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, 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

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.

Figures

Fig. 1
Fig. 1
Flow of patients in TANGO II. mCRE-MITT microbiologic-carbapenem-resistant Enterobacteriaceae-modified intent-to-treat, MITT modified intent-to-treat, m-MITT microbiologic modified intent-to-treat; M–V meropenem–vaborbactam, VABP ventilator-associated bacterial pneumonia. aBest available therapy included (alone or in combination): a carbapenem, aminoglycoside, polymyxin B, colistin, tigecycline, or (monotherapy only) ceftazidime-avibactam
Fig. 2
Fig. 2
Subgroup analysis. mCRE-MITT microbiologic carbapenem-resistant Enterobacteriaceae modified intent-to-treat, SIRS systemic inflammatory response syndrome

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