Biomarker-guided antibiotic stewardship in suspected ventilator-associated pneumonia (VAPrapid2): a randomised controlled trial and process evaluation

Abstract

Background Ventilator-associated pneumonia is the most common intensive care unit (ICU)-acquired infection, yet accurate diagnosis remains difficult, leading to overuse of antibiotics. Low concentrations of IL-1β and IL-8 in bronchoalveolar lavage fluid have been validated as effective markers for exclusion of ventilator-associated pneumonia. The VAPrapid2 trial aimed to determine whether measurement of bronchoalveolar lavage fluid IL-1β and IL-8 could effectively and safely improve antibiotic stewardship in patients with clinically suspected ventilator-associated pneumonia. Methods VAPrapid2 was a multicentre, randomised controlled trial in patients admitted to 24 ICUs from 17 National Health Service hospital trusts across England, Scotland, and Northern Ireland. Patients were screened for eligibility and included if they were 18 years or older, intubated and mechanically ventilated for at least 48 h, and had suspected ventilator-associated pneumonia. Patients were randomly assigned (1:1) to biomarker-guided recommendation on antibiotics (intervention group) or routine use of antibiotics (control group) using a web-based randomisation service hosted by Newcastle Clinical Trials Unit. Patients were randomised using randomly permuted blocks of size four and six and stratified by site, with allocation concealment. Clinicians were masked to patient assignment for an initial period until biomarker results were reported. Bronchoalveolar lavage was done in all patients, with concentrations of IL-1β and IL-8 rapidly determined in bronchoalveolar lavage fluid from patients randomised to the biomarker-based antibiotic recommendation group. If concentrations were below a previously validated cutoff, clinicians were advised that ventilator-associated pneumonia was unlikely and to consider discontinuing antibiotics. Patients in the routine use of antibiotics group received antibiotics according to usual practice at sites. Microbiology was done on bronchoalveolar lavage fluid from all patients and ventilator-associated pneumonia was confirmed by at least 10⁴ colony forming units per mL of bronchoalveolar lavage fluid. The primary outcome was the distribution of antibiotic-free days in the 7 days following bronchoalveolar lavage. Data were analysed on an intention-to-treat basis, with an additional per-protocol analysis that excluded patients randomly assigned to the intervention group who defaulted to routine use of antibiotics because of failure to return an adequate biomarker result. An embedded process evaluation assessed factors influencing trial adoption, recruitment, and decision making. This study is registered with ISRCTN, ISRCTN65937227, and ClinicalTrials.gov, NCT01972425. Findings Between Nov 6, 2013, and Sept 13, 2016, 360 patients were screened for inclusion in the study. 146 patients were ineligible, leaving 214 who were recruited to the study. Four patients were excluded before randomisation, meaning that 210 patients were randomly assigned to biomarker-guided recommendation on antibiotics (n=104) or routine us...

Performing Bronchoscopy in Times of the COVID-19 Pandemic: Practice Statement from an International Expert Panel

“…Given that associated bacterial, viral, and fungal coinfection should not be underestimated, the value of directed sampling as well as mycology and Galactomannan are important in these sickest patients [14]. Moreover, ventilator-associated pneumonia occurs in up to ∼30% patients, and accurate sampling can reduce unnecessary antibiotics [15]. − The cause of lobar collapse in the critical care setting is often multifactorial.…”

Will biomarkers be the answer for antibiotic stewardship?

“…The results of this trial-which did not show a difference in antibiotic-free days between the intervention (biomarker-guided recommendation on antibiotics) and control (routine use of antibiotics) groups-were disappointing, although unsurprising given existing knowledge about antibiotic prescribing behaviour and results of previous studies that have implemented diagnostic tests aiming to improve antibiotic stewardship. 3 Only 17 (17%) of 103 patients in the intervention group had the opportunity for early discontinuation of antibiotics based on the test results, and of these, only four had antibiotics stopped. The high rate of assay failure (21%) should also be mentioned, although this did not affect the overall results.…”

“…The high rate of assay failure (21%) should also be mentioned, although this did not affect the overall results. 3 Taking stock of other data that support early discontinuation of empirical antibiotics for suspected ventilator-associated pneumonia is important. Many routine clinical, radiographical, and laboratory assessments help identify whether a patient has ventilator-associated pneumonia, particularly when used in combination.…”

“…Small single-centre studies have shown successful cessation of antibiotics based on negative cultures or clinical pulmonary infection scores, but larger randomised trials of procalcitonin to guide discontinuation of antibiotics for ventilator-associated pneumonia have only been successful at shortening durations to accepted standards, rather than allowing early discontinuation. [5][6][7] Hellyer and colleagues 3 did not ascertain what other antibiotic stewardship strategies were in use at the study centres, which would have helped to contextualise the VAPrapid2 intervention.…”

“…In this landscape, why did the VAPrapid2 study have negative results? The authors did a process evaluation of the intervention and a major identified issue was "deeply entrenched prescribing characteristics", 3 which suggests that even the most precise and perfect test might not be used in practice without addressing these norms. This study was pragmatic, in that it did not require additional personnel time to reinforce the results of the testing, which is probably similar to what would happen in most routine practice settings.…”