Effect of meropenem-vaborbactam vs piperacillin-Tazobactam on clinical cure or improvement and microbial eradication in complicated urinary tract infection the TANGO I randomized clinical trial

Keith S. Kaye, Tanaya Bhowmick, Symeon Metallidis, Susan C. Bleasdale, Olexiy S. Sagan, Viktor Stus, Jose Antonio Vazquez, Valerii Zaitsev, Mohamed Bidair, Erik Chorvat, Petru Octavian Dragoescu, Elena Fedosiuk, Juan P. Horcajada, Claudia Murta, Yaroslav Sarychev, Ventsislav Stoev, Elizabeth Morgan, Karen Fusaro, David Griffith, Olga LomovskayaElizabeth L. Alexander, Jeffery Loutit, Michael N. Dudley, Evangelos J. Giamarellos-Bourboulis

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

IMPORTANCE Meropenem-vaborbactam is a combination carbapenem/beta-lactamase inhibitor and a potential treatment for severe drug-resistant gram-negative infections. OBJECTIVE To evaluate efficacy and adverse events of meropenem-vaborbactam in complicated urinary tract infection (UTI), including acute pyelonephritis. DESIGN, SETTING, AND PARTICIPANTS Phase 3, multicenter, multinational, randomized clinical trial (TANGO I) conducted November 2014 to April 2016 and enrolling patients (18 years) with complicated UTI, stratified by infection type and geographic region. INTERVENTIONS Eligible patients were randomized 1:1 to receive meropenem-vaborbactam (2g/2g over 3 hours; n = 274) or piperacillin-Tazobactam (4g/0.5g over 30 minutes; n = 276) every 8 hours. After 15 or more doses, patients could be switched to oral levofloxacin if they met prespecified criteria for improvement, to complete 10 days of total treatment. MAIN OUTCOMES AND MEASURES Primary end point for FDA criteriawas overall success (clinical cure or improvement and microbial eradication composite) at end of intravenous treatment in the microbiologic modified intent-To-Treat (ITT) population. Primary end point for European Medicines Agency (EMA) criteria was microbial eradication at test-of-cure visit in the microbiologic modified ITT and microbiologic evaluable populations. Prespecified noninferiority margin was 15%. Because the protocol prespecified superiority testing in the event of noninferiority, 2-sided 95%CIs were calculated. RESULTS Among 550 patients randomized, 545 received study drug (mean age, 52.8 years; 361 [66.2%]women; 374 [68.6%] in the microbiologic modified ITT population; 347 [63.7%] in the microbiologic evaluable population; 508 [93.2%] completed the trial). For the FDA primary end point, overall success occurred in 189 of 192 (98.4%) with meropenem-vaborbactam vs 171 of 182 (94.0%) with piperacillin-Tazobactam (difference, 4.5%[95%CI, 0.7%to 9.1%]; P < .001 for noninferiority). For the EMA primary end point, microbial eradication in the microbiologic modified ITT population occurred in 128 of 192 (66.7%) with meropenemvaborbactam vs 105 of 182 (57.7%) with piperacillin-Tazobactam (difference, 9.0%[95%CI, 0.9%to 18.7%]; P < .001 for noninferiority); microbial eradication in the microbiologic evaluable population occurred in 118 of 178 (66.3%) vs 102 of 169 (60.4%) (difference, 5.9%[95%CI, 4.2%to 16.0%]; P < .001 for noninferiority). Adverse eventswere reported in 106 of 272 (39.0%) with meropenem-vaborbactam vs 97 of 273 (35.5%) with piperacillin-Tazobactam. CONCLUSIONSANDRELEVANCE Amongpatient swith complicatedUTI,includingacutepyelonephritis andgrowthof a baseline pathogen,meropenem-vaborbactamvs piperacillin-Tazobactamresulted in a compositeoutcomeofcomplete resolution orimprovementof symptomsalongwith microbial eradication thatmet the noninferiority criterion. Further research is needed to understand the spectrum of patients inwhommeropenem-vaborbactam offers a clinical advantage.

