Emulating the MERINO randomised control trial using data from an observational cohort and trial of rapid diagnostic (BSI-FOO)

Rebecca N Evans; Jessica Harris; Chris A Rogers; Alasdair MacGowan

doi:10.1371/journal.pone.0268807

Emulating the MERINO randomised control trial using data from an observational cohort and trial of rapid diagnostic (BSI-FOO)

Rebecca N Evans, Jessica Harris, Chris A Rogers, Alasdair MacGowan

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Abstract

OBJECTIVE: The aim of this study was to emulate the MERINO trial of piperacillin-tazobactam vs meropenem for the definitive treatment of bloodstream infection (BSI) caused by ceftriaxone-nonsusceptible E coli or Klebsiella spp.

METHODS: Data from an observational study of BSI and a randomised controlled trial of a rapid diagnostic in BSI were used to emulate the MERINO trial. The primary outcome of the emulated trial was 28-day mortality after blood culture. Outcomes were compared using logistic regression adjusted for propensity score for emulated intervention.

RESULTS: Of the 6,371 observational study and RCT participants, 1,968 had a bloodstream infection with E. coli or Klebsiella spp. of which 121 met the eligibility criteria. In the emulated trial, a total of 14/82 patients (17.1%) allocated to piperacillin-tazobactam met the primary outcome compared with 6/39 (15.4%) in the meropenem group (unadjusted odds ratio 1.13 (95% CI 0.40 to 3.21)). After adjustment for propensity score, the odds ratio increased to 1.31 (95% CI 0.40 to 4.26). This difference is in the same direction but of a smaller magnitudethan observed in the MERINO trial, where 30-day mortality was met by 23/187 patients (12.3%) in the piperacillin-tazobactam and 7/191 (3.7%) in the meropenem group (unadjusted odds ratio of 3.69 (95% CI 1.48 to 10.41)).

CONCLUSIONS: The mortality rate in an emulated trial population was more than double the mortality rate in the MERINO trial. The methodology used attempts to address the concern that previous results could be explained by biases such as selection bias and uncontrolled confounding and provides information on how a trial such as the MERINO trial may have performed in the NHS.

Original language	English
Article number	e0268807
Pages (from-to)	e0268807
Journal	PLOS ONE
Volume	17
Issue number	5
DOIs	https://doi.org/10.1371/journal.pone.0268807
Publication status	Published - 20 May 2022

Bibliographical note

Funding Information:
This National Institute for Health Research (NIHR) Programme Grants for Applied Research funded the BSI-FOO and RAPIDO studies (RP-PG-0707-10043). The British Heart Foundation and NIHR Bristol Biomedical Research Unit for Cardiovascular Disease and North Bristol Charitable Funds funded some staff time (JH, CR, RE). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
Copyright: © 2022 Evans et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Keywords

Anti-Bacterial Agents/pharmacology
Escherichia coli
Humans
Meropenem/therapeutic use
Piperacillin, Tazobactam Drug Combination/therapeutic use
Sepsis/diagnosis

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title = "Emulating the MERINO randomised control trial using data from an observational cohort and trial of rapid diagnostic (BSI-FOO)",

abstract = "OBJECTIVE: The aim of this study was to emulate the MERINO trial of piperacillin-tazobactam vs meropenem for the definitive treatment of bloodstream infection (BSI) caused by ceftriaxone-nonsusceptible E coli or Klebsiella spp.METHODS: Data from an observational study of BSI and a randomised controlled trial of a rapid diagnostic in BSI were used to emulate the MERINO trial. The primary outcome of the emulated trial was 28-day mortality after blood culture. Outcomes were compared using logistic regression adjusted for propensity score for emulated intervention.RESULTS: Of the 6,371 observational study and RCT participants, 1,968 had a bloodstream infection with E. coli or Klebsiella spp. of which 121 met the eligibility criteria. In the emulated trial, a total of 14/82 patients (17.1\%) allocated to piperacillin-tazobactam met the primary outcome compared with 6/39 (15.4\%) in the meropenem group (unadjusted odds ratio 1.13 (95\% CI 0.40 to 3.21)). After adjustment for propensity score, the odds ratio increased to 1.31 (95\% CI 0.40 to 4.26). This difference is in the same direction but of a smaller magnitudethan observed in the MERINO trial, where 30-day mortality was met by 23/187 patients (12.3\%) in the piperacillin-tazobactam and 7/191 (3.7\%) in the meropenem group (unadjusted odds ratio of 3.69 (95\% CI 1.48 to 10.41)).CONCLUSIONS: The mortality rate in an emulated trial population was more than double the mortality rate in the MERINO trial. The methodology used attempts to address the concern that previous results could be explained by biases such as selection bias and uncontrolled confounding and provides information on how a trial such as the MERINO trial may have performed in the NHS.",

keywords = "Anti-Bacterial Agents/pharmacology, Escherichia coli, Humans, Meropenem/therapeutic use, Piperacillin, Tazobactam Drug Combination/therapeutic use, Sepsis/diagnosis",

author = "Evans, \{Rebecca N\} and Jessica Harris and Rogers, \{Chris A\} and Alasdair MacGowan",

note = "Funding Information: This National Institute for Health Research (NIHR) Programme Grants for Applied Research funded the BSI-FOO and RAPIDO studies (RP-PG-0707-10043). The British Heart Foundation and NIHR Bristol Biomedical Research Unit for Cardiovascular Disease and North Bristol Charitable Funds funded some staff time (JH, CR, RE). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: Copyright: {\textcopyright} 2022 Evans et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

year = "2022",

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doi = "10.1371/journal.pone.0268807",

language = "English",

volume = "17",

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T1 - Emulating the MERINO randomised control trial using data from an observational cohort and trial of rapid diagnostic (BSI-FOO)

