INHALE WP3, a multicentre, open-label, pragmatic randomised controlled trial assessing the impact of rapid, ICU-based, syndromic PCR, versus standard-of-care on antibiotic stewardship and clinical outcomes in hospital-acquired and ventilator-associated pneumonia

Virve I. Enne; Susan Stirling; Julie A. Barber; Juliet High; Charlotte Russell; David Brealey; Zaneeta Dhesi; Antony Colles; Suveer Singh; Robert Parker; Mark Peters; Benny P. Cherian; Peter Riley; Matthew Dryden; Ruan Simpson; Nehal Patel; Jane Cassidy; Daniel Martin; Ingeborg D. Welters; Valerie Page; Hala Kandil; Eleanor Tudtud; David Turner; Robert Horne; Justin O'Grady; Ann Marie Swart; David M. Livermore; Vanya Gant; INHALE WP3 Study 12 Group

doi:10.1007/s00134-024-07772-2

INHALE WP3, a multicentre, open-label, pragmatic randomised controlled trial assessing the impact of rapid, ICU-based, syndromic PCR, versus standard-of-care on antibiotic stewardship and clinical outcomes in hospital-acquired and ventilator-associated pneumonia

Virve I. Enne, Susan Stirling, Julie A. Barber, Juliet High, Charlotte Russell, David Brealey, Zaneeta Dhesi, Antony Colles, Suveer Singh, Robert Parker, Mark Peters, Benny P. Cherian, Peter Riley, Matthew Dryden, Ruan Simpson, Nehal Patel, Jane Cassidy, Daniel Martin, Ingeborg D. Welters, Valerie PageHala Kandil, Eleanor Tudtud, David Turner, Robert Horne, Justin O'Grady, Ann Marie Swart, David M. Livermore, Vanya Gant, INHALE WP3 Study 12 Group

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Abstract

Purpose: INHALE investigated the impact of seeking pathogens by PCR on antibiotic stewardship and clinical outcomes in hospital-acquired and ventilator-associated pneumonia (HAP and VAP).

Methods: This pragmatic multicentre, open-label RCT enrolled adults and children with suspected HAP and VAP at 14 ICUs. Patients were randomly allocated to standard of care, or rapid in-ICU syndromic PCR coupled with optional prescribing guidance. Co-primary outcomes were superiority in antibiotic stewardship at 24 h and non-inferiority in clinical cure of pneumonia 14 days post-randomisation. Secondary outcomes included mortality, ICU length of stay and evolution of clinical scores.

Results: 554 eligible patients were recruited from 5th July 2019 to 18th August 2021, with a COVID-enforced pause from 16th March 2020 and 9th July 2020. Data were analysed for 453 adults and 92 children (68.4% male; 31.6% female). ITT analysis showed 205/268 (76.5%) reviewable intervention patients receiving antibacterially appropriate and proportionate antibiotics at 24 h, versus 147/263 (55.9%) standard-of-care patients (estimated difference 21%; 95% CI 13–28%). However, only 152/268 (56.7%) intervention patients were deemed cured of pneumonia at 14 days, versus 171/265 (64.5%) standard-of-care patients (estimated difference − 6%, 95% CI − 15 to 2%; predefined non-inferiority margin -13%). Secondary mortality and ΔSOFA outcomes narrowly favoured the control arm, without clear statistical significance.

Conclusions: In-ICU PCR for pathogens resulted in improved antibiotic stewardship. However, non-inferiority was not demonstrated for cure of pneumonia at 14 days. Further research should focus on clinical effectiveness studies to elucidate whether antibiotic stewardship gains achieved by rapid PCR can be safely and advantageously implemented.

Original language	English
Pages (from-to)	272–286
Number of pages	15
Journal	Intensive Care Medicine
Volume	51
Early online date	17 Feb 2025
DOIs	https://doi.org/10.1007/s00134-024-07772-2
Publication status	Published - Feb 2025

Keywords

Antibiotic stewardship
Hospital-acquired pneumonia (HAP)
Molecular diagnostics
Point-of-care
Rapid PCR
Syndromic PCR
Ventilator-associated pneumonia (VAP)

