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      Effect and Safety of Meropenem–Vaborbactam versus Best-Available Therapy in Patients with Carbapenem-Resistant Enterobacteriaceae Infections: The TANGO II Randomized Clinical Trial

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          Abstract

          Introduction

          Treatment options for carbapenem-resistant Enterobacteriaceae (CRE) infections are limited and CRE infections remain associated with high clinical failure and mortality rates, particularly in vulnerable patient populations. A Phase 3, multinational, open-label, randomized controlled trial (TANGO II) was conducted from 2014 to 2017 to evaluate the efficacy/safety of meropenem–vaborbactam monotherapy versus best available therapy (BAT) for CRE.

          Methods

          A total of 77 patients with confirmed/suspected CRE infection (bacteremia, hospital-acquired/ventilator-associated bacterial pneumonia, complicated intra-abdominal infection, complicated urinary tract infection/acute pyelonephritis) were randomized, and 47 with confirmed CRE infection formed the primary analysis population (microbiologic-CRE-modified intent-to-treat, mCRE-MITT). Eligible patients were randomized 2:1 to meropenem–vaborbactam (2 g/2 g over 3 h, q8h for 7–14 days) or BAT (mono/combination therapy with polymyxins, carbapenems, aminoglycosides, tigecycline; or ceftazidime-avibactam alone). Efficacy endpoints included clinical cure, Day-28 all-cause mortality, microbiologic cure, and overall success (clinical cure + microbiologic eradication). Safety endpoints included adverse events (AEs) and laboratory findings.

          Results

          Within the mCRE-MITT population, cure rates were 65.6% (21/32) and 33.3% (5/15) [95% confidence interval (CI) of difference, 3.3% to 61.3%; P = 0.03)] at End of Treatment and 59.4% (19/32) and 26.7% (4/15) (95% CI of difference, 4.6% to 60.8%; P = 0.02) at Test of Cure;.Day-28 all-cause mortality was 15.6% (5/32) and 33.3% (5/15) (95% CI of difference, − 44.7% to 9.3%) for meropenem–vaborbactam versus BAT, respectively. Treatment-related AEs and renal-related AEs were 24.0% (12/50) and 4.0% (2/50) for meropenem–vaborbactam versus 44.0% (11/25) and 24.0% (6/25) for BAT. Exploratory risk–benefit analyses of composite clinical failure or nephrotoxicity favored meropenem–vaborbactam versus BAT (31.3% [10/32] versus 80.0% [12/15]; 95% CI of difference, − 74.6% to − 22.9%; P < 0.001).

          Conclusions

          Monotherapy with meropenem–vaborbactam for CRE infection was associated with increased clinical cure, decreased mortality, and reduced nephrotoxicity compared with BAT.

          Clinical Trials Registration

          NCT02168946.

          Funding

          The Medicines Company.

          Electronic supplementary material

          The online version of this article (10.1007/s40121-018-0214-1) contains supplementary material, which is available to authorized users.

          Related collections

          Most cited references 14

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          Extended-spectrum beta-lactamase-producing Enterobacteriaceae: an emerging public-health concern.

          The medical community relies on clinical expertise and published guidelines to assist physicians with choices in empirical therapy for system-based infectious syndromes, such as community-acquired pneumonia and urinary-tract infections (UTIs). From the late 1990s, multidrug-resistant Enterobacteriaceae (mostly Escherichia coli) that produce extended-spectrum beta lactamases (ESBLs), such as the CTX-M enzymes, have emerged within the community setting as an important cause of UTIs. Recent reports have also described ESBL-producing E coli as a cause of bloodstream infections associated with these community-onset UTIs. The carbapenems are widely regarded as the drugs of choice for the treatment of severe infections caused by ESBL-producing Enterobacteriaceae, although comparative clinical trials are scarce. Thus, more rapid diagnostic testing of ESBL-producing bacteria and the possible modification of guidelines for community-onset bacteraemia associated with UTIs are required.
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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.
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              Prospective observational study of the impact of VIM-1 metallo-beta-lactamase on the outcome of patients with Klebsiella pneumoniae bloodstream infections.

              VIM-1-producing Klebsiella pneumoniae (VPKP) is an emerging pathogen. A prospective observational study was conducted to evaluate the importance of VIM production on outcome of patients with K. pneumoniae bloodstream infections (BSIs). Consecutive patients with K. pneumoniae BSIs were identified and followed up until patient discharge or death. A total of 162 patients were included in the analysis; 67 (41.4%) were infected with VPKP, and 95 were infected with non-VPKP. Fourteen of the patients infected with VPKP were carbapenem resistant (Carb(r)) (MIC > 4 mug/ml), whereas none of the non-VPKP exhibited carbapenem resistance. The patients infected with a Carb(r) organism were more likely (odds ratio, 4.08; 95% confidence interval [CI], 1.29 to 12.85; P = 0.02) to receive inappropriate empirical therapy. The all-cause 14-day mortality rates were 15.8% (15 of 95) for patients infected with VIM-negative organisms, 18.9% (10 of 53) for those infected with VIM-positive carbapenem-susceptible organisms, and 42.9% (6 of 14) for those infected with VIM-positive Carb(r) organisms (P = 0.044). In Cox regression analysis, age (hazard ratio [HR], 1.03; 95% CI, 1.01 to 1.06; P = 0.021), rapidly fatal underlying disease (HR, 2.84; 95% CI, 1.26 to 6.39; P = 0.012), and carbapenem resistance (HR, 2.83; 95% CI, 1.08 to 7.41; P = 0.035) were independent predictors of death. After adjustment for inappropriate empirical or definitive therapy, the effect of carbapenem resistance on outcome was reduced to a level of nonsignificance. In patients with K. pneumoniae BSIs, carbapenem resistance, advanced, age, and severity of underlying disease were independent predictors of outcome, whereas VIM production had no effect on mortality. The higher mortality associated with carbapenem resistance was probably mediated by the failure to provide effective therapy.
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                Author and article information

