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

Abstract

IntroductionTreatment 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.MethodsA 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.ResultsWithin 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).ConclusionsMonotherapy with meropenem–vaborbactam for CRE infection was associated with increased clinical cure, decreased mortality, and reduced nephrotoxicity compared with BAT.Clinical Trials RegistrationNCT02168946.FundingThe Medicines Company.Electronic supplementary materialThe online version of this article (10.1007/s40121-018-0214-1) contains supplementary material, which is available to authorized users.

Efficacy and Safety of Meropenem–Vaborbactam Versus Best Available Therapy for the Treatment of Carbapenem-Resistant Enterobacteriaceae Infections in Patients Without Prior Antimicrobial Failure: A Post Hoc Analysis

“…This was a post hoc analysis of a phase 3, multicenter, multinational, randomized, open-label, active-controlled study comparing MV monotherapy to BAT for the treatment of serious infections suspected or known to be caused by CRE in patients aged 18 years or older, from November 2014 to June 2017 (NCT02168946) [12]. Serious CRE infections included cUTI and acute pyelonephritis (AP), hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP), bacteremia, or cIAI [12].…”

“…Serious CRE infections included cUTI and acute pyelonephritis (AP), hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP), bacteremia, or cIAI [12]. …”

“…Furthermore, MV has also been recently approved by the European Medicines Agency (EMA) for cUTI and pyelonephritis, complicated intra-abdominal infections (cIAI), hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and infections due to aerobic Gram-negative organisms in adult patients with limited treatment options. Results of the TANGO-II RCT, in which MV monotherapy was compared with best available therapy (BAT) for the treatment of adults with serious infections due to CRE, have also been recently published [12]. In TANGO-II, MV was associated with increased clinical cure and decreased mortality in comparison with BAT, and less nephrotoxicity [12].…”

“…Results of the TANGO-II RCT, in which MV monotherapy was compared with best available therapy (BAT) for the treatment of adults with serious infections due to CRE, have also been recently published [12]. In TANGO-II, MV was associated with increased clinical cure and decreased mortality in comparison with BAT, and less nephrotoxicity [12]. However, patients with prior antimicrobial failure (PAF), who are expected to have a lower response also to salvage therapy, were enrolled only in the MV arm [12].…”

“…In TANGO-II, MV was associated with increased clinical cure and decreased mortality in comparison with BAT, and less nephrotoxicity [12]. However, patients with prior antimicrobial failure (PAF), who are expected to have a lower response also to salvage therapy, were enrolled only in the MV arm [12]. Therefore, the advantage of MV over BAT could be expected to be even higher than observed in the TANGO-II RCT when both MV and BAT are employed as first-line therapies.…”