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

Journal Article


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.

Authors


  •   Narris, Patrick NA. (external author)
  •   Tambyah, Paul (external author)
  •   Lye, David C. (external author)
  •   Mo, Yin (external author)
  •   Lee, Tau (external author)
  •   Yilmaz, Mesut (external author)
  •   Alenazi, Thamer (external author)
  •   Arabi, Yaseen (external author)
  •   Falcone, Marco (external author)
  •   Bassetti, Matteo (external author)
  •   Righi, Elda (external author)
  •   Rogers, Benjamin A. (external author)
  •   Kanj, Souha (external author)
  •   Bhally, Hasan (external author)
  •   Iredell, Jon (external author)
  •   Mendelson, Marc (external author)
  •   Boyles, Tom (external author)
  •   Looke, David (external author)
  •   Miyakis, Spiros
  •   Walls, Genevieve (external author)
  •   Al Khamis, Mohammed (external author)
  •   Zikri, Ahmed (external author)
  •   Crowe, Amy (external author)
  •   Ingram, Paul R. (external author)
  •   Daneman, Nick (external author)
  •   Griffin, Paul (external author)
  •   Athan, Eugene (external author)
  •   Lorenc, Penelope (external author)
  •   Baker, Peter (external author)
  •   Roberts, Leah (external author)
  •   Beatson, Scott A. (external author)
  •   Peleg, Anton Y. (external author)
  •   Harris-Brown, Tiffany (external author)
  •   Paterson, David L. (external author)

Publication Date


  • 2018

Citation


  • 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.

Scopus Eid


  • 2-s2.0-85053263956

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/1278

Number Of Pages


  • 10

Start Page


  • 984

End Page


  • 994

Volume


  • 320

Issue


  • 10

Place Of Publication


  • United States

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.

Authors


  •   Narris, Patrick NA. (external author)
  •   Tambyah, Paul (external author)
  •   Lye, David C. (external author)
  •   Mo, Yin (external author)
  •   Lee, Tau (external author)
  •   Yilmaz, Mesut (external author)
  •   Alenazi, Thamer (external author)
  •   Arabi, Yaseen (external author)
  •   Falcone, Marco (external author)
  •   Bassetti, Matteo (external author)
  •   Righi, Elda (external author)
  •   Rogers, Benjamin A. (external author)
  •   Kanj, Souha (external author)
  •   Bhally, Hasan (external author)
  •   Iredell, Jon (external author)
  •   Mendelson, Marc (external author)
  •   Boyles, Tom (external author)
  •   Looke, David (external author)
  •   Miyakis, Spiros
  •   Walls, Genevieve (external author)
  •   Al Khamis, Mohammed (external author)
  •   Zikri, Ahmed (external author)
  •   Crowe, Amy (external author)
  •   Ingram, Paul R. (external author)
  •   Daneman, Nick (external author)
  •   Griffin, Paul (external author)
  •   Athan, Eugene (external author)
  •   Lorenc, Penelope (external author)
  •   Baker, Peter (external author)
  •   Roberts, Leah (external author)
  •   Beatson, Scott A. (external author)
  •   Peleg, Anton Y. (external author)
  •   Harris-Brown, Tiffany (external author)
  •   Paterson, David L. (external author)

Publication Date


  • 2018

Citation


  • 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.

Scopus Eid


  • 2-s2.0-85053263956

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/1278

Number Of Pages


  • 10

Start Page


  • 984

End Page


  • 994

Volume


  • 320

Issue


  • 10

Place Of Publication


  • United States