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      Colistin versus meropenem in the empirical treatment of ventilator-associated pneumonia (Magic Bullet study): an investigator-driven, open-label, randomized, noninferiority controlled trial

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          Abstract

          Background

          Colistin is recommended in the empirical treatment of ventilator-associated pneumonia (VAP) with a high prevalence of carbapenem-resistant gram-negative bacilli (CR-GNB). However, the efficacy and safety of colistin are not well defined.

          Methods

          A multicenter prospective randomized trial conducted in 32 European centers compared the efficacy and safety of colistin (4.5 million unit loading dose followed by a maintenance dose of 3 million units every 8 h) versus meropenem (2 g every 8 h), both in combination with levofloxacin (500 mg every 12 h) for 7–14 days in patients with late VAP. Between May 2012 and October 2015, 232 patients were randomly assigned to the 2 treatment groups. The primary endpoint was mortality at 28 days after randomization in the microbiologically modified intention-to-treat (mMITT) population. Secondary outcomes included clinical and microbiological cure, renal function at the end of the treatment, and serious adverse events. The study was interrupted after the interim analysis due to excessive nephrotoxicity in the colistin group; therefore, the sample size was not achieved.

          Results

          A total of 157 (67.7%) patients were included in the mMITT population, 36 of whom (22.9%) had VAP caused by CR-GNB. In the mMITT population, no significant difference in mortality between the colistin group (19/82, 23.2%) and the meropenem group (19/75, 25.3%) was observed, with a risk difference of − 2.16 (− 15.59 to 11.26, p = 0.377); the noninferiority of colistin was not demonstrated due to early termination and limited number of patients infected by carbapenem-resistant pathogens. Colistin plus levofloxacin increased the incidence of renal failure (40/120, 33.3%, versus 21/112, 18.8%; p = 0.012) and renal replacement therapy (11/120, 9.1%, versus 2/112, 1.8%; p = 0.015).

          Conclusions

          This study did not demonstrate the noninferiority of colistin compared with meropenem, both combined with levofloxacin, in terms of efficacy in the empirical treatment of late VAP but demonstrated the greater nephrotoxicity of colistin. These findings do not support the empirical use of colistin for the treatment of late VAP due to early termination.

          Trial registration

          ClinicalTrials.gov, NCT01292031. Registered 9 February 2011.

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          Most cited references27

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          Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial

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            Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial

            Nosocomial pneumonia is commonly associated with antimicrobial-resistant Gram-negative pathogens. We aimed to assess the efficacy and safety of ceftazidime-avibactam in patients with nosocomial pneumonia, including ventilator-associated pneumonia, compared with meropenem in a multinational, phase 3, double-blind, non-inferiority trial (REPROVE).
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              Colistin and rifampicin compared with colistin alone for the treatment of serious infections due to extensively drug-resistant Acinetobacter baumannii: a multicenter, randomized clinical trial.

              Extensively drug-resistant (XDR) Acinetobacter baumannii may cause serious infections in critically ill patients. Colistin often remains the only therapeutic option. Addition of rifampicin to colistin may be synergistic in vitro. In this study, we assessed whether the combination of colistin and rifampicin reduced the mortality of XDR A. baumannii infections compared to colistin alone. This multicenter, parallel, randomized, open-label clinical trial enrolled 210 patients with life-threatening infections due to XDR A. baumannii from intensive care units of 5 tertiary care hospitals. Patients were randomly allocated (1:1) to either colistin alone, 2 MU every 8 hours intravenously, or colistin (as above), plus rifampicin 600 mg every 12 hours intravenously. The primary end point was overall 30-day mortality. Secondary end points were infection-related death, microbiologic eradication, and hospitalization length. Death within 30 days from randomization occurred in 90 (43%) subjects, without difference between treatment arms (P = .95). This was confirmed by multivariable analysis (odds ratio, 0.88 [95% confidence interval, .46-1.69], P = .71). A significant increase of microbiologic eradication rate was observed in the colistin plus rifampicin arm (P = .034). No difference was observed for infection-related death and length of hospitalization. In serious XDR A. baumannii infections, 30-day mortality is not reduced by addition of rifampicin to colistin. These results indicate that, at present, rifampicin should not be routinely combined with colistin in clinical practice. The increased rate of A. baumannii eradication with combination treatment could still imply a clinical benefit. NCT01577862.
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                Author and article information

                Contributors
                34 697958658 , jmcisnerosh@gmail.com
                Journal
                Crit Care
                Critical Care
                BioMed Central (London )
                1364-8535
                1466-609X
                28 November 2019
                28 November 2019
                2019
                : 23
                : 383
                Affiliations
                [1 ]ISNI 0000 0001 2168 1229, GRID grid.9224.d, Department of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocio CSIC, , University of Seville, ; Avenida Manuel Siurot s/n, 41013 Seville, Spain
                [2 ]ISNI 0000 0000 9542 1158, GRID grid.411109.c, Clinical Trial Unit, , Hospital Universitario Virgen del Rocío, ; Avenida Manuel Siurot s/n, 41013 Seville, Spain
                [3 ]GRID grid.414603.4, Fondazione Policlinico Universitario A. Gemelli IRCCS, ; Rome, Italy
                [4 ]ISNI 0000 0000 9542 1158, GRID grid.411109.c, Intensive Care Clinical Unit, , Hospital Universitario Virgen del Rocío, ; Avenida Manuel Siurot s/n, 41013 Seville, Spain
                [5 ]ISNI 0000 0001 2155 0800, GRID grid.5216.0, Department of Critical Care, University Hospital ATTIKON, , National and Kapodistrian University of Athens, ; Athens, Greece
                [6 ]ISNI 0000 0001 0360 9602, GRID grid.84393.35, Intensive Medicine Unit, , Hospital Universitario y Politécnico La Fe, ; Avinguda de Fernando Abril Martorell, 106, 46026 Valencia, Spain
                [7 ]GRID grid.411096.b, Intensive Medicine Unit, , Hospital General Universitario de Ciudad Real, ; Calle Obispo Rafael Torija s/n, 13005 Ciudad Real, Spain
                [8 ]Intensive Care Unit, Hospital Universitario de Jerez, Carretera Nacional IV s/n, 11407 Jerez de la Frontera, Cádiz Spain
                [9 ]ISNI 0000 0001 0941 3192, GRID grid.8142.f, Università Cattolica del Sacro Cuore, ; Rome, Italy
                [10 ]ISNI 0000 0004 1768 164X, GRID grid.411375.5, Intensive Care Clinical Unit, , Hospital Universitario Virgen Macarena, ; Calle Dr. Fedriani, 3, 41009 Seville, Spain
                Article
                2627
                10.1186/s13054-019-2627-y
                6883535
                31779711
                b2c0ba3e-ae79-4c5e-b9ae-aa5493841d0c
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 24 July 2019
                : 27 September 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100011272, FP7 Health;
                Award ID: 278232
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2019

                Emergency medicine & Trauma
                colistin,ventilator-associated pneumonia,multidrug-resistant bacteria,carbapenem-resistant gram-negative bacilli

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