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Randomised controlled trial and process evaluation of biomarker-guided antibiotic stewardship in suspected ventilator-associated pneumonia

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cam.issuedOnline2019-12-03
cam.orpheus.successThu Jan 30 10:42:03 GMT 2020 - The item has an open VoR version.
dc.contributor.authorHellyer, Thomas
dc.contributor.authorMcAuley, Daniel F
dc.contributor.authorWalsh, Timothy S
dc.contributor.authorAnderson, Niall
dc.contributor.authorConway Morris, Andrew
dc.contributor.authorSingh, Suveer
dc.contributor.authorDark, Paul
dc.contributor.authorRoy, Alistair I
dc.contributor.authorPerkins, Gavin D
dc.contributor.authorMcMullan, Ronan
dc.contributor.authorEmerson, Lydia M
dc.contributor.authorBlackwood, Bronagh
dc.contributor.authorWright, Stephen E
dc.contributor.authorKefala, Kallirroi
dc.contributor.authorO’Kane, Cecilia M
dc.contributor.authorBaudouin, Simon V
dc.contributor.authorPaterson, Ross L
dc.contributor.authorRostron, Anthony J
dc.contributor.authorAgus, Ashley
dc.contributor.authorBannard-Smith, Jonathan
dc.contributor.authorRobin, Nicole M
dc.contributor.authorWelters, Ingeborg D
dc.contributor.authorBassford, Christopher
dc.contributor.authorYates, Bryan
dc.contributor.authorSpencer, Craig
dc.contributor.authorLaha, Shondipon K
dc.contributor.authorHulme, Jonathan
dc.contributor.authorBonner, Stephen
dc.contributor.authorLinnett, Vanessa
dc.contributor.authorSonksen, Julian
dc.contributor.authorVan Den Broeck, Tina
dc.contributor.authorBoschman, Gert
dc.contributor.authorKeenan, James
dc.contributor.authorScott, Jonathan
dc.contributor.authorAllen, A Joy
dc.contributor.authorPhair, Glenn
dc.contributor.authorParker, Jennie
dc.contributor.authorBowett, Susan A
dc.contributor.authorSimpson, A John
dc.contributor.orcidConway Morris, Andrew [0000-0002-3211-3216]
dc.date.accessioned2019-08-08T23:30:28Z
dc.date.available2019-08-08T23:30:28Z
dc.date.issued2020-02
dc.description.abstractBACKGROUND. Ventilator-associated pneumonia (VAP) is the most common intensive care unit (ICU)-acquired infection, yet accurate diagnosis remains difficult, leading to overuse of antibiotics. Low concentrations of IL-1 and IL-8 in bronchoalveolar lavage (BAL) fluid have been validated as effective markers for excluding VAP. VAP-Rapid-2 sought to determine whether a rapid IL-1/IL-8 test could effectively and safely improve antibiotic stewardship in patients with clinically suspected VAP. METHODS. VAP-Rapid-2 was a multi-centre randomised controlled trial in 24 intensive care units in the United Kingdom. Patients with suspected VAP in 24 ICUs were randomised 1:1, via a web-based randomisation service, to a “biomarker-based recommendation on antibiotics” or “routine use of antibiotics”. Clinicians were blinded to randomisation for an initial period until the biomarker results were reported. Bronchoalveolar lavage (BAL) was performed in all patients, with concentrations of IL-1 and IL-8 rapidly determined in BAL fluid from patients randomised to the “biomarker-based antibiotic recommendation” arm. If concentrations were below a previously validated cut-off, clinicians were advised that VAP was unlikely and to consider discontinuing antibiotics. Patients in the “routine use of antibiotics” arm received antibiotics according to usual practice. Microbiology was performed on BAL fluid from all patients and VAP was confirmed by ≥104 colony forming units per mL of BAL fluid. The primary outcome measure was the distribution of antibiotic-free days (AFD) in the seven days following BAL. Data were analysed on an intention-to-treat basis, with an additional per-protocol analysis that excluded patients randomised to the intervention arm who defaulted to routine use of antibiotics due to failure to return an adequate biomarker result. An embedded process evaluation assessed factors influencing trial adoption, recruitment and decision making. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN: 65937227, and with ClinicalTrials.gov: NCT01972425. FINDINGS. The trial randomised the target number of 210 patients with suspected VAP. One patient was withdrawn by the clinical team prior to bronchoscopy and so was excluded from the intention-to-treat analysis (‘biomarker-guided recommendation on antibiotics’, n=103; ‘routine use of antibiotics’, n=106). Antibiotics were being used at baseline in 83 (n=103, 80·6%) patients in the intervention arm and 87 (n=106, 82·1%) patients in the control arm. The negative likelihood ratio of the IL-1/IL-8 test was 0·09. There was no difference in the frequency distribution of AFD at day seven (p=0·58). There were no between-group differences in AFD at day 14 (HR 1·13 [95% CI 0·83-1·54]), in AFD at day 28 (HR 1·01 [95% CI 0·73-1·40]) or in mortality at 28 days (OR 1·52 [95% CI 0·78-2·98]). BAL was associated with a small and transient increase in oxygen requirements. Established prescribing practices, reluctance for BAL, and dependence on a chain of trial-related procedures emerged as factors impairing trial processes. INTERPRETATION. Antibiotic use remains high in patients with suspected VAP. Antibiotic stewardship was not improved by a rapid, highly sensitive rule-out test. Prescribing culture, rather than poor test performance, may explain the lack of effect.
dc.description.sponsorshipThis publication presents independent research supported by the Health Innovation Challenge Fund (HICF-510-078; 094949/Z/10/X), a parallel funding partnership between the Department of Health and Wellcome Trust. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health or Wellcome Trust. The study was also supported by the NIHR Newcastle Biomedical Research Centre (IS-BRC-1215-20001). Dr Conway Morris is supported by a Clinical Research Career Development Fellowship from the Wellcome Trust (WT 2055214/Z/16/Z).
dc.identifier.doi10.17863/CAM.42581
dc.identifier.eissn2213-2619
dc.identifier.issn2213-2600
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/295526
dc.language.isoeng
dc.publisherElsevier
dc.publisher.urlhttp://dx.doi.org/10.1016/s2213-2600(19)30367-4
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rightsAttribution 4.0 International (CC BY)
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectAnti-Bacterial Agents
dc.subjectAntimicrobial Stewardship
dc.subjectBiomarkers
dc.subjectBronchoalveolar Lavage
dc.subjectBronchoalveolar Lavage Fluid
dc.subjectFemale
dc.subjectHumans
dc.subjectMale
dc.subjectMiddle Aged
dc.subjectPneumonia, Ventilator-Associated
dc.subjectProcess Assessment, Health Care
dc.subjectState Medicine
dc.subjectUnited Kingdom
dc.titleRandomised controlled trial and process evaluation of biomarker-guided antibiotic stewardship in suspected ventilator-associated pneumonia
dc.typeArticle
dcterms.dateAccepted2019-08-06
prism.publicationNameThe Lancet Respiratory Medicine
pubs.funder-project-idWellcome Trust (205214/Z/16/Z)
pubs.funder-project-idWellcome Trust (094949/Z/10/Z)
rioxxterms.licenseref.startdate2019-08-06
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1016/S2213-2600(19)30367-4

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