Τίτλος:
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
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2018 American Medical Association. All rights reserved.
Συγγραφείς:
Kaye, K.S.
Bhowmick, T.
Metallidis, S.
Bleasdale, S.C.
Sagan, O.S.
Stus, V.
Vazquez, J.
Zaitsev, V.
Bidair, M.
Chorvat, E.
Dragoescu, P.O.
Fedosiuk, E.
Horcajada, J.P.
Murta, C.
Sarychev, Y.
Stoev, V.
Morgan, E.
Fusaro, K.
Griffith, D.
Lomovskaya, O.
Alexander, E.L.
Loutit, J.
Dudley, M.N.
Giamarellos-Bourboulis, E.J.
Περιοδικό:
JAMA - JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION - INTERNATIONAL EDITION
Εκδότης:
American Medical Association
Λέξεις-κλειδιά:
alanine aminotransferase; aspartate aminotransferase; levofloxacin; meropenem plus vaborbactam; piperacillin plus tazobactam; antiinfective agent; meropenem; penicillanic acid; piperacillin; piperacillin, tazobactam drug combination; thienamycin derivative, acute pyelonephritis; adult; aged; alanine aminotransferase blood level; anemia; Article; aspartate aminotransferase blood level; asymptomatic bacteriuria; catheter site phlebitis; catheter site phlebitisc; comparative effectiveness; controlled study; diarrhea; double blind procedure; drug efficacy; drug safety; dyspnea; European Medicines Agency; female; fever; food and drug administration; headache; human; hypokalemia; infusion site phlebitis; intention to treat analysis; major clinical study; male; middle aged; multicenter study; nausea; pathogen clearance; phase 3 clinical trial; phlebitis; priority journal; randomized controlled trial; side effect; treatment duration; treatment outcome; urinary tract infection; vaginitis; acute disease; analogs and derivatives; clinical trial; comparative study; drug combination; microbiology; practice guideline; pyelonephritis; urinary tract infection; urine, Acute Disease; Adult; Aged; Anti-Bacterial Agents; Drug Combinations; Female; Humans; Intention to Treat Analysis; Male; Middle Aged; Penicillanic Acid; Piperacillin; Practice Guidelines as Topic; Pyelonephritis; Thienamycins; Urinary Tract Infections; Urine
DOI:
10.1001/jama.2018.0438