Original languageEnglish (US)
Pages (from-to)788-799
Number of pages12
JournalJAMA - Journal of the American Medical Association
Volume319
Issue number8
DOIs
StatePublished - Feb 27 2018

Fingerprint

meropenem
Urinary Tract Infections
Randomized Controlled Trials
Population
Levofloxacin
Piperacillin
Carbapenems
Pyelonephritis
Infection
Pharmaceutical Preparations
tazobactam drug combination piperacillin
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Effect of meropenem-vaborbactam vs piperacillin-Tazobactam on clinical cure or improvement and microbial eradication in complicated urinary tract infection the TANGO I randomized clinical trial. / Kaye, Keith S.; Bhowmick, Tanaya; Metallidis, Symeon; Bleasdale, Susan C.; Sagan, Olexiy S.; Stus, Viktor; Vazquez, Jose Antonio; Zaitsev, Valerii; Bidair, Mohamed; Chorvat, Erik; Dragoescu, Petru Octavian; Fedosiuk, Elena; Horcajada, Juan P.; Murta, Claudia; Sarychev, Yaroslav; Stoev, Ventsislav; Morgan, Elizabeth; Fusaro, Karen; Griffith, David; Lomovskaya, Olga; Alexander, Elizabeth L.; Loutit, Jeffery; Dudley, Michael N.; Giamarellos-Bourboulis, Evangelos J.

In: JAMA - Journal of the American Medical Association, Vol. 319, No. 8, 27.02.2018, p. 788-799.