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Enne, V. I., Stirling, S., Barber, J. A., High, J., Russell, C., Brealey, D., Dhesi, Z., Colles, A., Singh, S., Parker, R., Peters, M., Cherian, B. P., Riley, P., Dryden, M., Simpson, R., Patel, N., Cassidy, J., Martin, D., Welters, I. D., ... INHALE WP3 Study 12 Group (2025). INHALE WP3, a multicentre, open-label, pragmatic randomised controlled trial assessing the impact of rapid, ICU-based, syndromic PCR, versus standard-of-care on antibiotic stewardship and clinical outcomes in hospital-acquired and ventilator-associated pneumonia. Intensive Care Medicine, 51, 272–286. https://doi.org/10.1007/s00134-024-07772-2

Enne, Virve I. ; Stirling, Susan ; Barber, Julie A. et al. / INHALE WP3, a multicentre, open-label, pragmatic randomised controlled trial assessing the impact of rapid, ICU-based, syndromic PCR, versus standard-of-care on antibiotic stewardship and clinical outcomes in hospital-acquired and ventilator-associated pneumonia. In: Intensive Care Medicine. 2025 ; Vol. 51. pp. 272–286.

@article{c500f6b2e90c4cc0afbd3d9271a795ee,

title = "INHALE WP3, a multicentre, open-label, pragmatic randomised controlled trial assessing the impact of rapid, ICU-based, syndromic PCR, versus standard-of-care on antibiotic stewardship and clinical outcomes in hospital-acquired and ventilator-associated pneumonia",

abstract = "Purpose: INHALE investigated the impact of seeking pathogens by PCR on antibiotic stewardship and clinical outcomes in hospital-acquired and ventilator-associated pneumonia (HAP and VAP). Methods: This pragmatic multicentre, open-label RCT enrolled adults and children with suspected HAP and VAP at 14 ICUs. Patients were randomly allocated to standard of care, or rapid in-ICU syndromic PCR coupled with optional prescribing guidance. Co-primary outcomes were superiority in antibiotic stewardship at 24 h and non-inferiority in clinical cure of pneumonia 14 days post-randomisation. Secondary outcomes included mortality, ICU length of stay and evolution of clinical scores. Results: 554 eligible patients were recruited from 5th July 2019 to 18th August 2021, with a COVID-enforced pause from 16th March 2020 and 9th July 2020. Data were analysed for 453 adults and 92 children (68.4% male; 31.6% female). ITT analysis showed 205/268 (76.5%) reviewable intervention patients receiving antibacterially appropriate and proportionate antibiotics at 24 h, versus 147/263 (55.9%) standard-of-care patients (estimated difference 21%; 95% CI 13–28%). However, only 152/268 (56.7%) intervention patients were deemed cured of pneumonia at 14 days, versus 171/265 (64.5%) standard-of-care patients (estimated difference − 6%, 95% CI − 15 to 2%; predefined non-inferiority margin -13%). Secondary mortality and ΔSOFA outcomes narrowly favoured the control arm, without clear statistical significance. Conclusions: In-ICU PCR for pathogens resulted in improved antibiotic stewardship. However, non-inferiority was not demonstrated for cure of pneumonia at 14 days. Further research should focus on clinical effectiveness studies to elucidate whether antibiotic stewardship gains achieved by rapid PCR can be safely and advantageously implemented.",

keywords = "Antibiotic stewardship, Hospital-acquired pneumonia (HAP), Molecular diagnostics, Point-of-care, Rapid PCR, Syndromic PCR, Ventilator-associated pneumonia (VAP)",

author = "Enne, {Virve I.} and Susan Stirling and Barber, {Julie A.} and Juliet High and Charlotte Russell and David Brealey and Zaneeta Dhesi and Antony Colles and Suveer Singh and Robert Parker and Mark Peters and Cherian, {Benny P.} and Peter Riley and Matthew Dryden and Ruan Simpson and Nehal Patel and Jane Cassidy and Daniel Martin and Welters, {Ingeborg D.} and Valerie Page and Hala Kandil and Eleanor Tudtud and David Turner and Robert Horne and Justin O'Grady and Swart, {Ann Marie} and Livermore, {David M.} and Vanya Gant and {INHALE WP3 Study 12 Group}",

note = "Data availability statement: The data dictionary and deidentified patient data analysed and presented in this study are available from NCTU following publication, on reasonable request and subject to appropriate data sharing agreements. The statistical analysis plan is publicly available at https://norwichctu.uea.ac.uk/inhale/.” Funding information: This research was funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research Programme (Reference Number: RP-PG-0514-20018). Infrastructure support was provided by the NIHR University College London and Imperial College London Biomedical Research Centres. The views expressed are those of the authors and not necessarily those of the NIHR, or the Department of Health and Social Care. The study funder had no role in design, data collection, data analysis, data interpretation, or writing of the manuscript. biom{\'e}rieux provided FilmArray Torch instruments, Pneumonia Panel tests and quality control materials free of charge. The manufacturer had no input into the conception, design, data analysis or interpretation of the study and no input into writing of the manuscript.",

