Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with e coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance


Patrick NA Harris, Princess Alexandra Hospital, University of Queensland, Royal Brisbane and Women's hospitalFollow
Paul Tambyah, National University Hospital Singapore
David C. Lye, Tan Tock Seng Hospital, National University of Singapore, Nanyang Technological University
Yin Mo, National University Hospital Singapore
Tau Lee, Nanyang Technological University, Tan Tock Seng Hospital
Mesut Yilmaz, Istanbul Medipol University
Thamer Alenazi, King Saud Bin Abdulaziz University for Health Sciences
Yaseen Arabi, King Saud Bin Abdulaziz University for Health Sciences
Marco Falcone, University of Rome La Sapienza
Matteo Bassetti, University of Udine, Santa Maria Misericordia Hospital
Elda Righi, University of Udine, Santa Maria Misericordia Hospital
Benjamin A. Rogers, Monash University, Monash Health
Souha Kanj, American University of Beirut
Hasan Bhally, North Shore Hospital
Jon Iredell, University of Sydney, Westmead Hospital
Marc Mendelson, University of Cape Town
Tom Boyles, University of Cape Town
David Looke, University of Queensland, Princess Alexandra Hospital
Spiros Miyakis, University of WollongongFollow
Genevieve Walls, Middlemore Hospital
Mohammed Al Khamis, King Fahad Specialist Hospital
Ahmed Zikri, King Fahad Specialist Hospital
Amy Crowe, St Vincent's Hospital
Paul R. Ingram, PathWest Laboratory Medicine, University of Western Australia, Fiona Stanley Hospital
Nick Daneman, University of Toronto
Paul Griffin, Mater Medical Research Institute, University of Queensland
Eugene Athan, Deakin University, University of MelbourneFollow
Penelope Lorenc, University of Queensland
Peter Baker, University of Queensland
Leah Roberts, University of Queensland
Scott A. Beatson, University of Queensland
Anton Y. Peleg, Monash University
Tiffany Harris-Brown, Royal Brisbane and Women's hospital, University of Queensland, Princess Alexandra Hospital
David L. Paterson, Royal Brisbane and Women's hospital, University of Queensland



Publication Details

Harris, P. N. A., Tambyah, P. A., Lye, D. C., Mo, Y., Lee, T. H., Yilmaz, M., Alenazi, T. H., Arabi, Y., Falcone, M., Bassetti, M., Righi, E., Rogers, B. A., Kanj, S., Bhally, H., Iredell, J., Mendelson, M., Boyles, T. H., Looke, D., Miyakis, S., Walls, G., Al Khamis, M., Zikri, A., Crowe, A., Ingram, P., Daneman, N., Griffin, P., Athan, E., Lorenc, P., Baker, P., Roberts, L., Beatson, S. A., Peleg, A. Y., Harris-Brown, T. & Paterson, D. (2018). Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with e coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance. JAMA: Journal of the American Medical Association, 320 (10), 984-994.


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.

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