AU - Evans, Rebecca N

AU - Harris, Jessica

AU - Rogers, Chris A

AU - MacGowan, Alasdair

N1 - Funding Information: This National Institute for Health Research (NIHR) Programme Grants for Applied Research funded the BSI-FOO and RAPIDO studies (RP-PG-0707-10043). The British Heart Foundation and NIHR Bristol Biomedical Research Unit for Cardiovascular Disease and North Bristol Charitable Funds funded some staff time (JH, CR, RE). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: Copyright: © 2022 Evans et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2022/5/20

Y1 - 2022/5/20

N2 - OBJECTIVE: The aim of this study was to emulate the MERINO trial of piperacillin-tazobactam vs meropenem for the definitive treatment of bloodstream infection (BSI) caused by ceftriaxone-nonsusceptible E coli or Klebsiella spp.METHODS: Data from an observational study of BSI and a randomised controlled trial of a rapid diagnostic in BSI were used to emulate the MERINO trial. The primary outcome of the emulated trial was 28-day mortality after blood culture. Outcomes were compared using logistic regression adjusted for propensity score for emulated intervention.RESULTS: Of the 6,371 observational study and RCT participants, 1,968 had a bloodstream infection with E. coli or Klebsiella spp. of which 121 met the eligibility criteria. In the emulated trial, a total of 14/82 patients (17.1%) allocated to piperacillin-tazobactam met the primary outcome compared with 6/39 (15.4%) in the meropenem group (unadjusted odds ratio 1.13 (95% CI 0.40 to 3.21)). After adjustment for propensity score, the odds ratio increased to 1.31 (95% CI 0.40 to 4.26). This difference is in the same direction but of a smaller magnitudethan observed in the MERINO trial, where 30-day mortality was met by 23/187 patients (12.3%) in the piperacillin-tazobactam and 7/191 (3.7%) in the meropenem group (unadjusted odds ratio of 3.69 (95% CI 1.48 to 10.41)).CONCLUSIONS: The mortality rate in an emulated trial population was more than double the mortality rate in the MERINO trial. The methodology used attempts to address the concern that previous results could be explained by biases such as selection bias and uncontrolled confounding and provides information on how a trial such as the MERINO trial may have performed in the NHS.

AB - OBJECTIVE: The aim of this study was to emulate the MERINO trial of piperacillin-tazobactam vs meropenem for the definitive treatment of bloodstream infection (BSI) caused by ceftriaxone-nonsusceptible E coli or Klebsiella spp.METHODS: Data from an observational study of BSI and a randomised controlled trial of a rapid diagnostic in BSI were used to emulate the MERINO trial. The primary outcome of the emulated trial was 28-day mortality after blood culture. Outcomes were compared using logistic regression adjusted for propensity score for emulated intervention.RESULTS: Of the 6,371 observational study and RCT participants, 1,968 had a bloodstream infection with E. coli or Klebsiella spp. of which 121 met the eligibility criteria. In the emulated trial, a total of 14/82 patients (17.1%) allocated to piperacillin-tazobactam met the primary outcome compared with 6/39 (15.4%) in the meropenem group (unadjusted odds ratio 1.13 (95% CI 0.40 to 3.21)). After adjustment for propensity score, the odds ratio increased to 1.31 (95% CI 0.40 to 4.26). This difference is in the same direction but of a smaller magnitudethan observed in the MERINO trial, where 30-day mortality was met by 23/187 patients (12.3%) in the piperacillin-tazobactam and 7/191 (3.7%) in the meropenem group (unadjusted odds ratio of 3.69 (95% CI 1.48 to 10.41)).CONCLUSIONS: The mortality rate in an emulated trial population was more than double the mortality rate in the MERINO trial. The methodology used attempts to address the concern that previous results could be explained by biases such as selection bias and uncontrolled confounding and provides information on how a trial such as the MERINO trial may have performed in the NHS.

KW - Anti-Bacterial Agents/pharmacology

KW - Escherichia coli

KW - Humans

KW - Meropenem/therapeutic use

KW - Piperacillin, Tazobactam Drug Combination/therapeutic use

KW - Sepsis/diagnosis

U2 - 10.1371/journal.pone.0268807

DO - 10.1371/journal.pone.0268807

M3 - Article (Academic Journal)

C2 - 35594284

SN - 1932-6203

VL - 17

SP - e0268807

JO - PLOS ONE

JF - PLOS ONE

IS - 5

M1 - e0268807

ER -

Emulating the MERINO randomised control trial using data from an observational cohort and trial of rapid diagnostic (BSI-FOO)

Abstract

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