Discussion
In this multicenter randomized trial, BDG guidance in critically ill patients with sepsis or septic shock and at high risk for ICI resulted in a more frequent and earlier initiation of antifungal therapy but did not improve 28-day mortality. None of the pre-defined subgroups showed a benefit from the BDG guided early antifungal therapy. However, we observed a higher antifungal free survival at day 28 in the control group compared to the BDG-group. Thus, BDG-guided patients were more likely to receive antifungal therapy and thereby might generate higher costs for antifungal therapy.
International guidelines [
5‐
7] recommend antifungal therapy in critically ill patients without proven Candida infection but with inherent risk factors. This recommendation is based on the high risk of developing ICI [
18,
22] and the high mortality rate in case of untreated ICI [
4] in this patient population. Some studies suggested a benefit for risk-based antifungal therapy [
23,
24] while other randomized controlled trials did not show a benefit for such an approach [
12,
25‐
27]. Our study now demonstrates that a BDG-guided initiation of early antifungal therapy was not superior to a wait-and-see culture-based approach in a sepsis population with a high risk of ICI.
Specificity of BDG was low in our study. Various factors have been discussed for triggering false positive BDG results including administration of antimicrobials [
28], blood products including albumin [
29], and immunoglobulins [
30], all of which may be applied in the care of sepsis patients. However, significance of these factors is not undisputed [
31]. Previous abdominal surgery was the most prevalent risk factor predisposing for ICI in our trial. However, open gut surgery results in elevated serum BDG concentrations for up to 5 days which might have impacted our BDG-measurements [
32]. Although BDG was eliminated within 4 days in pediatric patients [
33], animal experiments described a BDG-clearance of 9 days [
34]. The most recent Cochrane analysis concluded that it remains unclear whether BDG can identify ICI early [
35]. This lack of specificity likely caused an overuse of antifungals in the BDG-group as many patients without microbiological proof of ICI were treated without having a benefit. We aimed to improve BDG-specificity by excluding patients treated with immunoglobulins [
30] or cardiopulmonary bypass surgery [
36] and by requiring two positive BDG measurements from two consecutive days [
37,
38]. Although a BDG cut-off of 80 pg/mL has been successfully used to diagnose candidemia and intraabdominal candidiasis [
8,
39,
40], a higher cut-off such as 200 pg/mL has been suggested to increase specificity [
41]. Sensitivity was only 54.3% in our study. A sensitivity as low as 20% has been observed in several studies [
35] and may be associated with a low pathogen load [
39]. Current data rather suggest that BDG can be used as a surrogate for withdrawal of empirically started antifungal treatment rather than early initiation [
10,
11,
42].
Our sample size calculation was based on a mortality rate of 49.8% considering the high-risk profile of this patient population [
14]. However, the mortality rate in the control group was 30.5% and, thereby, lower than expected. This might be partly explained by the high frequency of
C. albicans-infections being associated with a lower mortality than infections with
C. glabrata or
C. krusei [
43]. In addition, our inclusion criteria aimed for a patient population with a high risk for ICI, but surprisingly, we only observed fifteen cases of proven candidemia, 48 patients with ICI and a low Candida colonization rate. A low rate of Candida colonization is associated with lower risk for developing ICI [
44]. This was accompanied by a low positivity rate of the Candida-PCR. Therefore, the inclusion criteria did not result in a pre-selection of a population with high risk of ICI, and BDG may thus not unfold its full diagnostic benefit. Interestingly, this observation does not align with studies with a similar patient profile but a higher proportion of patients with candidemia [
11,
40,
45]. Prediction of ICI solely based on risk factors may be too inaccurate to select patients for antifungal therapy.
Strengths and Limitations
The strengths of our trial include the randomized, controlled design, and its multicenter approach. The patients were efficiently enrolled shortly after onset of sepsis. Randomization resulted in an equal distribution of possible confounders between the two groups. Our trial achieved a sufficient separation between the groups regarding timing and frequency of antifungal therapy. Nevertheless, the trial also had limitations. Quality of BDG measurement required a central lab. Compared to in-house measurement, this approach resulted in a delay of measurement and reporting despite an established express delivery service. We increased the time window for recruitment from 12 to 24 h to facilitate sufficient enrollment. Both factors possibly inflicted a delay in antifungal therapy to the disadvantage of the BDG group. The strict time window and the exclusion criteria caused an enrolment rate of 14.7% of the screened patients. Such a low rate might affect the generalizability of the trial. We had a significant number of protocol deviations mainly addressing the duration of the antifungal therapy in the BDG group. The lower mortality in the BDG-group compared to the control group in the per-protocol analysis suggests that an improvement in algorithm adherence might have impacted the outcome. However, a per-protocol-analysis does not maintain internal validity as obtained by randomization and adequate sample size. Frequency of ICI was unexpectedly low. BDG-guidance might perform better in a study population with a higher rate of ICI. The investigated intervention did not allow for blinding. Therefore, this trial may be affected by performance and detection bias.
Conclusion
Early administration of antifungal therapy guided by serum BDG did not provide an advantage over standard of care as measured by 28-day mortality among critically ill patients with sepsis. These data do not support BDG guidance for initiation of antifungal therapy in this patient population if the observed rate of ICI is reasonably low. A possible benefit of serial BDG measurement in a more selected population at risk needs to be addressed in future studies.
