(1,3)-β-D-glucan-based diagnosis of invasive Candida infection versus culture-based diagnosis in patients with sepsis and with an increased risk of invasive Candida infection (CandiSep): study protocol for a randomized controlled trial

Frank Bloos, Jürgen Held, Peter Schlattmann, Nicole Brillinger, Oliver Kurzai, Oliver A Cornely, Daniel Thomas-Rüddel, Frank Bloos, Jürgen Held, Peter Schlattmann, Nicole Brillinger, Oliver Kurzai, Oliver A Cornely, Daniel Thomas-Rüddel

Abstract

Background: The time to diagnosis of invasive Candida infection (ICI) is often too long to initiate timely antifungal therapy in patients with sepsis. Elevated serum (1,3)-β-D-glucan (BDG) concentrations have a high diagnostic sensitivity for detecting ICI. However, the clinical significance of elevated BDG concentrations is unclear in critically ill patients. The goal of this study is to investigate whether measurement of BDG in patients with sepsis and a high risk for ICI can be used to decrease the time to empiric antifungal therapy and thus, increase survival.

Methods/design: This prospective multicenter open randomized controlled trial is being conducted in 19 German intensive care units. All adult patients with severe sepsis or septic shock and an increased risk for ICI are eligible for enrolment. Risk factors are total parenteral nutrition, previous abdominal surgery, previous antimicrobial therapy, and renal replacement therapy. Patients with proven ICI or those already treated with systemic antifungal substances are excluded. Patients are allocated to a BDG or standard care group. The standard care group receives targeted antifungal therapy as necessary. In the BDG group, BDG serum samples are taken after randomization and 24 h later. Antifungal therapy is initiated if BDG is ≥80 pg/ml in at least one sample. We plan to enroll 312 patients. The primary outcome is 28-day mortality. Other outcomes include antifungal-free survival within 28 days after enrolment, time to antifungal therapy, and the diagnostic performance of BDG compared to other laboratory tests for early ICI diagnosis. The statistical analysis will be performed according to the intent-to-treat principle.

Discussion: Because of the high risk of death, American guidelines recommend empiric antifungal therapy in sepsis patients with a high risk of ICI despite the limited evidence for such a recommendation. In contrast, empiric antifungal therapy is not recommended by European guidelines. BDG may offer a way out of this dilemma since BDG potentially identifies patients in need of early antifungals. However, the evidence for such an approach is inconclusive. This clinical study will generate solid evidence for health-care providers and authors of guidelines for the use of BDG in critically ill patients.

Trial registration: Clinicaltrials.gov, NCT02734550 . Registered 12 April 2016.

Keywords: (1,3)-β-D-glucan; Biomarker; Early antifungal therapy; Invasive Candida infection; Sepsis; Septic shock.

Conflict of interest statement

Consent for publication

Not applicable.

Competing interests

We have read and understood the TRIALS policy on declarations of interests and declare the following interests. FB, DTR, and OK belong to the institution receiving public funding for the trial. FB has received lecture honoraria from Biosyn, Gilead, and CSL Behring. JH received royalties for lectures from MSD as well as lecture royalties and a research grant from Pfizer. OAC is an unpaid member of the European Confederation of Medical Mycology and of the European Fungal Infection Study Group of the European Society for Clinical Microbiology and Infectious Diseases, which are developing joint guidelines. OAC has received research grants from Actelion, Amplyx, Arsanis, Astellas, AstraZeneca, Basilea, Bayer, Cidara, Duke University (NIH UM1AI104681), F2G, Gilead, GSK, Leeds University, Matinas, Medicines Company, MedPace, Melinta, Merck/MSD, Miltenyi, Pfizer, Rempex, Roche, Sanofi Pasteur, Scynexis, and Seres. OAC is a consultant to Amplyx, Actelion, Astellas, Basilea, Cidara, Da Volterra, F2G, Gilead, Janssen, Matinas, Menarini, Merck/MSD, Paratek, PSI, Scynexis, Seres, Summit, Tetraphase, and Vical. OAC has received lecture honoraria from Astellas, Basilea, Gilead, Merck/MSD, and Pfizer. NB and PS report no conflicts of interest.

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Figures

Fig. 1
Fig. 1
Study flow chart. Microbiological samples were taken from multiple anatomic sites to assess Candida colonization. BDG (1,3)-β-D-glucan, ICI invasive Candida infection
Fig. 2
Fig. 2
Study procedures and assessments. ICU intensive care unit, SOFA sequential organ failure assessment; 1 maximum of 1 h after randomization; 2 22–26 h after randomization; 3 ≤6 h before and maximum of 3 h after randomization; 4 Sepsis criteria, routine biochemistry, microbiological results, medication, anti-infectious measures, and SOFA score; 5 As soon as all baseline microbiological results are available

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