Abstract
Carbapenemase-producing Enterobacterales 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 Enterobacterales 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 Enterobacterales (producing blaKPC, blaNDM, coexisting blaNDM and blaIMP, and coexisting mcr-1/8/9 and blaNDM genes) and one carbapenem-susceptible Enterobacterales 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 blaNDM and blaIMP 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 Escherichia coli producing blaNDM–1 and Serratia marcescens. Time-kill curves showed that antimicrobial combinations achieved an eradication effect (≥ 3 log10 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.
Highlights
During the last decade, carbapenemase-producing Enterobacterales (CPE) have gradually become the main pathogen responsible for significant hospital-acquired infections
We explored the synergistic effect of seven antimicrobial combinations against 24 CPE and one carbapenem-susceptible Enterobacterales (CSE) in vitro
Genotypic and phenotypic characteristics of carbapenem-resistant Enterobacterales (CRE) and CSE isolates used in this study are displayed in Table 1, including
Summary
Carbapenemase-producing Enterobacterales (CPE) have gradually become the main pathogen responsible for significant hospital-acquired infections. Because of limited therapeutic options, infections caused by these “super bacteria” are associated with high mortality rates (Logan and Weinstein, 2017). In 2017, the World Health Organization’s priority pathogens list indicated that development of novel antibiotics to treat carbapenem-resistant Enterobacterales (CRE) was urgently required (Shrivastava et al, 2018). In the current post-antibiotic era, novel antibiotics for treating CRE infections are unavailable owing to the lengthy process of drug discovery and low success rate, which has become a serious concern over the past decade (Luepke et al, 2017). Drug-resistant pathogens are resistant to the most frequently used antibiotics and second-line drugs, resulting in an increased burden of infectious diseases (WHO Pathogens Priority List Working Group, 2018). Antimicrobial combinations may offer an alternative for treating CRE pathogens that are resistant to most available therapies
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