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

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 tr...

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Autores principales: Wunderink, Richard G., Giamarellos-Bourboulis, Evangelos J., Rahav, Galia, Mathers, Amy J., Bassetti, Matteo, Vazquez, Jose, Cornely, Oliver A., Solomkin, Joseph, Bhowmick, Tanaya, Bishara, Jihad, Daikos, George L., Felton, Tim, Furst, Maria Jose Lopez, Kwak, Eun Jeong, Menichetti, Francesco, Oren, Ilana, Alexander, Elizabeth L., Griffith, David, Lomovskaya, Olga, Loutit, Jeffery, Zhang, Shu, Dudley, Michael N., Kaye, Keith S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Healthcare 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249182/
https://www.ncbi.nlm.nih.gov/pubmed/30270406
http://dx.doi.org/10.1007/s40121-018-0214-1
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author Wunderink, Richard G.
Giamarellos-Bourboulis, Evangelos J.
Rahav, Galia
Mathers, Amy J.
Bassetti, Matteo
Vazquez, Jose
Cornely, Oliver A.
Solomkin, Joseph
Bhowmick, Tanaya
Bishara, Jihad
Daikos, George L.
Felton, Tim
Furst, Maria Jose Lopez
Kwak, Eun Jeong
Menichetti, Francesco
Oren, Ilana
Alexander, Elizabeth L.
Griffith, David
Lomovskaya, Olga
Loutit, Jeffery
Zhang, Shu
Dudley, Michael N.
Kaye, Keith S.
author_facet Wunderink, Richard G.
Giamarellos-Bourboulis, Evangelos J.
Rahav, Galia
Mathers, Amy J.
Bassetti, Matteo
Vazquez, Jose
Cornely, Oliver A.
Solomkin, Joseph
Bhowmick, Tanaya
Bishara, Jihad
Daikos, George L.
Felton, Tim
Furst, Maria Jose Lopez
Kwak, Eun Jeong
Menichetti, Francesco
Oren, Ilana
Alexander, Elizabeth L.
Griffith, David
Lomovskaya, Olga
Loutit, Jeffery
Zhang, Shu
Dudley, Michael N.
Kaye, Keith S.
author_sort Wunderink, Richard G.
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40121-018-0214-1) contains supplementary material, which is available to authorized users.
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spelling pubmed-62491822018-12-06 Effect and Safety of Meropenem–Vaborbactam versus Best-Available Therapy in Patients with Carbapenem-Resistant Enterobacteriaceae Infections: The TANGO II Randomized Clinical Trial Wunderink, Richard G. Giamarellos-Bourboulis, Evangelos J. Rahav, Galia Mathers, Amy J. Bassetti, Matteo Vazquez, Jose Cornely, Oliver A. Solomkin, Joseph Bhowmick, Tanaya Bishara, Jihad Daikos, George L. Felton, Tim Furst, Maria Jose Lopez Kwak, Eun Jeong Menichetti, Francesco Oren, Ilana Alexander, Elizabeth L. Griffith, David Lomovskaya, Olga Loutit, Jeffery Zhang, Shu Dudley, Michael N. Kaye, Keith S. Infect Dis Ther Original Research 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40121-018-0214-1) contains supplementary material, which is available to authorized users. Springer Healthcare 2018-10-01 2018-12 /pmc/articles/PMC6249182/ /pubmed/30270406 http://dx.doi.org/10.1007/s40121-018-0214-1 Text en © The Author(s) 2018 https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Research
Wunderink, Richard G.
Giamarellos-Bourboulis, Evangelos J.
Rahav, Galia
Mathers, Amy J.
Bassetti, Matteo
Vazquez, Jose
Cornely, Oliver A.
Solomkin, Joseph
Bhowmick, Tanaya
Bishara, Jihad
Daikos, George L.
Felton, Tim
Furst, Maria Jose Lopez
Kwak, Eun Jeong
Menichetti, Francesco
Oren, Ilana
Alexander, Elizabeth L.
Griffith, David
Lomovskaya, Olga
Loutit, Jeffery
Zhang, Shu
Dudley, Michael N.
Kaye, Keith S.
Effect and Safety of Meropenem–Vaborbactam versus Best-Available Therapy in Patients with Carbapenem-Resistant Enterobacteriaceae Infections: The TANGO II Randomized Clinical Trial
title Effect and Safety of Meropenem–Vaborbactam versus Best-Available Therapy in Patients with Carbapenem-Resistant Enterobacteriaceae Infections: The TANGO II Randomized Clinical Trial
title_full Effect and Safety of Meropenem–Vaborbactam versus Best-Available Therapy in Patients with Carbapenem-Resistant Enterobacteriaceae Infections: The TANGO II Randomized Clinical Trial
title_fullStr Effect and Safety of Meropenem–Vaborbactam versus Best-Available Therapy in Patients with Carbapenem-Resistant Enterobacteriaceae Infections: The TANGO II Randomized Clinical Trial
title_full_unstemmed Effect and Safety of Meropenem–Vaborbactam versus Best-Available Therapy in Patients with Carbapenem-Resistant Enterobacteriaceae Infections: The TANGO II Randomized Clinical Trial
title_short Effect and Safety of Meropenem–Vaborbactam versus Best-Available Therapy in Patients with Carbapenem-Resistant Enterobacteriaceae Infections: The TANGO II Randomized Clinical Trial
title_sort effect and safety of meropenem–vaborbactam versus best-available therapy in patients with carbapenem-resistant enterobacteriaceae infections: the tango ii randomized clinical trial
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249182/
https://www.ncbi.nlm.nih.gov/pubmed/30270406
http://dx.doi.org/10.1007/s40121-018-0214-1
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