Will biomarkers be the answer for antibiotic stewardship?
Authors: Sarah B Doernberg
Journal: The Lancet Respiratory Medicine (2019)

Over 50% of patients in critical care settings receive antibiotics on any given day.1Zarb P Amadeo B Muller A et al.Identification of targets for quality improvement in antimicrobial prescribing: the web-based ESAC Point Prevalence Survey 2009.J Antimicrob Chemother. 2011; 66: 443-449Crossref PubMed Scopus (125) Google Scholar Because of the high incidence of resistant organisms, risk of inadequate empirical therapy in patients who are critically ill, and uncertainty of diagnosis in this setting, de-escalation of antibiotics poses a unique challenge. Therefore, clinicians tend to prescribe antibiotics expansively, even in the face of data suggesting appropriateness of narrower antibiotic courses or shorter durations.2Metlay JP Shea JA Asch DA Antibiotic prescribing decisions of generalists and infectious disease specialists: thresholds for adopting new drug therapies.Med Decis Making. 2002; 22: 498-505Crossref PubMed Scopus (13) Google Scholar Ventilator-associated pneumonia, a common indication for antibiotics in the intensive care unit, poses a major diagnostic challenge, often leading to indiscriminate antibiotic use. In The Lancet Respiratory Medicine, Thomas Hellyer and colleagues3Hellyer TP McAuley DF Walsh TS et al.Biomarker-guided antibiotic stewardship in suspected ventilator-associated pneumonia (VAPrapid2): a randomised controlled trial and process evaluation.Lancet Respir Med. 2019; (published online Dec 3)https://doi.org/10.1016/S2213-2600(19)30367-4Summary Full Text Full Text PDF PubMed Scopus (31) Google Scholar present the results of a randomised trial (VAPrapid2) designed to determine whether measurement of two previously validated inflammatory biomarkers (IL-1β and IL-8) from bronchoalveolar lavage fluid would allow for ventilator-associated pneumonia to be ruled out early so that antibiotics could be stopped safely. Although only 70 (33%) of 209 patients had confirmed ventilator-associated pneumonia according to the study definition, 170 (81%) received antibiotics for a median of 8 days in the 2 weeks after bronchoalveolar lavage. 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.3Hellyer TP McAuley DF Walsh TS et al.Biomarker-guided antibiotic stewardship in suspected ventilator-associated pneumonia (VAPrapid2): a randomised controlled trial and process evaluation.Lancet Respir Med. 2019; (published online Dec 3)https://doi.org/10.1016/S2213-2600(19)30367-4Summary Full Text Full Text PDF PubMed Scopus (31) Google Scholar 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.3Hellyer TP McAuley DF Walsh TS et al.Biomarker-guided antibiotic stewardship in suspected ventilator-associated pneumonia (VAPrapid2): a randomised controlled trial and process evaluation.Lancet Respir Med. 2019; (published online Dec 3)https://doi.org/10.1016/S2213-2600(19)30367-4Summary Full Text Full Text PDF PubMed Scopus (31) Google Scholar 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.4Klompas M Does this patient have ventilator-associated pneumonia.JAMA. 2007; 297: 1583-1593Crossref PubMed Scopus (235) Google Scholar The small number of existing studies that report on implementation of these assessments for antibiotic discontinuation have mixed results. 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.5Raman K Nailor MD Nicolau DP Aslanzadeh J Nadeau M Kuti JL Early antibiotic discontinuation in patients with clinically suspected ventilator-associated pneumonia and negative quantitative bronchoscopy cultures.Crit Care Med. 2013; 41: 1656-1663Crossref PubMed Scopus (62) Google Scholar, 6Singh N Rogers P Atwood C Wagener M Yu V Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit.Am J Respir Crit Care Med. 2000; 162: 505-511Crossref PubMed Scopus (847) Google Scholar, 7Stolz D Smyrnios N Eggimann P et al.Procalcitonin for reduced antibiotic exposure in ventilator-associated pneumonia: a randomised study.Eur Respir J. 2009; 34: 1364-1375Crossref PubMed Scopus (252) Google Scholar Hellyer and colleagues3Hellyer TP McAuley DF Walsh TS et al.Biomarker-guided antibiotic stewardship in suspected ventilator-associated pneumonia (VAPrapid2): a randomised