Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With <i>E coli</i> or <i>Klebsiella pneumoniae</i> Bloodstream Infection and Ceftriaxone Resistance
Authors: Patrick N. A. Harris, Paul A. Tambyah, David C. Lye, Yin Mo, Tau H. Lee, Mesut Yilmaz, Thamer H. Alenazi, Yaseen Arabi, Marco Falcone, Matteo Bassetti, Elda Righi, Benjamin A. Rogers, Souha Kanj, Hasan Bhally, Jon Iredell, Marc Mendelson, Tom H. Boyles, David Looke, Spiros Miyakis, Genevieve Walls, Mohammed Al Khamis, Ahmed Zikri, Amy Crowe, Paul Ingram, Nick Daneman, Paul Griffin, Eugene Athan, Penelope Lorenc, Peter Baker, Leah Roberts, Scott A. Beatson, Anton Y. Peleg, Tiffany Harris-Brown, David L. Paterson
Journal: JAMA (2018)

<h3>Importance</h3> Extended-spectrum β-lactamases mediate resistance to third-generation cephalosporins (eg, ceftriaxone) in<i>Escherichia coli</i>and<i>Klebsiella pneumoniae.</i>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. <h3>Objectives</h3> To determine whether definitive therapy with piperacillin-tazobactam is noninferior to meropenem (a carbapenem) in patients with bloodstream infection caused by ceftriaxone-nonsusceptible<i>E coli</i>or<i>K pneumoniae</i>. <h3>Design, Setting, and Participants</h3> 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<i>E coli</i>or<i>Klebsiella</i>spp testing nonsusceptible to ceftriaxone but susceptible to piperacillin-tazobactam. Of 1646 patients screened, 391 were included in the study. <h3>Interventions</h3> 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. <h3>Main Outcomes and Measures</h3> The primary outcome was all-cause mortality at 30 days after randomization. A noninferiority margin of 5% was used. <h3>Results</h3> 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%];<i>P</i> = .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. <h3>Conclusions and relevance</h3> Among patients with<i>E coli</i>or<i>K pneumoniae</i>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. <h3>Trial Registration</h3> anzctr.org.au Identifiers:ACTRN12613000532707andACTRN12615000403538and ClinicalTrials.gov Identifier:NCT02176122