目的：
NDM-和MCR-1共同产生的大肠杆菌的出现已经损害了碳青霉烯和粘菌素的使用，这在临床治疗中是至关重要的，并且对全世界的公共健康构成严重威胁。在这里，我们展示了粘菌素与现有抗生素结合的协同作用，作为克服XDR大肠杆菌共同携带NDM和MCR-1基因的潜在策略。

方法：
为了全面评估它们的组合活性，针对携带NDM和MCR-1基因的34种不同的大肠杆菌菌株测试抗生素组合。通过药敏试验，PCR，MLST，S1-PFGE和WGS研究抗生素抗性谱和分子特征。通过体外棋盘实验和剂量反应测定评估抗生素协同功效。小鼠模型用于确认活性组合疗法。另外，测试组合物防止高水平的粘菌素抗性突变体（HLCRM）的能力。

结果：
粘菌素与利福平，利福布汀和米诺环素的组合显示出对34种产生XDR NDM-和MCR-1的大肠杆菌菌株的协同活性，部分恢复对粘菌素和伴侣抗生素的敏感性。在小鼠模型中证实了粘菌素与利福平或米诺环素组合的治疗效果。此外，粘菌素和利福平在预防HLCRM的发生方面显示出显着的活性。

结论：
粘菌素与利福平，利福布汀或米诺环素组合的协同作用提供了针对XDR NDM-和MCR-阳性大肠杆菌的可行的治疗选择。

OBJECTIVES:
The emergence of NDM- and MCR-1-co-producing Escherichia coli has compromised the use of carbapenems and colistin, which are critically important in clinical therapy, and represents a severe threat to public health worldwide. Here, we demonstrate synergism of colistin combined with existing antibiotics as a potential strategy to overcome XDR E. coli co-harbouring NDM and MCR-1 genes.

METHODS:
To comprehensively evaluate their combined activity, antibiotic combinations were tested against 34 different E. coli strains carrying both NDM and MCR-1 genes. Antibiotic resistance profiles and molecular characteristics were investigated by susceptibility testing, PCR, MLST, S1-PFGE and WGS. Antibiotic synergistic efficacy was evaluated through in vitro chequerboard experiments and dose-response assays. A mouse model was used to confirm active combination therapies. Additionally, combinations were tested for their ability to prevent high-level colistin-resistant mutants (HLCRMs).

RESULTS:
Combinations of colistin with rifampicin, rifabutin and minocycline showed synergistic activity against 34 XDR NDM- and MCR-1-co-producing E. coli strains, restoring, in part, susceptibility to both colistin and the partnering antibiotics. The therapeutic effectiveness of colistin combined with rifampicin or minocycline was demonstrated in a mouse model. Furthermore, colistin plus rifampicin showed significant activity in preventing the occurrence of HLCRMs.

CONCLUSIONS:
The synergism of colistin in combinations with rifampicin, rifabutin or minocycline offers viable therapeutic alternatives against XDR NDM- and MCR-positive E. coli.

https://www.ncbi.nlm.nih.gov/pubmed/30346547