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<h4>Importance</h4>Extended-spectrum β-lactamases mediate resistance to third-generation cephalosporins (eg, ceftriaxone) in Escherichia coli and Klebsiella pneumoniae. Significant infections caused by these strains are usually treated with carbapenems, potentially selecting for carbapenem resistance. Piperacillin-tazobactam may be an effective "carbapenem-sparing" option to treat extended-spectrum β-lactamase producers.<h4>Objectives</h4>To determine whether definitive therapy with piperacillin-tazobactam is noninferior to meropenem (a carbapenem) in patients with bloodstream infection caused by ceftriaxone-nonsusceptible E coli or K pneumoniae.<h4>Design, setting, and participants</h4>Noninferiority, parallel group, randomized clinical trial included hospitalized patients enrolled from 26 sites in 9 countries from February 2014 to July 2017. Adult patients were eligible if they had at least 1 positive blood culture with E coli or Klebsiella spp testing nonsusceptible to ceftriaxone but susceptible to piperacillin-tazobactam. Of 1646 patients screened, 391 were included in the study.<h4>Interventions</h4>Patients were randomly assigned 1:1 to intravenous piperacillin-tazobactam, 4.5 g, every 6 hours (n = 188 participants) or meropenem, 1 g, every 8 hours (n = 191 participants) for a minimum of 4 days, up to a maximum of 14 days, with the total duration determined by the treating clinician.<h4>Main outcomes and measures</h4>The primary outcome was all-cause mortality at 30 days after randomization. A noninferiority margin of 5% was used.<h4>Results</h4>Among 379 patients (mean age, 66.5 years; 47.8% women) who were randomized appropriately, received at least 1 dose of study drug, and were included in the primary analysis population, 378 (99.7%) completed the trial and were assessed for the primary outcome. A total of 23 of 187 patients (12.3%) randomized to piperacillin-tazobactam met the primary outcome of mortality at 30 days compared with 7 of 191 (3.7%) randomized to meropenem (risk difference, 8.6% [1-sided 97.5% CI, -∞ to 14.5%]; P = .90 for noninferiority). Effects were consistent in an analysis of the per-protocol population. Nonfatal serious adverse events occurred in 5 of 188 patients (2.7%) in the piperacillin-tazobactam group and 3 of 191 (1.6%) in the meropenem group.<h4>Conclusions and relevance</h4>Among patients with E coli or K pneumoniae bloodstream infection and ceftriaxone resistance, definitive treatment with piperacillin-tazobactam compared with meropenem did not result in a noninferior 30-day mortality. These findings do not support use of piperacillin-tazobactam in this setting.<h4>Trial registration</h4>anzctr.org.au Identifiers: ACTRN12613000532707 and ACTRN12615000403538 and ClinicalTrials.gov Identifier: NCT02176122.

Original publication

DOI

10.1001/jama.2018.12163

Type

Journal

JAMA

Publication Date

09/2018

Volume

320

Pages

984 - 994

Addresses

University of Queensland, UQ Centre for Clinical Research, Brisbane, Queensland, Australia.

Keywords

MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN), Humans, Escherichia coli, Klebsiella pneumoniae, Bacteremia, Escherichia coli Infections, Klebsiella Infections, Thienamycins, Ceftriaxone, Penicillanic Acid, Piperacillin, Anti-Bacterial Agents, Cause of Death, Drug Resistance, Bacterial, Adult, Aged, Middle Aged, Female, Male, Piperacillin, Tazobactam Drug Combination, Meropenem