year = "2025",

month = feb,

doi = "10.1007/s00134-024-07772-2",

language = "English",

volume = "51",

pages = "272–286",

journal = "Intensive Care Medicine",

issn = "0342-4642",

publisher = "Springer",

}

Enne, VI, Stirling, S, Barber, JA, High, J , Russell, C, Brealey, D, Dhesi, Z, Colles, A, Singh, S, Parker, R, Peters, M, Cherian, BP, Riley, P, Dryden, M, Simpson, R, Patel, N, Cassidy, J, Martin, D, Welters, ID, Page, V, Kandil, H, Tudtud, E, Turner, D, Horne, R, O'Grady, J , Swart, AM , Livermore, DM, Gant, V & INHALE WP3 Study 12 Group 2025, 'INHALE WP3, a multicentre, open-label, pragmatic randomised controlled trial assessing the impact of rapid, ICU-based, syndromic PCR, versus standard-of-care on antibiotic stewardship and clinical outcomes in hospital-acquired and ventilator-associated pneumonia', Intensive Care Medicine, vol. 51, pp. 272–286. https://doi.org/10.1007/s00134-024-07772-2

INHALE WP3, a multicentre, open-label, pragmatic randomised controlled trial assessing the impact of rapid, ICU-based, syndromic PCR, versus standard-of-care on antibiotic stewardship and clinical outcomes in hospital-acquired and ventilator-associated pneumonia. / Enne, Virve I.; Stirling, Susan; Barber, Julie A. et al.
In: Intensive Care Medicine, Vol. 51, 02.2025, p. 272–286.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - INHALE WP3, a multicentre, open-label, pragmatic randomised controlled trial assessing the impact of rapid, ICU-based, syndromic PCR, versus standard-of-care on antibiotic stewardship and clinical outcomes in hospital-acquired and ventilator-associated pneumonia

AU - Enne, Virve I.

AU - Stirling, Susan

AU - Barber, Julie A.

AU - High, Juliet

AU - Russell, Charlotte

AU - Brealey, David

AU - Dhesi, Zaneeta

AU - Colles, Antony

AU - Singh, Suveer

AU - Parker, Robert

AU - Peters, Mark

AU - Cherian, Benny P.

AU - Riley, Peter

AU - Dryden, Matthew

AU - Simpson, Ruan

AU - Patel, Nehal

AU - Cassidy, Jane

AU - Martin, Daniel

AU - Welters, Ingeborg D.

AU - Page, Valerie

AU - Kandil, Hala

AU - Tudtud, Eleanor

AU - Turner, David

AU - Horne, Robert

AU - O'Grady, Justin

AU - Swart, Ann Marie

AU - Livermore, David M.

AU - Gant, Vanya

AU - INHALE WP3 Study 12 Group

N1 - Data availability statement: The data dictionary and deidentified patient data analysed and presented in this study are available from NCTU following publication, on reasonable request and subject to appropriate data sharing agreements. The statistical analysis plan is publicly available at https://norwichctu.uea.ac.uk/inhale/.” Funding information: This research was funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research Programme (Reference Number: RP-PG-0514-20018). Infrastructure support was provided by the NIHR University College London and Imperial College London Biomedical Research Centres. The views expressed are those of the authors and not necessarily those of the NIHR, or the Department of Health and Social Care. The study funder had no role in design, data collection, data analysis, data interpretation, or writing of the manuscript. biomérieux provided FilmArray Torch instruments, Pneumonia Panel tests and quality control materials free of charge. The manufacturer had no input into the conception, design, data analysis or interpretation of the study and no input into writing of the manuscript.

