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


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          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 10cfu/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.

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          Most cited references42

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          Towards Understanding MCR-like Colistin Resistance

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            Plasmid-encoded tet (X) genes that confer high-level tigecycline resistance in Escherichia coli

            Tigecycline is one of the last-resort antibiotics to treat complicated infections caused by both multidrug-resistant (MDR) Gram-negative and Gram-positive bacteria1. Tigecycline resistance has sporadically occurred in recent years, primarily due to chromosome-encoding mechanisms, such as overexpression of efflux pumps and ribosome protection 2,3 . Here we report the emergence of plasmid-mediated mobile tigecycline resistance mechanism Tet(X4) in Escherichia coli isolates from China, which is capable of degrading all tetracyclines, including tigecycline and the FDA newly approved eravacycline. The tet(X4)-harboring IncQ1 plasmid is highly transferable, and can be successfully mobilized and stabilized in recipient clinical and laboratory strains of Enterobacteriaceae bacteria. It is noteworthy that tet(X4)-positive E. coli strains, including isolates co-harboring mcr-1, have been widely detected in pigs, chickens, soil, and dust samples in China. In vivo murine models demonstrated that the presence of Tet(X4) led to tigecycline treatment failure. Consequently, the emergence of plasmid-mediated Tet(X4) challenges the clinical efficacy of the entire family of tetracycline antibiotics. Importantly, our study raises concern that the plasmid-mediated tigecycline resistance may further spread into a variety of ecological niches and into clinical high-risk pathogens. Collective efforts are in urgent need to preserve the potency of these essential antibiotics.
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              Antibiotic treatment of infections due to carbapenem-resistant Enterobacteriaceae: systematic evaluation of the available evidence.

              We sought to evaluate the effectiveness of the antibiotic treatment administered for infections caused by carbapenemase-producing Enterobacteriaceae. The PubMed and Scopus databases were systematically searched. Articles reporting the clinical outcomes of patients infected with carbapenemase-producing Enterobacteriaceae according to the antibiotic treatment administered were eligible. Twenty nonrandomized studies comprising 692 patients who received definitive treatment were included. Almost all studies reported on Klebsiella spp. In 8 studies, the majority of infections were bacteremia, while pneumonia and urinary tract infections were the most common infections in 12 studies. In 10 studies, the majority of patients were critically ill. There are methodological issues, including clinical heterogeneity, that preclude the synthesis of the available evidence using statistical analyses, including meta-analysis. From the descriptive point of view, among patients who received combination treatment, mortality was up to 50% for the tigecycline-gentamicin combination, up to 64% for tigecycline-colistin, and up to 67% for carbapenem-colistin. Among the monotherapy-treated patients, mortality was up to 57% for colistin and up to 80% for tigecycline. Certain regimens were administered to a small number of patients in certain studies. Three studies reporting on 194 critically ill patients with bacteremia showed individually significantly lower mortality in the combination arm than in the monotherapy arm. In the other studies, no significant difference in mortality was recorded between the compared groups. Combination antibiotic treatment may be considered the optimal option for severely ill patients with severe infections. However, well-designed randomized studies of specific patient populations are needed to further clarify this issue.

                Author and article information

                Front Microbiol
                Front Microbiol
                Front. Microbiol.
                Frontiers in Microbiology
                Frontiers Media S.A.
                08 January 2020
                : 10
                [1] 1National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, College of Veterinary Medicine, South China Agricultural University , Guangzhou, China
                [2] 2Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, South China Agricultural University , Guangzhou, China
                [3] 3Jiangsu Co-innovation Center for the Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou University , Yangzhou, China
                Author notes

                Edited by: Gian Maria Rossolini, University of Florence, Italy

                Reviewed by: Jianfeng Wang, Jilin University, China; Song Lin Chua, Hong Kong Polytechnic University, Hong Kong

                *Correspondence: Ya-Hong Liu, lyh@ 123456scau.edu.cn

                This article was submitted to Antimicrobials, Resistance, and Chemotherapy, a section of the journal Frontiers in Microbiology

                Copyright © 2020 Zhou, Liu, Zhang, Liao, Sun and Liu.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 5, Tables: 2, Equations: 0, References: 51, Pages: 11, Words: 0
                Original Research

                Microbiology & Virology
                carbapenem-resistant enterobacteriaceae,carbapenem-resistance,colistin-resistance,combination therapy,mcr-1,new delhi metallo-β-lactamases-5


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