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Original Investigation
September 11, 2018

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

Author Affiliations
  • 1University of Queensland, UQ Centre for Clinical Research, Brisbane, Queensland, Australia
  • 2Department of Microbiology, Pathology Queensland, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
  • 3Infection Management Services, Princess Alexandra Hospital, Brisbane, Queensland, Australia
  • 4Department of Infectious Diseases, National University Hospital, Singapore
  • 5Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  • 6Department of Infectious Diseases, Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital, Singapore
  • 7Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
  • 8Department of Infectious Diseases and Clinical Microbiology, School of Medicine, Istanbul Medipol University, Istanbul, Turkey
  • 9King Saud Bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
  • 10Department of Public Health and Infectious Diseases, “Sapienza” University of Rome, Italy
  • 11Infectious Diseases Clinic, Department of Medicine University of Udine and Santa Maria Misericordia Hospital, Udine, Italy
  • 12Monash University, Centre for Inflammatory Diseases, Melbourne, Victoria, Australia
  • 13Monash Infectious Diseases, Monash Health, Melbourne, Victoria, Australia
  • 14Division of Infectious Diseases, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
  • 15Department of Medicine and Infectious Diseases, North Shore Hospital, Auckland, New Zealand
  • 16Marie Bashir Institute for Infectious Disease and Biosecurity, University of Sydney, Sydney, New South Wales, Australia
  • 17Centre for Infectious Diseases and Microbiology, Westmead Hospital, Westmead, New South Wales, Australia
  • 18Division of Infectious Diseases & HIV Medicine, Department of Medicine, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa
  • 19University of Queensland, Brisbane, Queensland, Australia
  • 20School of Medicine, University of Wollongong, Wollongong, New South Wales, Australia
  • 21Illawarra Health and Medical Research Institute, Wollongong, New South Wales, Australia
  • 22Department of Infectious Diseases, Wollongong Hospital, Wollongong, New South Wales, Australia
  • 23Department of Infectious Diseases, Middlemore Hospital, Auckland, New Zealand
  • 24King Fahad Specialist Hospital, Dammam, Saudi Arabia
  • 25Department of Infectious Diseases, St Vincent’s Hospital, Melbourne, Victoria, Australia
  • 26Department of Microbiology, St Vincent’s Hospital, Melbourne, Victoria, Australia
  • 27School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, Australia
  • 28Department of Infectious Diseases, Fiona Stanley Hospital, Murdoch, Australia
  • 29Department of Microbiology, PathWest Laboratory Medicine, Perth, Western Australia
  • 30Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
  • 31Department of Medicine and Infectious Diseases, Mater Hospital and Mater Medical Research Institute, Brisbane, Queensland, Australia
  • 32QIMR Berghofer, Brisbane, Queensland, Australia
  • 33Department of Infectious Diseases, Barwon Health and Deakin University, Geelong, Victoria, Australia
  • 34School of Public Health, University of Queensland, Brisbane, Queensland, Australia
  • 35Australian Centre for Ecogenomics, School of Chemistry and Molecular Biosciences, The University of Queensland, Queensland, Australia
  • 36Infection & Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, Australia
  • 37Department of Microbiology, Monash University, Clayton, Australia
  • 38Department of Infectious Diseases, Alfred Hospital and Central Clinical School, Monash University, Melbourne, Victoria, Australia
  • 39Department of Infectious Diseases, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
JAMA. 2018;320(10):984-994. doi:10.1001/jama.2018.12163
Key Points

Question  Can piperacillin-tazobactam be used as carbapenem-sparing therapy in patients with bloodstream infections caused by ceftriaxone-resistant Escherichia coli or Klebsiella pneumoniae?

Findings  In this noninferiority randomized clinical trial that included 391 patients with E coli or K pneumoniae bloodstream infection and ceftriaxone resistance, the 30-day mortality rate for patients treated with piperacillin-tazobactam compared with meropenem was 12.3% vs 3.7%, respectively. The difference did not meet the noninferiority margin of 5%.

Meaning  These findings do not support piperacillin-tazobactam compared with meropenem for these infections.


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