Research output: Contribution to journalArticle

Kaye, KS, Bhowmick, T, Metallidis, S, Bleasdale, SC, Sagan, OS, Stus, V, Vazquez, JA, Zaitsev, V, Bidair, M, Chorvat, E, Dragoescu, PO, Fedosiuk, E, Horcajada, JP, Murta, C, Sarychev, Y, Stoev, V, Morgan, E, Fusaro, K, Griffith, D, Lomovskaya, O, Alexander, EL, Loutit, J, Dudley, MN & Giamarellos-Bourboulis, EJ 2018, 'Effect of meropenem-vaborbactam vs piperacillin-Tazobactam on clinical cure or improvement and microbial eradication in complicated urinary tract infection the TANGO I randomized clinical trial', JAMA - Journal of the American Medical Association, vol. 319, no. 8, pp. 788-799. https://doi.org/10.1001/jama.2018.0438
Kaye, Keith S. ; Bhowmick, Tanaya ; Metallidis, Symeon ; Bleasdale, Susan C. ; Sagan, Olexiy S. ; Stus, Viktor ; Vazquez, Jose Antonio ; Zaitsev, Valerii ; Bidair, Mohamed ; Chorvat, Erik ; Dragoescu, Petru Octavian ; Fedosiuk, Elena ; Horcajada, Juan P. ; Murta, Claudia ; Sarychev, Yaroslav ; Stoev, Ventsislav ; Morgan, Elizabeth ; Fusaro, Karen ; Griffith, David ; Lomovskaya, Olga ; Alexander, Elizabeth L. ; Loutit, Jeffery ; Dudley, Michael N. ; Giamarellos-Bourboulis, Evangelos J. / Effect of meropenem-vaborbactam vs piperacillin-Tazobactam on clinical cure or improvement and microbial eradication in complicated urinary tract infection the TANGO I randomized clinical trial. In: JAMA - Journal of the American Medical Association. 2018 ; Vol. 319, No. 8. pp. 788-799.
@article{92f6187795f8422abfadee90343fcf30,
title = "Effect of meropenem-vaborbactam vs piperacillin-Tazobactam on clinical cure or improvement and microbial eradication in complicated urinary tract infection the TANGO I randomized clinical trial",
abstract = "IMPORTANCE Meropenem-vaborbactam is a combination carbapenem/beta-lactamase inhibitor and a potential treatment for severe drug-resistant gram-negative infections. OBJECTIVE To evaluate efficacy and adverse events of meropenem-vaborbactam in complicated urinary tract infection (UTI), including acute pyelonephritis. DESIGN, SETTING, AND PARTICIPANTS Phase 3, multicenter, multinational, randomized clinical trial (TANGO I) conducted November 2014 to April 2016 and enrolling patients (18 years) with complicated UTI, stratified by infection type and geographic region. INTERVENTIONS Eligible patients were randomized 1:1 to receive meropenem-vaborbactam (2g/2g over 3 hours; n = 274) or piperacillin-Tazobactam (4g/0.5g over 30 minutes; n = 276) every 8 hours. After 15 or more doses, patients could be switched to oral levofloxacin if they met prespecified criteria for improvement, to complete 10 days of total treatment. MAIN OUTCOMES AND MEASURES Primary end point for FDA criteriawas overall success (clinical cure or improvement and microbial eradication composite) at end of intravenous treatment in the microbiologic modified intent-To-Treat (ITT) population. Primary end point for European Medicines Agency (EMA) criteria was microbial eradication at test-of-cure visit in the microbiologic modified ITT and microbiologic evaluable populations. Prespecified noninferiority margin was 15{\%}. Because the protocol prespecified superiority testing in the event of noninferiority, 2-sided 95{\%}CIs were calculated. RESULTS Among 550 patients randomized, 545 received study drug (mean age, 52.8 years; 361 [66.2{\%}]women; 374 [68.6{\%}] in the microbiologic modified ITT population; 347 [63.7{\%}] in the microbiologic evaluable population; 508 [93.2{\%}] completed the trial). For the FDA primary end point, overall success occurred in 189 of 192 (98.4{\%}) with meropenem-vaborbactam vs 171 of 182 (94.0{\%}) with piperacillin-Tazobactam (difference, 4.5{\%}[95{\%}CI, 0.7{\%}to 9.1{\%}]; P < .001 for noninferiority). For the EMA primary end point, microbial eradication in the microbiologic modified ITT population occurred in 128 of 192 (66.7{\%}) with meropenemvaborbactam vs 105 of 182 (57.7{\%}) with piperacillin-Tazobactam (difference, 9.0{\%}[95{\%}CI, 0.9{\%}to 18.7{\%}]; P < .001 for noninferiority); microbial eradication in the microbiologic evaluable population occurred in 118 of 178 (66.3{\%}) vs 102 of 169 (60.4{\%}) (difference, 5.9{\%}[95{\%}CI, 4.2{\%}to 16.0{\%}]; P < .001 for noninferiority). Adverse eventswere reported in 106 of 272 (39.0{\%}) with meropenem-vaborbactam vs 97 of 273 (35.5{\%}) with piperacillin-Tazobactam. CONCLUSIONSANDRELEVANCE Amongpatient swith complicatedUTI,includingacutepyelonephritis andgrowthof a baseline pathogen,meropenem-vaborbactamvs piperacillin-Tazobactamresulted in a compositeoutcomeofcomplete resolution orimprovementof symptomsalongwith microbial eradication thatmet the noninferiority criterion. Further research is needed to understand the spectrum of patients inwhommeropenem-vaborbactam offers a clinical advantage.",
author = "Kaye, {Keith S.} and Tanaya Bhowmick and Symeon Metallidis and Bleasdale, {Susan C.} and Sagan, {Olexiy S.} and Viktor Stus and Vazquez, {Jose Antonio} and Valerii Zaitsev and Mohamed Bidair and Erik Chorvat and Dragoescu, {Petru Octavian} and Elena Fedosiuk and Horcajada, {Juan P.} and Claudia Murta and Yaroslav Sarychev and Ventsislav Stoev and Elizabeth Morgan and Karen Fusaro and David Griffith and Olga Lomovskaya and Alexander, {Elizabeth L.} and Jeffery Loutit and Dudley, {Michael N.} and Giamarellos-Bourboulis, {Evangelos J.}",
year = "2018",
month = "2",
day = "27",
doi = "10.1001/jama.2018.0438",
language = "English (US)",
volume = "319",
pages = "788--799",
journal = "JAMA - Journal of the American Medical Association",
issn = "0002-9955",
publisher = "American Medical Association",
number = "8",

}

TY - JOUR

T1 - Effect of meropenem-vaborbactam vs piperacillin-Tazobactam on clinical cure or improvement and microbial eradication in complicated urinary tract infection the TANGO I randomized clinical trial

AU - Kaye, Keith S.

