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Reducing Antibiotic Treatment Duration for Ventilator-Associated Pneumonia - A Multicentre, Individually-Randomised, Open-Label, Non-Inferiority Trial (REGARD-VAP)

41 Pages Posted: 29 Jun 2023

See all articles by Yin Mo

Yin Mo

National University of Singapore (NUS) - Infectious Disease Translational Research Programme

Suchart Booraphun

Sunpasitthiprasong Hospital

Andrew Li

National University of Singapore (NUS) - Infectious Disease Translational Research Programme

Pornanan Domthong

Khon Kaen University - Khon Kaen Hospital

Gyan Kayastha

Patan Academy of Health Sciences - Patan Hospital

Yie Hui Lau

Tan Tock Seng Hospital - Anaesthesiology, Intensive Care and Pain Medicine

Ploenchan Chetchotisakd

Khon Kaen University - Srinagarind Hospital

Direk Limmathurotsakul

Mahidol University - Mahidol-Oxford Tropical Medicine Research Unit

Paul Anantharajah Tambyah

National University of Singapore (NUS) - Infectious Disease Translational Research Programme

Ben S. Cooper

University of Oxford - Centre for Tropical Medicine & Global Health

REGARD-VAP Investigators

Independent

More...

Abstract

Background: Ventilator-associated pneumonia (VAP) is associated with increased mortality, prolonged hospitalisation, and excessive antimicrobial use and resistance. Individualised short-course antibiotic treatment for VAP has not been evaluated in a randomised trial.

Methods: We conducted a randomised, non-inferiority trial in 39 intensive care units in Nepal, Singapore and Thailand from 25 May 2018 to 16 December 2022. We enrolled adults who met the US CDC National Healthcare Safety Network criteria and were administered culture-directed antibiotics. Participants were assessed until fever resolution and hemodynamic stability, then randomised to individualised short-course (as short as three or five days) or standard-of-care arms (at least eight days). Physicians were not masked to treatment allocation. The primary outcome was 60-day composite death or pneumonia recurrence. Analyses were based on both intention-to-treat and per-protocol populations. This study is registered with ClinicalTrials.gov, number NCT03382548.

Findings: Among 461 randomised patients (median age 64, 39% females), 460 were included in the intention-to-treat analysis after excluding one withdrawal (231 short-course, 229 standard-of-care). 436 patients received the allocated treatment and were included in the per-protocol population. 41% (95/231) in the individualised short-course arm experienced the primary outcome, compared with 43% (99/229) in the standard-of-care arm (risk difference -2·1%, one-sided 95% confidence interval (CI), −∞ to 5·9 %). Results were similar in the per-protocol population. The intervention reduced median antibiotic duration from 14 days (interquartile range (IQR) 10 to 21 days) to 6 days (IQR 5 to 7), and antibiotic side effects from 44% to 10% (risk difference -34·0%, 95% CI, -42·1 to -25·9%).

Interpretation: In adults with VAP, individualised shortened antibiotic duration guided by clinical response is non-inferior to longer durations in terms of 60-day mortality and pneumonia recurrence, and can substantially reduce antibiotic usage and side effects.

Trial Registration: The study is funded by the UK Medical Research Council/ Department for International Development (Grant reference: MR/K006924/1) and Singapore National Medical Research Council (Grant reference: CoSTAR-HS/ARGSeedGrant/2017/01 and MOH-CTGIIT18may- 0003). MY is supported by the Singapore National Medical Research Council Research Fellowship (Grant reference: NMRC/Fellowship/0051/2017). This study was also supported by the Wellcome Trust as part of the Wellcome Trust–Mahidol Oxford Tropical Medicine Research Programme (106698/Z/14/Z).

Funding: UK Medical Research Council; Singapore National Medical Research Counc.

Declaration of Interest: The authors have no conflicts of interests to declare.

Ethical Approval: The overall sponsor of the study was the University of Oxford. The Oxford Tropical Research Ethics Committee approval was obtained prior to applications to the respective local ethics committees (reference number OxTREC 40-17). Written informed consent was obtained from every participant, or the participant’s legal representative, or next-of-kin if the participant was sedated and did not have decision-making capacity. This trial protocol was developed in accordance with the SPIRIT 2013 Statement and CONSORT statement extension for "Non-inferiority and Equivalence Trials". The clinical trial was conducted in accordance with ICH Good Clinical Practice guidelines.

Keywords: Ventilator-associated pneumonia, Intensive care, Antibiotic duration, Antimicrobial resistance

Suggested Citation

Mo, Yin and Booraphun, Suchart and Li, Andrew and Domthong, Pornanan and Kayastha, Gyan and Lau, Yie Hui and Chetchotisakd, Ploenchan and Limmathurotsakul, Direk and Tambyah, Paul Anantharajah and Cooper, Ben S. and Investigators, REGARD-VAP, Reducing Antibiotic Treatment Duration for Ventilator-Associated Pneumonia - A Multicentre, Individually-Randomised, Open-Label, Non-Inferiority Trial (REGARD-VAP). Available at SSRN: https://ssrn.com/abstract=4492691 or http://dx.doi.org/10.2139/ssrn.4492691

Yin Mo (Contact Author)

National University of Singapore (NUS) - Infectious Disease Translational Research Programme ( email )

Suchart Booraphun

Sunpasitthiprasong Hospital ( email )

Andrew Li

National University of Singapore (NUS) - Infectious Disease Translational Research Programme ( email )

Pornanan Domthong

Khon Kaen University - Khon Kaen Hospital ( email )

Khon Kaen
Thailand

Gyan Kayastha

Patan Academy of Health Sciences - Patan Hospital ( email )

Yie Hui Lau

Tan Tock Seng Hospital - Anaesthesiology, Intensive Care and Pain Medicine ( email )

Ploenchan Chetchotisakd

Khon Kaen University - Srinagarind Hospital ( email )

Direk Limmathurotsakul

Mahidol University - Mahidol-Oxford Tropical Medicine Research Unit ( email )

Thailand

Paul Anantharajah Tambyah

National University of Singapore (NUS) - Infectious Disease Translational Research Programme ( email )

Ben S. Cooper

University of Oxford - Centre for Tropical Medicine & Global Health ( email )

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