PY - 2025/2

Y1 - 2025/2

N2 - Purpose: INHALE investigated the impact of seeking pathogens by PCR on antibiotic stewardship and clinical outcomes in hospital-acquired and ventilator-associated pneumonia (HAP and VAP). Methods: This pragmatic multicentre, open-label RCT enrolled adults and children with suspected HAP and VAP at 14 ICUs. Patients were randomly allocated to standard of care, or rapid in-ICU syndromic PCR coupled with optional prescribing guidance. Co-primary outcomes were superiority in antibiotic stewardship at 24 h and non-inferiority in clinical cure of pneumonia 14 days post-randomisation. Secondary outcomes included mortality, ICU length of stay and evolution of clinical scores. Results: 554 eligible patients were recruited from 5th July 2019 to 18th August 2021, with a COVID-enforced pause from 16th March 2020 and 9th July 2020. Data were analysed for 453 adults and 92 children (68.4% male; 31.6% female). ITT analysis showed 205/268 (76.5%) reviewable intervention patients receiving antibacterially appropriate and proportionate antibiotics at 24 h, versus 147/263 (55.9%) standard-of-care patients (estimated difference 21%; 95% CI 13–28%). However, only 152/268 (56.7%) intervention patients were deemed cured of pneumonia at 14 days, versus 171/265 (64.5%) standard-of-care patients (estimated difference − 6%, 95% CI − 15 to 2%; predefined non-inferiority margin -13%). Secondary mortality and ΔSOFA outcomes narrowly favoured the control arm, without clear statistical significance. Conclusions: In-ICU PCR for pathogens resulted in improved antibiotic stewardship. However, non-inferiority was not demonstrated for cure of pneumonia at 14 days. Further research should focus on clinical effectiveness studies to elucidate whether antibiotic stewardship gains achieved by rapid PCR can be safely and advantageously implemented.

AB - Purpose: INHALE investigated the impact of seeking pathogens by PCR on antibiotic stewardship and clinical outcomes in hospital-acquired and ventilator-associated pneumonia (HAP and VAP). Methods: This pragmatic multicentre, open-label RCT enrolled adults and children with suspected HAP and VAP at 14 ICUs. Patients were randomly allocated to standard of care, or rapid in-ICU syndromic PCR coupled with optional prescribing guidance. Co-primary outcomes were superiority in antibiotic stewardship at 24 h and non-inferiority in clinical cure of pneumonia 14 days post-randomisation. Secondary outcomes included mortality, ICU length of stay and evolution of clinical scores. Results: 554 eligible patients were recruited from 5th July 2019 to 18th August 2021, with a COVID-enforced pause from 16th March 2020 and 9th July 2020. Data were analysed for 453 adults and 92 children (68.4% male; 31.6% female). ITT analysis showed 205/268 (76.5%) reviewable intervention patients receiving antibacterially appropriate and proportionate antibiotics at 24 h, versus 147/263 (55.9%) standard-of-care patients (estimated difference 21%; 95% CI 13–28%). However, only 152/268 (56.7%) intervention patients were deemed cured of pneumonia at 14 days, versus 171/265 (64.5%) standard-of-care patients (estimated difference − 6%, 95% CI − 15 to 2%; predefined non-inferiority margin -13%). Secondary mortality and ΔSOFA outcomes narrowly favoured the control arm, without clear statistical significance. Conclusions: In-ICU PCR for pathogens resulted in improved antibiotic stewardship. However, non-inferiority was not demonstrated for cure of pneumonia at 14 days. Further research should focus on clinical effectiveness studies to elucidate whether antibiotic stewardship gains achieved by rapid PCR can be safely and advantageously implemented.

KW - Antibiotic stewardship

KW - Hospital-acquired pneumonia (HAP)

KW - Molecular diagnostics

KW - Point-of-care

KW - Rapid PCR

KW - Syndromic PCR

KW - Ventilator-associated pneumonia (VAP)

UR - http://www.scopus.com/inward/record.url?scp=86000470045&partnerID=8YFLogxK

U2 - 10.1007/s00134-024-07772-2

DO - 10.1007/s00134-024-07772-2

M3 - Article

SN - 0342-4642

VL - 51

SP - 272

EP - 286

JO - Intensive Care Medicine

JF - Intensive Care Medicine

ER -

Enne VI, Stirling S, Barber JA, High J , Russell C, Brealey D et al. INHALE WP3, a multicentre, open-label, pragmatic randomised controlled trial assessing the impact of rapid, ICU-based, syndromic PCR, versus standard-of-care on antibiotic stewardship and clinical outcomes in hospital-acquired and ventilator-associated pneumonia. Intensive Care Medicine. 2025 Feb;51:272–286. Epub 2025 Feb 17. doi: 10.1007/s00134-024-07772-2

INHALE WP3, a multicentre, open-label, pragmatic randomised controlled trial assessing the impact of rapid, ICU-based, syndromic PCR, versus standard-of-care on antibiotic stewardship and clinical outcomes in hospital-acquired and ventilator-associated pneumonia

Abstract

Keywords

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