(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

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.

Diagnosis and Treatment of Candidemia in the Intensive Care Unit

“…102 Other RCTs evaluating the impact of BDG results on early therapeutic choices are ongoing or have been recently completed (NCT02734550, NCT03117439, NCT03090334, and NCT03538912). 103 Their results are awaited to ultimately firmly delineate the impact of BDG results on pre-emptive therapeutic choices in ICU patients with suspected candidemia.…”

Soluble Intercellular Adhesion Molecule- (sICAM-) 1, Thrombospondin-1, and Vinculin for the Identification of Septic Shock Patients Suffering from an Invasive Fungal Infection

“…This will hopefully be associated with the following most appreciated side effects: (1) primary cost savings (e.g., due to the waiving of expensive antifungal drugs and reduced hospital and ICU stay) and (2) reducing drug resistance rates (with secondary cost savings). Although the combined use of BDG and PCT was recently described to be suitable for early differential diagnosis between candidemia and bacteremia in intensive care units [22], the diagnostic value of BDG for IFI diagnosis is not free of doubts and subject of controversial discussions [37][38][39][40]. In line with that, BDG recently failed to be a suitable biomarker for reliable IFI diagnosis in septic shock within the presented cohort [21].…”

Risk Factors for Invasive Candida Infection in Critically Ill Patients

“…This would result in overtreatment for a large proportion, or it would require a complicated risk assessment incorporating multiple factors to treat only the highest risk patients. Strategies using biomarkers in addition to clinical risk factors 70 , 71 , 72 could be a solution for this dilemma and should be further assessed in large high-quality studies.…”