，并在动物与人之间传播。

　　为明确mcr-1基因在我国临床感染病人分离菌中的分布、多黏菌素耐药性水平、携带mcr-1质粒的分子流行病学特征及其对感染病人治疗选择和预后的影响，俞云松研究团队开展了大范围、大样本量的临床感染病例研究，从2066株临床重要感染类型——血流感染致病菌大肠埃希菌和肺炎克雷伯菌中筛选多黏菌素耐药株和mcr-1基因阳性菌株。研究共获得21株mcr-1阳性菌株。研究团队利用常规细菌学药敏实验、分子分型、临床数据统计分析等手段，并通过印迹杂交技术和三代测序等技术，对mcr-1基因的分布、基因定位、传播机制以及对临床预后影响进行了系统研究。

　　研究结果显示，从我国临床血流感染病人分离的大肠埃希菌和肺炎克雷伯菌mcr-1基因阳性分离株少、散发。引起的患者中多黏菌素的耐药率为1.3%，其中大肠埃希菌为1.5%，肺炎克雷伯菌为0.7%；而mcr-1基因的检出率为1.0%，其中大肠埃希菌为1.3%，肺炎克雷伯菌为0.2%。大肠埃希菌是mcr-1基因的主要宿主。mcr-1基因往往导致低水平的多黏菌素耐药（最低抑菌浓度主要在4-16mg/L范围），且绝大部分携带mcr-1基因的菌株对许多其他类型的抗菌药物保持敏感。只有5株mcr-1阳性菌株同时携带CTX-M型超广谱β内酰胺酶，有1株mcr-1阳性菌株同时携带碳青霉烯酶基因blaNDM-5，但是与mcr-1基因不在同一个质粒上。

　　The Lancet·Infectious Diseases杂志对本成果专门发表了评论，高度评价了俞云松团队对于血流感染菌株mcr-1基因流行情况研究的意义；并据此认为中国目前所担忧的碳青霉烯和多黏菌素（mcr-1介导）同时耐药的“末日”尚未到来；但随着多黏菌素在中国临床上使用，其耐药菌的流行、危险因素、临床预后影响等需要进一步关注和研究。华盛顿邮报、雅虎新闻等国外主流媒体也竞相报道该研究成果。

原文摘要：

Prevalence of mcr-1 in Escherichia coli and Klebsiella pneumoniae recovered from bloodstream infections in China: a multicentre longitudinal study

Background

Polymyxin antibiotics are used as last-resort therapies to treat infections caused by multidrug-resistant Gram-negative bacteria. The plasmid-mediated colistin resistance determinant MCR-1 has been identified in Enterobacteriaceae in China. We did this study to investigate the prevalence of the mcr-1 gene in clinical isolates from patients with bloodstream infections in China.

Methods

Clinical isolates of Escherichia coli and Klebsiella pneumoniae were collected from patients with bloodstream infections at 28 hospitals in China, then screened for colistin resistance by broth microdilution and for the presence of the mcr-1 gene by PCR amplification. We subjected mcr-1-positive isolates to genotyping, susceptibility testing, and clinical data analysis. We established the genetic location of mcr-1 with Southern blot hybridisation, and we analysed plasmids containing mcr-1 with filter mating, electroporation, and DNA sequencing.

Findings

2066 isolates, consisting of 1495 E coli isolates and 571 K pneumoniae isolates were collected. Of the 1495 E coli isolates, 20 (1%) were mcr-1-positive, whereas we detected only one (<1%) mcr-1-positive isolate among the 571 K pneumoniae isolates. All mcr-1-positive E coli and K pneumoniae isolates were resistant to colistin, with minimum inhibitory concentrations values in the range of 4–32 mg/L, except for one E coli isolate that had a minimum inhibitory concentration less than or equal to 0·06 mg/L. All 21 mcr-1-positive isolates were susceptible to tigecycline and 20 isolates (95%) were susceptible to the carbapenem and β-lactamase inhibitor combination piperacillin and tazobactam. One mcr-1-positive E coli isolate also produced NDM-5, which confers resistance to beta-lactam antibiotics. The 21 mcr-1-positive isolates were clonally diverse and carried mcr-1 on two types of plasmids, a 33 kb IncX4 plasmid and a 61 kb Inc12 plasmid. The 30 day mortality of the patients with bloodstream infections caused by mcr-1-positive isolates was zero.