Colistin Combined With Tigecycline: A Promising Alternative Strategy to Combat Escherichia coli Harboring blaNDM–5 and mcr-1

• Published in: Frontiers in microbiology 2020-01, Vol.10
• Main Authors: Zhou, Yu-Feng, Liu, Ping, Zhang, Chuan-Jian, Liao, Xiao-Ping, Sun, Jian, Liu, Ya-Hong
• Format: Article
• Language: English
• Subjects: carbapenem-resistance; carbapenem-resistant Enterobacteriaceae; colistin-resistance; combination therapy; MCR-1; Microbiology; New Delhi metallo-β-lactamases-5
• ISSN: 1664-302X; 1664-302X
• DOI: 10.3389/fmicb.2019.02957

Infections due to carbapenem-resistant NDM-producing Escherichia coli represent a major therapeutic challenge, especially in situations of pre-existing colistin resistance. The aim of this study was to investigate combinatorial pharmacodynamics of colistin and tigecycline against E. coli harboring bla NDM– 5 and mcr-1 , with possible mechanisms explored as well. Colistin disrupted the bacterial outer-membrane and facilitated tigecycline uptake largely independent of mcr-1 expression, which allowed a potentiation of the tigecycline-colistin combination. A concentration-dependent decrease in colistin MIC and EC 50 was observed with increasing tigecycline levels. Clinically relevant concentrations of colistin and tigecycline combination significantly decreased bacterial density of colistin-resistant E. coli by 3.9 to 6.1-log 10 cfu/mL over 48 h at both inoculums of 10 6 and 10 8 cfu/mL, and were more active than each drug alone ( P < 0.01). Importantly, colistin and tigecycline combination therapy was efficacious in the murine thigh infection model at clinically relevant doses, resulting in >2.0-log 10 cfu/thigh reduction in bacterial density compared to each monotherapy. These data suggest that the use of colistin and tigecycline combination can provide a therapeutic alternative for infection caused by multidrug-resistant E. coli that harbored both bla NDM– 5 and mcr-1 .