Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With E coli or Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone Resistance: A Randomized Clinical Trial

JAMA. 2018 Sep 11;320(10):984-994. doi: 10.1001/jama.2018.12163.

Abstract

Importance: 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.

Objectives: 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.

Design, setting, and participants: 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.

Interventions: 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.

Main outcomes and measures: The primary outcome was all-cause mortality at 30 days after randomization. A noninferiority margin of 5% was used.

Results: 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.

Conclusions and relevance: 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.

Trial registration: anzctr.org.au Identifiers: ACTRN12613000532707 and ACTRN12615000403538 and ClinicalTrials.gov Identifier: NCT02176122.

Publication types

  • Comparative Study
  • Equivalence Trial
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Anti-Bacterial Agents / adverse effects
  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / therapeutic use*
  • Bacteremia / drug therapy
  • Bacteremia / mortality*
  • Cause of Death
  • Ceftriaxone / pharmacology
  • Drug Resistance, Bacterial
  • Escherichia coli / drug effects
  • Escherichia coli Infections / drug therapy*
  • Escherichia coli Infections / mortality
  • Female
  • Humans
  • Klebsiella Infections / drug therapy*
  • Klebsiella Infections / mortality
  • Klebsiella pneumoniae* / drug effects
  • Male
  • Meropenem
  • Middle Aged
  • Penicillanic Acid / adverse effects
  • Penicillanic Acid / analogs & derivatives*
  • Penicillanic Acid / therapeutic use
  • Piperacillin / adverse effects
  • Piperacillin / therapeutic use
  • Piperacillin, Tazobactam Drug Combination
  • Thienamycins / adverse effects
  • Thienamycins / therapeutic use*

Substances

  • Anti-Bacterial Agents
  • Thienamycins
  • Piperacillin, Tazobactam Drug Combination
  • Ceftriaxone
  • Penicillanic Acid
  • Meropenem
  • Piperacillin

Associated data

  • ANZCTR/ACTRN12613000532707
  • ANZCTR/ACTRN12615000403538
  • ClinicalTrials.gov/NCT02176122