Acknowledgements
The SepNet study group: Ulrich Jaschinski (University Hospital Augsburg, Dept. of Anesthesiology and Surgical Intensive Care Medicine, Augsburg), Christian Putensen (University Hospital Bonn Division of Intensive Care Medicine, Dept. of Anesthesiology and Intensive Care Medicine, Bonn), Klaus Kogelmann, Matthias Drüner (Hospital Emden, Dept. of Anesthesiology and Intensive Care Medicine, Emden), Ixchel Castellanos, Stefanie Schmidt, Andreas Wehrfritz, Diana Kränzlein (University Hospital Erlangen, Dept. of Anesthesiology, Erlangen), Jürgen Held (Universitätsklinikum Erlangen und Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Erlangen), Kai Zacharowski, Haitham Mutlak, Simone Lindau, Carolin Wiedenbeck (University Hospital Frankfurt, Dept. of Anesthesiology, Intensive Care Medicine, and Pain Therapy, Frankfurt), Onnen Mörer (Dept. of Anesthesiology, University Medical Center, Georg-August-University Göttingen, Göttingen), Sven-Olaf Kuhn, Matthias Gründling (University Hospital Greifswald, Dept. of Anesthesiology and Intensive Care Medicine, Greifswald), Stephan Kluge, Geraldine de Heer, Dominik Jarczak (University Hospital Hamburg-Eppendorf, Dept. of Intensive Care Medicine, Hamburg), Johann Motsch, Daniel Richter, Markus A. Weigand (University Hospital Heidelberg, Dept. of Anesthesiology, Heidelberg), Frank Bloos, Michael Bauer, Daniel Thomas-Rüddel (Jena University Hospital, Dept. of Anesthesiology and Intensive Care Medicine, Center for Sepsis Control & Care (CSCC), Jena), Peter Schlattmann, Thomas Lehmann (Jena University Hospital, Institute of Medical Statistics, Computer Sciences and Data Science, Jena), Norbert Weiler, Dirk Schädler (University Medical Center Kiel, Dept. of Anesthesiology and Intensive Care Medicine, Kiel), Oliver A. Cornely (University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Excellence Center for Medical Mycology (ECMM), Cologne, Germany; University of Cologne, Faculty of Medicine and University Hospital Cologne, Chair Translational Research, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany; University of Cologne, Faculty of Medicine and University Hospital Cologne, Clinical Trials Centre Cologne (ZKS Köln), Cologne, Germany; German Centre for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany), Philipp Simon, Gunther Hempel (University of Leipzig Medical Centre, Dept. of Anesthesiology and Intensive Care Medicine, Leipzig), Raphael Weiss, Alexander Zarbock (University Hospital Münster, Dept. of Anesthesiology, Surgical Intensive Care Medicine and Pain Therapy, Münster), Ulf Günther, Georg Rohe (Klinikum Oldenburg, University Clinic of Anesthesiology, Intensive Care, Emergency Medicine and Pain Therapy, Oldenburg), Andreas Weyland (Carl von Ossietzky Universität Oldenburg, Research Center Neurosensory Science, Oldenburg), Oliver Kurzai, Grit Walter (Julius Maximilians University Würzburg, Institute for Hygiene and Microbiology, Würzburg), Patrick Meybohm, Philipp Helmer (University Hospital Wuerzburg , Dept. of Anesthesiology, Emergency and Pain Medicine, Würzburg).
Declarations
Conflicts of interest
FB received honoraria for an expert board meeting by Baxter. Prof. Cornely reports grants or contracts from Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867), F2G, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, Scynexis; Consulting fees from Amplyx, Biocon, Biosys, Cidara, Da Volterra, Gilead, Matinas, MedPace, Menarini, Molecular Partners, MSG-ERC, Noxxon, Octapharma, PSI, Scynexis, Seres; Honoraria for lectures from Abbott, Al-Jazeera Pharmaceuticals, Astellas, Grupo Biotoscana/United Medical/Knight, Hikma, MedScape, MedUpdate, Merck/MSD, Mylan, Pfizer; Payment for expert testimony from Cidara; Participation on a Data Safety Monitoring Board or Advisory Board from Actelion, Allecra, Cidara, Entasis, IQVIA, Jannsen, MedPace, Paratek, PSI, Shionogi; A pending patent currently reviewed at the German Patent and Trade Mark Office; Other interests from DGHO, DGI, ECMM, ISHAM, MSG-ERC, Wiley. JH received grants and speaker honoraria from Pfizer, speaker honoraria from Gilead and consumables/test kits from Associates of Cape Cod. SK received research support from Cytosorbents and Daiichi Sankyo. He also received lecture fees from Astra, Bard, Baxter, Biotest, Cytosorbents, Daiichi Sankyo, Fresenius Medical Care, Gilead, Mitsubishi Tanabe Pharma, MSD, Pfizer, Philips and Zoll. He received consultant fees from Fresenius, Gilead, MSD and Pfizer. KK received honoraria for lecturing from Cytosorbents, Fresenius and Sedana. CP received lecture fees from Astra, C.R.Bard, Baxter, Biotest, Cytosorbents, Daiichi Sankyo, Fresenius, Gilead, Mitsubishi Tanabe Pharma, MSD, Pfizer, Philips and Zoll. He received consultant fees from Bayer, Fresenius, Gilead, MSD and Pfizer. He also received consultant fees from Messer, Pluristem, and Sedana and received lecture fees from Dräger Med. Inc. and Medronic. OM received honoraria for lectures during workshops on hemodynamic monitoring, supported by Pulsion (Maquet Critical Care) and for two lectures during industrial sessions at national congresses (HillRom, HepaWash); Unrestricted Research Grant from CSL Behring. DR has received support for attending meetings and/or travels from Gilead Sciences Inc., MSD, Pfizer. AW reported receiving honoraria for lecturing from Getinge and receiving personal fees from TEVA for consulting. No other disclosures were reported.
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