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

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.

Figure 1.. Patient Recruitment, Randomization, and Flow Through Study

^aPatients could meet more than 1 exclusion criteria. A total of 376 patients were excluded because more than 72 hours had elapsed since initial blood culture; 317, based on microbiology criteria; 110, allergy to trial drug; 94, polymicrobial infection; 78, not expected to survive more than 96 hours; 44, pregnant or breastfeeding; 28, no intent to cure; 20, younger than 18 years old (<21 years old in Singapore); and 20, previously enrolled. For 317 patients, microbiological exclusions based on susceptibility testing were as follows: 13.3% were susceptible to ceftriaxone, 10.7% were nonsusceptible to meropenem, and 78.9% were nonsusceptible to piperacillin-tazobactam. Other microbiological exclusions included organism not being E coli or Klebsiella spp (<1%). One patient was excluded from both the primary analysis and the per-protocol population following self-discharge and loss to follow-up.

Figure 2.. Secondary Outcomes

^aClinical and microbiological success defined as survival, negative blood cultures, temperature of 38°C or less, and peripheral white blood cell count of less than or equal to 12 000/μL (to convert to ×10⁹/L, multiply by 0.001). ^bTwelve patients with meropenem- or piperacillin-tazobactam–resistant organism and 3 with Clostridium difficile infection. ^cSix patients with meropenem- or piperacillin-tazobactam–resistant organism and 2 with Clostridium difficile infection.