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 language | English (US) |
|---|---|
| Pages (from-to) | 439-455 |
| Number of pages | 17 |
| Journal | Infectious Diseases and Therapy |
| Volume | 7 |
| Issue number | 4 |
| DOIs | |
| State | Published - Dec 1 2018 |
Funding
Funding. This project has been funded in part by The Medicines Company and the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority (BARDA), under Contract No. HHSO100201400002C with Rempex Pharmaceuticals, a wholly-owned subsidiary of The Medicines Company and Agreement no. HHSO100201600026C with The Medicines Company. The funder of this study was responsible for study design and data collection. The funder was also responsible for the funding of the journal’s page processing charges. All coauthors were responsible for data interpretation and writing of this report. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis. TANGO II investigators who made this study possible. A full list of TANGO II investigators is provided in the Supplemental Material. We thank Dan White, Elizabeth Morgan, Brian Murphy, and Carrie Messerschmidt for thoughtful contribution to this work. Medical writing and editorial support was provided by Purvi Kobawala Smith of Health and Wellness Partners, Upper Saddle River, NJ through funding by The Medicines Company.
Keywords
- Best available therapy
- Carbapenem-resistant Enterobacteriaceae
- Meropenem–vaborbactam
- Randomized clinical trial
- TANGO II
ASJC Scopus subject areas
- Microbiology (medical)
- Infectious Diseases
