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

Richard G. Wunderink, Evangelos J. Giamarellos-Bourboulis, Galia Rahav, Amy J. Mathers, Matteo Bassetti, Jose Antonio Vazquez, Oliver A. Cornely, Joseph Solomkin, Tanaya Bhowmick, Jihad Bishara, George L. Daikos, Tim Felton, Maria Jose Lopez Furst, Eun Jeong Kwak, Francesco Menichetti, Ilana Oren, Elizabeth L. Alexander, David Griffith, Olga Lomovskaya, Jeffery LoutitShu Zhang, Michael N. Dudley, Keith S. Kaye

Research output: Contribution to journalArticle

78 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)439-455
Number of pages17
JournalInfectious Diseases and Therapy
Volume7
Issue number4
DOIs
StatePublished - Dec 1 2018

Keywords

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

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases

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    Wunderink, R. G., Giamarellos-Bourboulis, E. J., Rahav, G., Mathers, A. J., Bassetti, M., Vazquez, J. A., Cornely, O. A., Solomkin, J., Bhowmick, T., Bishara, J., Daikos, G. L., Felton, T., Furst, M. J. L., Kwak, E. J., Menichetti, F., Oren, I., Alexander, E. L., Griffith, D., Lomovskaya, O., ... Kaye, K. S. (2018). Effect and Safety of Meropenem–Vaborbactam versus Best-Available Therapy in Patients with Carbapenem-Resistant Enterobacteriaceae Infections: The TANGO II Randomized Clinical Trial. Infectious Diseases and Therapy, 7(4), 439-455. https://doi.org/10.1007/s40121-018-0214-1