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
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.
N1 - Funding Information:
completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Kaye reported receiving grants and personal fees from The Medicines Company and Merck and receiving personal fees from Bayer and Allergan. Dr Metallidis reported receiving personal fees from Ahepa University Hospital. Dr Bleasdale reported receiving grants from Rempex Pharmaceuticals and personal fees from The Medicines Company. Dr Stus reported receiving personal fees from Dnipropetrovsk Medical Academy Ministry of Health of Ukraine. Dr Zaitsev reported receiving grants from Rempex Pharmaceuticals. Dr Dragoescu reported receiving personal fees from The Medicines Company, AstraZeneca, Tetraphase Pharmaceuticals, and Achaogen Inc. Dr Horcajada reported receiving grants and personal fees from MSD and personal fees from Pfizer, Angellini, Zambon, Astellas, and Astra Zeneca. Dr Sarychev reported receiving grants and personal fees from Rempex Pharmaceuticals. Ms Morgan reported that she was an employee of and shareholder in The Medicines Company. Ms Fusaro reported that she is an employee of The Medicines Company. Mr Griffith reported that he is an employee of The Medicines Company and has received funding from Rempex Pharmaceuticals. Dr Lomovskaya reported that she is an employee of and shareholder in The Medicines Company. Dr Alexander reported that she is an employee of and shareholder in The Medicines Company/Rempex Pharmaceuticals. Dr Loutit reported that he is an employee of and shareholder in The Medicines Company. Dr Dudley reported that he is an employee of and shareholder in The Medicines Company. Dr Giamarellos-Bourboulis reported receiving grants from FrameWork 7 EU program HemoSpec, Horizon2020 EU Marie-Curie Horoson ITN European Sepsis Academy, InflaRx GmbH, XBiotech, AIDA FP7 Consortium, Astellas, The Medicines Company, Paratek, Biotest GmbH, Brahms GmbH, and Axis Shield (all paid to the University of Athens) and receiving personal fees from AbbVie, InflaRx GmbH, The Medicines Company, XBiotech, Abbott CH, Biotest GmbH, Astellas, and Commonwealth. No other authors reported disclosures.
Funding Information:
Funding/Support: This project has been funded
Publisher Copyright:
© 2018 American Medical Association. All rights reserved.
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.
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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 -