(1-3)-beta-D-glucan guided early termination of antifungal therapy in ICU patients

• Applicant: Privatdozent Dr. Jürgen Held
• Subject Area: Clinical Infectiology and Tropical Medicine ; Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 400727961

Background: Approximately 70 % of ICU patients receive antibiotics and as a consequence the extent of Candida colonization in these patients increases daily. With Candida spp. detected from various body sites the urge to start antifungal treatment in case of a clinical deterioration is high and up to 65 % of ICU patients receiving such therapy have no documented invasive fungal disease (IFD). However, unnecessary antifungal treatment is associated with potentially severe side effects, an increase in multiresistent Candida spp. and a significant financial burden for the health care system. (1-3)-beta-D-glucan (BDG) is a main cell wall component of various medically relevant fungi and can be detected in serum of patients with IFD. BDG has a high sensitivity and a negative predictive value of up to 99.9 % for the detection of IFD. In contrast, the specificity is only moderate and the positive predictive value is poor. In the past, multiple studies have used serum BDG measurement for screening of patients at risk of IFD or to initiate antifungal treatment in patients with suspected IFD. However, this approach has led to a significant overuse of antifungal drugs with potentially severe side effects for the patients. It is now recognized, that diagnostic strategies should utilize the high negative predictive value of BDG measurement to rule out IFD and to discontinue antifungal therapy in case of negative BDG results. Methods: We plan to conduct a prospective, randomized intervention study using the Fungitell assay for BDG measurement to guide an early termination of antifungal therapy in ICU patients. All patients with an antifungal therapy that was started in the ICU and without proven IFD are included in the study. The patients will be randomized to an intervention group and a control group. In both groups serum BDG will be determined on day 1 and 2 of antifungal therapy. If both measurements are negative the antifungal therapy will be discontinued in the intervention group but not in the control group. The decision when to stop the antifungal treatment in the control group is made at the discretion of the treating physician without knowledge of the BDG results. The patients will be followed-up for 28 days and clinical as well as microbiological data will be collected. The primary endpoint is antifungal drug usage in daily defined doses. Secondary endpoints are 28 day mortality, development of a proven IFD, side effects attributable to antifungal therapy, SOFA score in the ICU, length of stay in the ICU and length of hospitalization. Hypothesis: By using the negative predictive value of two consecutive negative BDG-values to discontinue antifungal therapy in patients without proven fungal infection we will be able to significantly reduce antifungal consumption without negative consequences for the patient.

• DFG Programme: Research Grants
• Co-Investigators: Dr. Ixchel Castellanos; Privatdozent Dr. Richard Strauß; Professor Dr. Carsten Willam