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Infect Dis Ther. 2018 Dec;7(4):439-455. doi: 10.1007/s40121-018-0214-1. Epub 2018 Oct 1.

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

Author information

1
Division of Pulmonary and Critical Care, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. r-wunderink@northwestern.edu.
2
4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
3
Infectious Disease Unit and Laboratories, Sheba Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
4
Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA.
5
Infectious Diseases Clinic, Department of Medicine, University of Udine and Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy.
6
Division of Infectious Diseases, Medical College of Georgia/Augusta University, Augusta, GA, USA.
7
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
Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
9
Division of Allergy, Immunology, and Infectious Diseases, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
10
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
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
Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
15
Dipartimento di gastroenterologia e malattie infettive, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
16
Infectious Diseases Unit, Rambam Health Care Campus, Haifa, Israel.
17
The Medicines Company, Parsippany, NJ, USA.
18
The Medicines Company, San Diego, CA, USA.
19
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.

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.

KEYWORDS:

Best available therapy; Carbapenem-resistant Enterobacteriaceae; Meropenem–vaborbactam; Randomized clinical trial; TANGO II

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