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

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          Abstract

          Tigecycline is one of the last-resort antibiotics to treat complicated infections caused by both multidrug-resistant (MDR) Gram-negative and Gram-positive bacteria 1. 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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          Most cited references33

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          Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study

          Summary Background Gram-negative Enterobacteriaceae with resistance to carbapenem conferred by New Delhi metallo-β-lactamase 1 (NDM-1) are potentially a major global health problem. We investigated the prevalence of NDM-1, in multidrug-resistant Enterobacteriaceae in India, Pakistan, and the UK. Methods Enterobacteriaceae isolates were studied from two major centres in India—Chennai (south India), Haryana (north India)—and those referred to the UK's national reference laboratory. Antibiotic susceptibilities were assessed, and the presence of the carbapenem resistance gene bla NDM-1 was established by PCR. Isolates were typed by pulsed-field gel electrophoresis of XbaI-restricted genomic DNA. Plasmids were analysed by S1 nuclease digestion and PCR typing. Case data for UK patients were reviewed for evidence of travel and recent admission to hospitals in India or Pakistan. Findings We identified 44 isolates with NDM-1 in Chennai, 26 in Haryana, 37 in the UK, and 73 in other sites in India and Pakistan. NDM-1 was mostly found among Escherichia coli (36) and Klebsiella pneumoniae (111), which were highly resistant to all antibiotics except to tigecycline and colistin. K pneumoniae isolates from Haryana were clonal but NDM-1 producers from the UK and Chennai were clonally diverse. Most isolates carried the NDM-1 gene on plasmids: those from UK and Chennai were readily transferable whereas those from Haryana were not conjugative. Many of the UK NDM-1 positive patients had travelled to India or Pakistan within the past year, or had links with these countries. Interpretation The potential of NDM-1 to be a worldwide public health problem is great, and co-ordinated international surveillance is needed. Funding European Union, Wellcome Trust, and Wyeth.
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            Treatment of Infections Caused by Extended-Spectrum-Beta-Lactamase-, AmpC-, and Carbapenemase-Producing Enterobacteriaceae

            Therapy of invasive infections due to multidrug-resistant Enterobacteriaceae (MDR-E) is challenging, and some of the few active drugs are not available in many countries. For extended-spectrum β-lactamase and AmpC producers, carbapenems are the drugs of choice, but alternatives are needed because the rate of carbapenem resistance is rising. Potential active drugs include classic and newer β-lactam–β-lactamase inhibitor combinations, cephamycins, temocillin, aminoglycosides, tigecycline, fosfomycin, and, rarely, fluoroquinolones or trimethoprim-sulfamethoxazole. These drugs might be considered in some specific situations. AmpC producers are resistant to cephamycins, but cefepime is an option. In the case of carbapenemase-producing Enterobacteriaceae (CPE), only some “second-line” drugs, such as polymyxins, tigecycline, aminoglycosides, and fosfomycin, may be active; double carbapenems can also be considered in specific situations. Combination therapy is associated with better outcomes for high-risk patients, such as those in septic shock or with pneumonia. Ceftazidime-avibactam was recently approved and is active against KPC and OXA-48 producers; the available experience is scarce but promising, although development of resistance is a concern. New drugs active against some CPE isolates are in different stages of development, including meropenem-vaborbactam, imipenem-relebactam, plazomicin, cefiderocol, eravacycline, and aztreonam-avibactam. Overall, therapy of MDR-E infection must be individualized according to the susceptibility profile, type, and severity of infection and the features of the patient.
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              Methods for in vitro evaluating antimicrobial activity: A review

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                Author and article information

                Journal
                101674869
                44774
                Nat Microbiol
                Nat Microbiol
                Nature microbiology
                2058-5276
                23 May 2019
                24 June 2019
                September 2019
                24 December 2019
                : 4
                : 9
                : 1457-1464
                Affiliations
                [1 ]National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou, China.
                [2 ]College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
                [3 ]Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, South China Agricultural University, Guangzhou, China.
                [4 ]Intensive Care Unit, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
                [5 ]Intensive Care Unit, Huizhou Municipal Central Hospital, Huizhou, China.
                [6 ]Department of Clinical Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou, China.
                [7 ]Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
                [8 ]Department of Clinical Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
                [9 ]Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
                [10 ]Hackensack-Meridian Health Center for Discovery and Innovation, Nutley, NJ, USA.
                Author notes

                Author contributions

                JS and CC contributed equally in this study. Y-HL, LC, X-PL, and JS designed the study. CC, C-YC, YZ, XL, Z-HC, X-YM, K-XZ, H-ML, Z-HZ, S-DZ, J-NL, HD, BH, and F-YY collected the data. JS, CC, Y-JF, L-XF, X-LL, R-MZ, and Y-ZT analyzed and interpreted the data. Y-HL, BM, BNK, LC, JS, X-PL, and CC wrote the draft of the manuscript. All authors reviewed, revised, and approved the final report.

                [#]

                These authors contributed equally to this work: Jian Sun, Chong Chen.

                Correspondence and requests for materials should be addressed to Y-HL, LC, and X-PL.
                Article
                NIHMS1530158
                10.1038/s41564-019-0496-4
                6707864
                31235960
                3adfd75e-4c17-4ef5-8477-728af0c8b81f

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