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 Antonio 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 LoutitShu Zhang, Michael N. Dudley, Keith S. Kaye

Research output: Contribution to journalArticle

33 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)439-455
Number of pages17
JournalInfectious Diseases and Therapy
Volume7
Issue number4
DOIs
StatePublished - Dec 1 2018

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Enterobacteriaceae Infections
Carbapenems
Randomized Controlled Trials
Safety
Confidence Intervals
Therapeutics
Mortality
Enterobacteriaceae
Polymyxins
Intraabdominal Infections
Bacterial Pneumonia
Ventilator-Associated Pneumonia
Pyelonephritis
Aminoglycosides
Vulnerable Populations
Bacteremia
Urinary Tract Infections
Population

Keywords

  • Best available therapy
  • Carbapenem-resistant Enterobacteriaceae
  • Meropenem–vaborbactam
  • Randomized clinical trial
  • TANGO II

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases

Cite this

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 Antonio; 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.

In: Infectious Diseases and Therapy, Vol. 7, No. 4, 01.12.2018, p. 439-455.

Research output: Contribution to journalArticle

Wunderink, RG, Giamarellos-Bourboulis, EJ, Rahav, G, Mathers, AJ, Bassetti, M, Vazquez, JA, Cornely, OA, Solomkin, J, Bhowmick, T, Bishara, J, Daikos, GL, Felton, T, Furst, MJL, Kwak, EJ, Menichetti, F, Oren, I, Alexander, EL, Griffith, D, Lomovskaya, O, Loutit, J, Zhang, S, Dudley, MN & Kaye, KS 2018, 'Effect and Safety of Meropenem–Vaborbactam versus Best-Available Therapy in Patients with Carbapenem-Resistant Enterobacteriaceae Infections: The TANGO II Randomized Clinical Trial', Infectious Diseases and Therapy, vol. 7, no. 4, pp. 439-455. https://doi.org/10.1007/s40121-018-0214-1
Wunderink, Richard G. ; Giamarellos-Bourboulis, Evangelos J. ; Rahav, Galia ; Mathers, Amy J. ; Bassetti, Matteo ; Vazquez, Jose Antonio ; 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. In: Infectious Diseases and Therapy. 2018 ; Vol. 7, No. 4. pp. 439-455.
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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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author = "Wunderink, {Richard G.} and Giamarellos-Bourboulis, {Evangelos J.} and Galia Rahav and Mathers, {Amy J.} and Matteo Bassetti and Vazquez, {Jose Antonio} and Cornely, {Oliver A.} and Joseph Solomkin and Tanaya Bhowmick and Jihad Bishara and Daikos, {George L.} and Tim Felton and Furst, {Maria Jose Lopez} and Kwak, {Eun Jeong} and Francesco Menichetti and Ilana Oren and Alexander, {Elizabeth L.} and David Griffith and Olga Lomovskaya and Jeffery Loutit and Shu Zhang and Dudley, {Michael N.} and Kaye, {Keith S.}",
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TY - JOUR

T1 - Effect and Safety of Meropenem–Vaborbactam versus Best-Available Therapy in Patients with Carbapenem-Resistant Enterobacteriaceae Infections

T2 - The TANGO II Randomized Clinical Trial

AU - Wunderink, Richard G.

AU - Giamarellos-Bourboulis, Evangelos J.

AU - Rahav, Galia

AU - Mathers, Amy J.

AU - Bassetti, Matteo

AU - Vazquez, Jose Antonio

AU - Cornely, Oliver A.

AU - Solomkin, Joseph

AU - Bhowmick, Tanaya

AU - Bishara, Jihad

AU - Daikos, George L.

AU - Felton, Tim

AU - Furst, Maria Jose Lopez

AU - Kwak, Eun Jeong

AU - Menichetti, Francesco

AU - Oren, Ilana

AU - Alexander, Elizabeth L.

AU - Griffith, David

AU - Lomovskaya, Olga

AU - Loutit, Jeffery

AU - Zhang, Shu

AU - Dudley, Michael N.

AU - Kaye, Keith S.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

KW - Best available therapy

KW - Carbapenem-resistant Enterobacteriaceae

KW - Meropenem–vaborbactam

KW - Randomized clinical trial

KW - TANGO II

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