controlled trial and process evaluation.Lancet Respir Med. 2019; (published online Dec 3)https://doi.org/10.1016/S2213-2600(19)30367-4Summary Full Text Full Text PDF PubMed Scopus (31) Google Scholar 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",3Hellyer TP McAuley DF Walsh TS et al.Biomarker-guided antibiotic stewardship in suspected ventilator-associated pneumonia (VAPrapid2): a randomised controlled trial and process evaluation.Lancet Respir Med. 2019; (published online Dec 3)https://doi.org/10.1016/S2213-2600(19)30367-4Summary Full Text Full Text PDF PubMed Scopus (31) Google Scholar 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. However, other studies of rapid diagnostic testing and interpretation of biomarkers have shown that antibiotic stewardship reinforcement is crucial for uptake of the test and action based on the results.8Banerjee R Teng CB Cunningham SA et al.Randomized trial of rapid multiplex polymerase chain reaction-based blood culture identification and susceptibility testing.Clin Infect Dis. 2015; 61: 1071-1080Crossref PubMed Scopus (291) Google Scholar, 9Timbrook TT Morton JB McConeghy KW Caffrey AR Mylonakis E LaPlante KL The effect of molecular rapid diagnostic testing on clinical outcomes in bloodstream infections: a systematic review and meta-analysis.Clin Infect Dis. 2017; 64: 15-23Crossref PubMed Scopus (250) Google Scholar Perhaps the biomarkers in this study would have been more effective if paired with an intervention from the local antibiotic stewardship team. Furthermore, given data suggesting routinely collected information might be adequate to rule out ventilator-associated pneumonia, a trial of rigorous implementation of a strategy to assist with de-escalation for this diagnosis, similar to the recently reported trial for algorithm-based management of staphylococcal bloodstream infection,10Holland TL Raad I Boucher HW et al.Effect of algorithm-based therapy vs usual care on clinical success and serious adverse events in patients with staphylococcal bacteremia: a randomized clinical trial.JAMA. 2018; 320: 1249-1258Crossref PubMed Scopus (38) Google Scholar would be informative. The incremental value of biomarkers beyond routinely available measurements is unclear and is an important factor to assess in future studies. Several limitations in the definitions of ventilator-associated pneumonia merit discussion. First, respiratory viruses, which were not tested, comprise a portion of the infection. Second, antibiotic treatment could commence several days before bronchoalveolar lavage culture, reducing sensitivity for both the culture and possibly the biomarkers. Thus, a subset of patients with ventilator-associated pneumonia might have been misclassified, warranting treatment for at least 7 days. Finally, the authors included common commensals such as Enterococcus and Candida, in the ventilator-associated pneumonia definition. Although the authors acknowledge that these organisms spark controversy, inclusion of them might have led to misclassification of patients. Ultimately, how ventilator-associated pneumonia was classified did change the results of this study. Where does this leave us? In the age of precision medicine, as more diagnostic tests to identify pathogens, the microbiome, and host response come to market, it is crucial that the study of implementation science and a deep understanding of what motivates antibiotic prescribing advance simultaneously. We might not need better biomarkers, but instead need more effective strategies to implement the knowledge we have into practice. Without these strategies we will be left with another test that will add cost but not value to the care we provide to patients. I report personal fees from Genentech and Basilea Pharmaceutica, outside of the submitted work. Biomarker-guided antibiotic stewardship in suspected ventilator-associated pneumonia (VAPrapid2): a randomised controlled trial and process evaluationAntibiotic use remains high in patients with suspected ventilator-associated pneumonia. Antibiotic stewardship was not improved by a rapid, highly sensitive rule-out test. Prescribing culture, rather than poor test performance, might explain this absence of effect. Full-Text PDF Open Access