AUTHOR=Zhou Chaoe , Wang Qi , Jin Longyang , Wang Ruobing , Yin Yuyao , Sun Shijun , Zhang Jiangang , Wang Hui 

TITLE=In vitro Synergistic Activity of Antimicrobial Combinations Against blaKPC and blaNDM-Producing Enterobacterales With blaIMP or mcr Genes

JOURNAL=Frontiers in Microbiology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2020.533209

DOI=10.3389/fmicb.2020.533209

ISSN=1664-302X

ABSTRACT=<p>Carbapenemase-producing <italic>Enterobacterales</italic> have become a severe public health concern because of their rapidly transmissible resistance elements and limited treatment options. The most effective antimicrobial combinations against carbapenemase-producing <italic>Enterobacterales</italic> are currently unclear. Here, we aimed to assess the therapeutic effects of seven antimicrobial combinations (colistin-meropenem, colistin-tigecycline, colistin-rifampicin, colistin-erythromycin, meropenem-tigecycline, meropenem-rifampicin, and meropenem-tigecycline-colistin) against twenty-four carbapenem-producing <italic>Enterobacterales</italic> (producing <italic>bla</italic><sub>KPC</sub>, <italic>bla</italic><sub>NDM</sub>, coexisting <italic>bla</italic><sub>NDM</sub> and <italic>bla</italic><sub>IMP</sub>, and coexisting <italic>mcr-</italic>1/8/9 and <italic>bla</italic><sub>NDM</sub> genes) and one carbapenem-susceptible <italic>Enterobacterales</italic> using the checkerboard assay, time-kill curves, and scanning electron microscopy. None of the combinations were antagonistic. The combination of colistin-rifampicin showed the highest synergistic effect of 76% (19/25), followed by colistin-erythromycin at 60% (15/25), meropenem-rifampicin at 24% (6/25), colistin-meropenem at 20% (5/25), colistin-tigecycline at 20% (5/25), and meropenem-tigecycline at 4% (1/25). The triple antimicrobial combinations of meropenem-tigecycline-colistin had a synergistic effect of 100%. Most double antimicrobial combinations were ineffective on isolates with coexisting <italic>bla</italic><sub>NDM</sub> and <italic>bla</italic><sub>IMP</sub> genes. Meropenem with tigecycline showed no synergistic effect on isolates that produced different carbapenemase genes and were highly resistant to meropenem (92% meropenem MIC ≥ 16 mg/mL). Colistin-tigecycline showed no synergistic effect on <italic>Escherichia coli</italic> producing <italic>bla</italic><sub>NDM</sub><sub>–</sub><sub>1</sub> and <italic>Serratia marcescens</italic>. Time-kill curves showed that antimicrobial combinations achieved an eradication effect (≥ 3 log<sub>10</sub> decreases in colony counts) within 24 h without regrowth, based on 1 × MIC of each drug. The synergistic mechanism of colistin-rifampicin may involve the colistin-mediated disruption of bacterial membranes, leading to severe alterations in their permeability, then causes more rifampicin to enter the cell and induces cell death. In conclusion, the antimicrobial combinations evaluated in this study may facilitate the successful treatment of patients infected with carbapenemase-producing pathogens.</p>