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.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Harris reported receiving grants from the Australian Society for Antimicrobials; the International Society for Chemotherapy; the National University Hospital Singapore; the Study, Education, and Research Committee of Pathology; and the Royal College of Pathologists of Australasia Foundation. Dr Harris also reported receiving support to speak at an educational event sponsored by Pfizer. Dr Tambyah reported receiving grants from the National University Health System, GlaxoSmithKline, Janssen, Shionogi, Sanofi-Pasteur, Visterra, Baxter, ADAMAS, Merlion Pharmaceuticals, Fabentech, and Inviragen. He has also received honoraria from Novartis and AstraZeneca. Dr Falcone reported receiving personal fees from MSD, Angelini, and Astellas and grants from Gilead. Dr Bassetti reported receiving grants and/or personal fees from Pfizer, MSD, Astellas, Menarini, Roche, Tetraphase, Achaogen, Angelini, AstraZeneca, Bayer, Basilea, Cidara, Gilead, MSD, Paratek, Pfizer, The Medicines Company, and Vifor. Dr Rogers reported receiving grants and personal fees from MSD Australia for attending advisory boards and research and personal fees from Mayne Pharma for consulting. Dr Kanj reported receiving honoraria for speaking and serving on advisory boards for Pfizer, Merck, Bayer, Gilead, Hikma, and Aventis. Ms Lorenc reported receiving grants from the Australian Society for Antimicrobials, the International Society for Chemotherapy, and the National University Hospital Singapore. Dr Beatson reported receiving support for speaking at an educational event sponsored by Pfizer. Dr Peleg reported receiving grants from MSD. Dr Paterson reported receiving grants and/or personal fees from Merck, Pfizer, Shionogi, Achaogen, AstraZeneca, Leo Pharmaceuticals, Bayer, GlaxoSmithKline, and Cubist. No other disclosures were reported.

Figures

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.