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

Patrick N.A. Harris, Paul A. Tambyah, David C. Lye, Yin Mo, Tau H. Lee, Mesut Yilmaz, Thamer H. Alenazi, Yaseen Arabi, Marco Falcone, Matteo Bassetti, Elda Righi, Benjamin A. Rogers, Souha Kanj, Hasan Bhally, Jon Iredell, Marc Mendelson, Tom H. Boyles, David Looke, Spiros Miyakis, Genevieve Walls & 15 others Mohammed Al Khamis, Ahmed Zikri, Amy Crowe, Paul Ingram, Nick Daneman, Paul Griffin, Eugene Athan, Penelope Lorenc, Peter Baker, Leah Roberts, Scott A. Beatson, Anton Y. Peleg, Tiffany Harris-Brown, David L. Paterson, for the MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN)

Research output: Contribution to journalArticleResearchpeer-review

87 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)984-994
Number of pages11
JournalJAMA - Journal of the American Medical Association
Volume320
Issue number10
DOIs
Publication statusPublished - 11 Sep 2018

Cite this

Harris, P. N. A., Tambyah, P. A., Lye, D. C., Mo, Y., Lee, T. H., Yilmaz, M., ... for the MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN) (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. https://doi.org/10.1001/jama.2018.12163
Harris, Patrick N.A. ; Tambyah, Paul A. ; Lye, David C. ; Mo, Yin ; Lee, Tau H. ; Yilmaz, Mesut ; Alenazi, Thamer H. ; Arabi, Yaseen ; Falcone, Marco ; Bassetti, Matteo ; Righi, Elda ; Rogers, Benjamin A. ; Kanj, Souha ; Bhally, Hasan ; Iredell, Jon ; Mendelson, Marc ; Boyles, Tom H. ; Looke, David ; Miyakis, Spiros ; Walls, Genevieve ; Al Khamis, Mohammed ; Zikri, Ahmed ; Crowe, Amy ; Ingram, Paul ; Daneman, Nick ; Griffin, Paul ; Athan, Eugene ; Lorenc, Penelope ; Baker, Peter ; Roberts, Leah ; Beatson, Scott A. ; Peleg, Anton Y. ; Harris-Brown, Tiffany ; Paterson, David L. ; for the MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN). / Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with e coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance. In: JAMA - Journal of the American Medical Association. 2018 ; Vol. 320, No. 10. pp. 984-994.
@article{59fc072d41794831a08b64a2ccdc6f9f,
title = "Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with e coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance",
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.",
author = "Harris, {Patrick N.A.} and Tambyah, {Paul A.} and Lye, {David C.} and Yin Mo and Lee, {Tau H.} and Mesut Yilmaz and Alenazi, {Thamer H.} and Yaseen Arabi and Marco Falcone and Matteo Bassetti and Elda Righi and Rogers, {Benjamin A.} and Souha Kanj and Hasan Bhally and Jon Iredell and Marc Mendelson and Boyles, {Tom H.} and David Looke and Spiros Miyakis and Genevieve Walls and {Al Khamis}, Mohammed and Ahmed Zikri and Amy Crowe and Paul Ingram and Nick Daneman and Paul Griffin and Eugene Athan and Penelope Lorenc and Peter Baker and Leah Roberts and Beatson, {Scott A.} and Peleg, {Anton Y.} and Tiffany Harris-Brown and Paterson, {David L.} and {for the MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN)}",
year = "2018",
month = "9",
day = "11",
doi = "10.1001/jama.2018.12163",
language = "English",
volume = "320",
pages = "984--994",
journal = "JAMA",
issn = "0098-7484",
publisher = "American Medical Association (AMA)",
number = "10",

}

Harris, PNA, Tambyah, PA, Lye, DC, Mo, Y, Lee, TH, Yilmaz, M, Alenazi, TH, Arabi, Y, Falcone, M, Bassetti, M, Righi, E, Rogers, BA, Kanj, S, Bhally, H, Iredell, J, Mendelson, M, Boyles, TH, 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, SA, Peleg, AY, Harris-Brown, T, Paterson, DL & for the MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN) 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, vol. 320, no. 10, pp. 984-994. https://doi.org/10.1001/jama.2018.12163

Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with e coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance. / Harris, Patrick N.A.; Tambyah, Paul A.; Lye, David C.; Mo, Yin; Lee, Tau H.; Yilmaz, Mesut; Alenazi, Thamer H.; Arabi, Yaseen; Falcone, Marco; Bassetti, Matteo; Righi, Elda; Rogers, Benjamin A.; Kanj, Souha; Bhally, Hasan; Iredell, Jon; Mendelson, Marc; Boyles, Tom H.; Looke, David; Miyakis, Spiros; Walls, Genevieve; Al Khamis, Mohammed; Zikri, Ahmed; Crowe, Amy; Ingram, Paul; Daneman, Nick; Griffin, Paul; Athan, Eugene; Lorenc, Penelope; Baker, Peter; Roberts, Leah; Beatson, Scott A.; Peleg, Anton Y.; Harris-Brown, Tiffany; Paterson, David L.; for the MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN).

In: JAMA - Journal of the American Medical Association, Vol. 320, No. 10, 11.09.2018, p. 984-994.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with e coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance

AU - Harris, Patrick N.A.

AU - Tambyah, Paul A.

AU - Lye, David C.

AU - Mo, Yin

AU - Lee, Tau H.

AU - Yilmaz, Mesut

AU - Alenazi, Thamer H.

AU - Arabi, Yaseen

AU - Falcone, Marco

AU - Bassetti, Matteo

AU - Righi, Elda

AU - Rogers, Benjamin A.

AU - Kanj, Souha

AU - Bhally, Hasan

AU - Iredell, Jon

AU - Mendelson, Marc

AU - Boyles, Tom H.

AU - Looke, David

AU - Miyakis, Spiros

AU - Walls, Genevieve

AU - Al Khamis, Mohammed

AU - Zikri, Ahmed

AU - Crowe, Amy

AU - Ingram, Paul

AU - Daneman, Nick

AU - Griffin, Paul

AU - Athan, Eugene

AU - Lorenc, Penelope

AU - Baker, Peter

AU - Roberts, Leah

AU - Beatson, Scott A.

AU - Peleg, Anton Y.

AU - Harris-Brown, Tiffany

AU - Paterson, David L.

AU - for the MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN)

PY - 2018/9/11

Y1 - 2018/9/11

N2 - 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.

AB - 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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U2 - 10.1001/jama.2018.12163

DO - 10.1001/jama.2018.12163

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SP - 984

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JO - JAMA

JF - JAMA

SN - 0098-7484

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