AU - Bhowmick, Tanaya

AU - Metallidis, Symeon

AU - Bleasdale, Susan C.

AU - Sagan, Olexiy S.

AU - Stus, Viktor

AU - Vazquez, Jose Antonio

AU - Zaitsev, Valerii

AU - Bidair, Mohamed

AU - Chorvat, Erik

AU - Dragoescu, Petru Octavian

AU - Fedosiuk, Elena

AU - Horcajada, Juan P.

AU - Murta, Claudia

AU - Sarychev, Yaroslav

AU - Stoev, Ventsislav

AU - Morgan, Elizabeth

AU - Fusaro, Karen

AU - Griffith, David

AU - Lomovskaya, Olga

AU - Alexander, Elizabeth L.

AU - Loutit, Jeffery

AU - Dudley, Michael N.

AU - Giamarellos-Bourboulis, Evangelos J.

PY - 2018/2/27

Y1 - 2018/2/27

N2 - IMPORTANCE Meropenem-vaborbactam is a combination carbapenem/beta-lactamase inhibitor and a potential treatment for severe drug-resistant gram-negative infections. OBJECTIVE To evaluate efficacy and adverse events of meropenem-vaborbactam in complicated urinary tract infection (UTI), including acute pyelonephritis. DESIGN, SETTING, AND PARTICIPANTS Phase 3, multicenter, multinational, randomized clinical trial (TANGO I) conducted November 2014 to April 2016 and enrolling patients (18 years) with complicated UTI, stratified by infection type and geographic region. INTERVENTIONS Eligible patients were randomized 1:1 to receive meropenem-vaborbactam (2g/2g over 3 hours; n = 274) or piperacillin-Tazobactam (4g/0.5g over 30 minutes; n = 276) every 8 hours. After 15 or more doses, patients could be switched to oral levofloxacin if they met prespecified criteria for improvement, to complete 10 days of total treatment. MAIN OUTCOMES AND MEASURES Primary end point for FDA criteriawas overall success (clinical cure or improvement and microbial eradication composite) at end of intravenous treatment in the microbiologic modified intent-To-Treat (ITT) population. Primary end point for European Medicines Agency (EMA) criteria was microbial eradication at test-of-cure visit in the microbiologic modified ITT and microbiologic evaluable populations. Prespecified noninferiority margin was 15%. Because the protocol prespecified superiority testing in the event of noninferiority, 2-sided 95%CIs were calculated. RESULTS Among 550 patients randomized, 545 received study drug (mean age, 52.8 years; 361 [66.2%]women; 374 [68.6%] in the microbiologic modified ITT population; 347 [63.7%] in the microbiologic evaluable population; 508 [93.2%] completed the trial). For the FDA primary end point, overall success occurred in 189 of 192 (98.4%) with meropenem-vaborbactam vs 171 of 182 (94.0%) with piperacillin-Tazobactam (difference, 4.5%[95%CI, 0.7%to 9.1%]; P < .001 for noninferiority). For the EMA primary end point, microbial eradication in the microbiologic modified ITT population occurred in 128 of 192 (66.7%) with meropenemvaborbactam vs 105 of 182 (57.7%) with piperacillin-Tazobactam (difference, 9.0%[95%CI, 0.9%to 18.7%]; P < .001 for noninferiority); microbial eradication in the microbiologic evaluable population occurred in 118 of 178 (66.3%) vs 102 of 169 (60.4%) (difference, 5.9%[95%CI, 4.2%to 16.0%]; P < .001 for noninferiority). Adverse eventswere reported in 106 of 272 (39.0%) with meropenem-vaborbactam vs 97 of 273 (35.5%) with piperacillin-Tazobactam. CONCLUSIONSANDRELEVANCE Amongpatient swith complicatedUTI,includingacutepyelonephritis andgrowthof a baseline pathogen,meropenem-vaborbactamvs piperacillin-Tazobactamresulted in a compositeoutcomeofcomplete resolution orimprovementof symptomsalongwith microbial eradication thatmet the noninferiority criterion. Further research is needed to understand the spectrum of patients inwhommeropenem-vaborbactam offers a clinical advantage.

