Abstract
BackgroundThe 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/designThis 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.DiscussionBecause 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 registrationClinicaltrials.gov, NCT02734550. Registered 12 April 2016.
Highlights
The time to diagnosis of invasive Candida infection (ICI) is often too long to initiate timely antifungal therapy in patients with sepsis
Empiric antifungal therapy is not recommended by European guidelines
If culture results are negative for Candida spp., an initially started empirical antifungal therapy is continued only if serum BDG concentrations are above 80 pg/ml in both samples
Summary
European guidelines recommend antifungal therapy only in cases where Candida spp. are detected in physiologically sterile body fluids [10]. It might be helpful for patient management to have BDG guidance available during the whole ICU stay, this was beyond the financial scope of the study This is the first randomized controlled study to investigate whether BDG serum concentrations can guide a physician in supplementing the empiric antimicrobial therapy with an antifungal in critically ill patients with severe sepsis or septic shock. This clinical study will generate a solid evidence base for health-care providers and authors of guidelines for BDG in critically ill patients.
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