Infectious Diseases and Therapy (Oct 2018)

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 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 Loutit,
  • Shu Zhang,
  • Michael N. Dudley,
  • Keith S. Kaye

DOI
https://doi.org/10.1007/s40121-018-0214-1
Journal volume & issue
Vol. 7, no. 4
pp. 439 – 455

Abstract

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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.

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