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

Abstract

Infections due to carbapenem-resistant NDM-producing <i>Escherichia coli</i> 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 <i>E. coli</i> harboring <i>bla</i> _NDM- ₅ and <i>mcr-1</i>, with possible mechanisms explored as well. Colistin disrupted the bacterial outer-membrane and facilitated tigecycline uptake largely independent of <i>mcr-1</i> expression, which allowed a potentiation of the tigecycline-colistin combination. A concentration-dependent decrease in colistin MIC and EC₅₀ was observed with increasing tigecycline levels. Clinically relevant concentrations of colistin and tigecycline combination significantly decreased bacterial density of colistin-resistant <i>E. coli</i> by 3.9 to 6.1-log₁₀ cfu/mL over 48 h at both inoculums of 10⁶ and 10⁸ cfu/mL, and were more active than each drug alone (<i>P</i> < 0.01). Importantly, colistin and tigecycline combination therapy was efficacious in the murine thigh infection model at clinically relevant doses, resulting in >2.0-log₁₀cfu/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 <i>E. coli</i> that harbored both <i>bla</i> _NDM- ₅ and <i>mcr-1</i>.