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      Colistin Update on Its Mechanism of Action and Resistance, Present and Future Challenges

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          Abstract

          Colistin has been extensively used since the middle of the last century in animals, particularly in swine, for the control of enteric infections. Colistin is presently considered the last line of defense against human infections caused by multidrug-resistant Gram-negative organisms such as carbapenemase-producer Enterobacterales, Acinetobacter baumanni, and Pseudomonas aeruginosa. Transferable bacterial resistance like mcr-genes was reported in isolates from both humans and animals. Researchers actively seek strategies to reduce colistin resistance. The definition of guidelines for colistin therapy in veterinary and human medicine is thus crucial. The ban of colistin use in swine as a growth promoter and for prophylactic purposes, and the implementation of sustainable measures in farm animals for the prevention of infections, would help to avoid resistance and should be encouraged. Colistin resistance in the human–animal–environment interface stresses the relevance of the One Health approach to achieve its effective control. Such measures should be addressed in a cooperative way, with efforts from multiple disciplines and with consensus among doctors, veterinary surgeons, and environment professionals. A revision of the mechanism of colistin action, resistance, animal and human use, as well as colistin susceptibility evaluation is debated here.

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          Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study.

          Until now, polymyxin resistance has involved chromosomal mutations but has never been reported via horizontal gene transfer. During a routine surveillance project on antimicrobial resistance in commensal Escherichia coli from food animals in China, a major increase of colistin resistance was observed. When an E coli strain, SHP45, possessing colistin resistance that could be transferred to another strain, was isolated from a pig, we conducted further analysis of possible plasmid-mediated polymyxin resistance. Herein, we report the emergence of the first plasmid-mediated polymyxin resistance mechanism, MCR-1, in Enterobacteriaceae.
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            Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections.

            The emergence of multidrug-resistant gram-negative bacteria and the lack of new antibiotics to combat them have led to the revival of polymyxins, an old class of cationic, cyclic polypeptide antibiotics. Polymyxin B and polymyxin E (colistin) are the 2 polymyxins used in clinical practice. Most of the reintroduction of polymyxins during the last few years is related to colistin. The polymyxins are active against selected gram-negative bacteria, including Acinetobacter species, Pseudomonas aeruginosa, Klebsiella species, and Enterobacter species. These drugs have been used extensively worldwide for decades for local use. However, parenteral use of these drugs was abandoned approximately 20 years ago in most countries, except for treatment of patients with cystic fibrosis, because of reports of common and serious nephrotoxicity and neurotoxicity. Recent studies of patients who received intravenous polymyxins for the treatment of serious P. aeruginosa and Acinetobacter baumannii infections of various types, including pneumonia, bacteremia, and urinary tract infections, have led to the conclusion that these antibiotics have acceptable effectiveness and considerably less toxicity than was reported in old studies.
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              International Consensus Guidelines for the Optimal Use of the Polymyxins

              The polymyxin antibiotics colistin (polymyxin E) and polymyxin B became available in the 1950s and thus did not undergo contemporary drug development procedures. Their clinical use has recently resurged, assuming an important role as salvage therapy for otherwise untreatable gram-negative infections. Since their reintroduction into the clinic, significant confusion remains due to the existence of several different conventions used to describe doses of the polymyxins, differences in their formulations, outdated product information, and uncertainties about susceptibility testing that has led to lack of clarity on how to optimally utilize and dose colistin and polymyxin B. We report consensus therapeutic guidelines for agent selection and dosing of the polymyxin antibiotics for optimal use in adult patients, as endorsed by the American College of Clinical Pharmacy (ACCP), Infectious Diseases Society of America (IDSA), International Society of Anti-Infective Pharmacology (ISAP), Society for Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). The European Society for Clinical Microbiology and Infectious Diseases (ESCMID) endorses this document as a consensus statement. The overall conclusions in the document are endorsed by the European Committee on Antimicrobial Susceptibility Testing (EUCAST). We established a diverse international expert panel to make therapeutic recommendations regarding the pharmacokinetic and pharmacodynamic properties of the drugs and pharmacokinetic targets, polymyxin agent selection, dosing, dosage adjustment and monitoring of colistin and polymyxin B, use of polymyxin-based combination therapy, intrathecal therapy, inhalation therapy, toxicity, and prevention of renal failure. The treatment guidelines provide the first ever consensus recommendations for colistin and polymyxin B therapy that are intended to guide optimal clinical use.
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                Author and article information

                Journal
                Microorganisms
                Microorganisms
                microorganisms
                Microorganisms
                MDPI
                2076-2607
                02 November 2020
                November 2020
                : 8
                : 11
                : 1716
                Affiliations
                [1 ]Division of Microbiology, Department of Pathology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal; agr@ 123456med.up.pt (A.R.); cpinavaz@ 123456med.up.pt (C.P.-V.)
                [2 ]Farmanimal Veterinary Centre, 2500-323 Caldas da Rainha, Portugal
                [3 ]Clinical Microbiology Department, Porto University Hospital Center, 4099-001 Porto, Portugal; daniela.sfsilva@ 123456gmail.com
                [4 ]Abel Salazar Institute of Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal
                [5 ]CINTESIS—Center for Health Technology and Services Research, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
                [6 ]Burn Unit, S. João University Hospital Center, 4200-319 Porto, Portugal
                Author notes
                [* ]Correspondence: franca.andrade@ 123456gmail.com ; Tel.: +351-917283283
                Author information
                https://orcid.org/0000-0002-7933-3910
                Article
                microorganisms-08-01716
                10.3390/microorganisms8111716
                7692639
                33147701
                48d17dce-fbf6-43e2-aa76-0e9780b234b2
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 01 September 2020
                : 30 October 2020
                Categories
                Review

                colistin,polymyxin,antimicrobial resistance,multidrug-resistant gram-negative organisms

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