AB - IMPORTANCE Meropenem-vaborbactam is a combination carbapenem/beta-lactamase inhibitor and a potential treatment for severe drug-resistant gram-negative infections. OBJECTIVE To evaluate efficacy and adverse events of meropenem-vaborbactam in complicated urinary tract infection (UTI), including acute pyelonephritis. DESIGN, SETTING, AND PARTICIPANTS Phase 3, multicenter, multinational, randomized clinical trial (TANGO I) conducted November 2014 to April 2016 and enrolling patients (18 years) with complicated UTI, stratified by infection type and geographic region. INTERVENTIONS Eligible patients were randomized 1:1 to receive meropenem-vaborbactam (2g/2g over 3 hours; n = 274) or piperacillin-Tazobactam (4g/0.5g over 30 minutes; n = 276) every 8 hours. After 15 or more doses, patients could be switched to oral levofloxacin if they met prespecified criteria for improvement, to complete 10 days of total treatment. MAIN OUTCOMES AND MEASURES Primary end point for FDA criteriawas overall success (clinical cure or improvement and microbial eradication composite) at end of intravenous treatment in the microbiologic modified intent-To-Treat (ITT) population. Primary end point for European Medicines Agency (EMA) criteria was microbial eradication at test-of-cure visit in the microbiologic modified ITT and microbiologic evaluable populations. Prespecified noninferiority margin was 15%. Because the protocol prespecified superiority testing in the event of noninferiority, 2-sided 95%CIs were calculated. RESULTS Among 550 patients randomized, 545 received study drug (mean age, 52.8 years; 361 [66.2%]women; 374 [68.6%] in the microbiologic modified ITT population; 347 [63.7%] in the microbiologic evaluable population; 508 [93.2%] completed the trial). For the FDA primary end point, overall success occurred in 189 of 192 (98.4%) with meropenem-vaborbactam vs 171 of 182 (94.0%) with piperacillin-Tazobactam (difference, 4.5%[95%CI, 0.7%to 9.1%]; P < .001 for noninferiority). For the EMA primary end point, microbial eradication in the microbiologic modified ITT population occurred in 128 of 192 (66.7%) with meropenemvaborbactam vs 105 of 182 (57.7%) with piperacillin-Tazobactam (difference, 9.0%[95%CI, 0.9%to 18.7%]; P < .001 for noninferiority); microbial eradication in the microbiologic evaluable population occurred in 118 of 178 (66.3%) vs 102 of 169 (60.4%) (difference, 5.9%[95%CI, 4.2%to 16.0%]; P < .001 for noninferiority). Adverse eventswere reported in 106 of 272 (39.0%) with meropenem-vaborbactam vs 97 of 273 (35.5%) with piperacillin-Tazobactam. CONCLUSIONSANDRELEVANCE Amongpatient swith complicatedUTI,includingacutepyelonephritis andgrowthof a baseline pathogen,meropenem-vaborbactamvs piperacillin-Tazobactamresulted in a compositeoutcomeofcomplete resolution orimprovementof symptomsalongwith microbial eradication thatmet the noninferiority criterion. Further research is needed to understand the spectrum of patients inwhommeropenem-vaborbactam offers a clinical advantage.

UR - http://www.scopus.com/inward/record.url?scp=85042594840&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85042594840&partnerID=8YFLogxK

U2 - 10.1001/jama.2018.0438

DO - 10.1001/jama.2018.0438

M3 - Article

C2 - 29486041

AN - SCOPUS:85042594840

VL - 319

SP - 788

EP - 799

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

SN - 0002-9955

IS - 8

ER -