                Contributors
                r-wunderink@northwestern.edu
                734-615-3604 , keithka@med.umich.edu
                Journal
                Infect Dis Ther
                Infect Dis Ther
                Infectious Diseases and Therapy
                Springer Healthcare (Cheshire )
                2193-8229
                2193-6382
                1 October 2018
                1 October 2018
                December 2018
                : 7
                : 4
                : 439-455
                Affiliations
                [1 ]ISNI 0000 0001 2299 3507, GRID grid.16753.36, Division of Pulmonary and Critical Care, Department of Medicine, Feinberg School of Medicine, , Northwestern University, ; Chicago, IL USA
                [2 ]ISNI 0000 0001 2155 0800, GRID grid.5216.0, 4th Department of Internal Medicine, , National and Kapodistrian University of Athens, Medical School, ; Athens, Greece
                [3 ]ISNI 0000 0004 1937 0546, GRID grid.12136.37, Infectious Disease Unit and Laboratories, Sheba Medical Center and Sackler Faculty of Medicine, , Tel Aviv University, ; Tel Aviv, Israel
                [4 ]ISNI 0000 0000 9136 933X, GRID grid.27755.32, Infectious Diseases and International Health, Department of Medicine, , University of Virginia School of Medicine, ; Charlottesville, VA USA
                [5 ]GRID grid.411492.b, Infectious Diseases Clinic, Department of Medicine, , University of Udine and Azienda Sanitaria Universitaria Integrata di Udine, ; Udine, Italy
                [6 ]ISNI 0000 0001 2284 9329, GRID grid.410427.4, Division of Infectious Diseases, , Medical College of Georgia/Augusta University, ; Augusta, GA USA
                [7 ]ISNI 0000 0000 8852 305X, GRID grid.411097.a, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Zentrum für klinische Studien (ZKS Köln), and Department I of Internal Medicine, , University Hospital of Cologne, ; Cologne, Germany
                [8 ]ISNI 0000 0001 2179 9593, GRID grid.24827.3b, Department of Surgery, , University of Cincinnati College of Medicine, ; Cincinnati, OH USA
                [9 ]ISNI 0000 0004 1936 8796, GRID grid.430387.b, Division of Allergy, Immunology, and Infectious Diseases, Department of Medicine, , Rutgers Robert Wood Johnson Medical School, ; New Brunswick, NJ USA
                [10 ]ISNI 0000 0004 1937 0546, GRID grid.12136.37, Infectious Disease Unit, Rabin Medical Center, Beilinson Hospital and Sackler Faculty of Medicine, , Tel Aviv University, ; Tel Aviv, Israel
                [11 ]First Department of Medicine, National and Kapodistrian University of Athens, Laiko Hospital, Athens, Greece
                [12 ]ISNI 0000000121662407, GRID grid.5379.8, University Hospital of South Manchester and Division of Infection, Immunity and Respiratory Medicine, , University of Manchester, ; Manchester, UK
                [13 ]Unidad de Infectología, Sanatorio Municipal Dr. Julio Méndez, Buenos Aires, Argentina
                [14 ]ISNI 0000 0001 0650 7433, GRID grid.412689.0, Division of Infectious Diseases, Department of Medicine, , University of Pittsburgh Medical Center, ; Pittsburgh, PA USA
                [15 ]ISNI 0000 0004 1756 8209, GRID grid.144189.1, Dipartimento di gastroenterologia e malattie infettive, , Azienda Ospedaliero-Universitaria Pisana, ; Pisa, Italy
                [16 ]ISNI 0000 0000 9950 8111, GRID grid.413731.3, Infectious Diseases Unit, , Rambam Health Care Campus, ; Haifa, Israel
                [17 ]GRID grid.476418.8, The Medicines Company, ; Parsippany, NJ USA
                [18 ]GRID grid.476418.8, The Medicines Company, ; San Diego, CA USA
                [19 ]ISNI 0000000086837370, GRID grid.214458.e, Professor of Internal Medicine, Director of Clinical Research, Division of Infectious Diseases, , University of Michigan Medical School, ; 5510A MSRB I, SPC 5680, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-5680 USA
                Article
                214
                10.1007/s40121-018-0214-1
                6249182
                30270406
                © The Author(s) 2018
                Categories
                Original Research
                Custom metadata
                © Springer Healthcare Ltd., part of Springer Nature 2018

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