https://journals.asm.org/doi/10.1128/aac.00725-23?s=09

ABSTRACT

Candida spp. are frequently encountered in specimens from ICUs. However, most of these detections represent colonization. Nevertheless, clinical practice shows that a considerable proportion of these patients will receive antifungal therapy (AT). β-(1→3)-D-glucan (BDG) and mannan are fungal biomarkers with high negative predictive values. We aimed to examine whether biomarker-guided discontinuation of AT can reduce the antifungal consumption. Therefore, we conducted a prospective, randomized intervention study between 1 April 2019 and 31 March 2020. All adult ICU patients with a newly started systemic AT but without fungal infection were eligible for inclusion. Enrolled patients were randomized into an intervention and a control group. In both groups, serum BDG and mannan were determined on days 1 and 2 of AT. If all measurements were negative, AT was discontinued in the intervention group. The primary endpoint was antifungal use. The study was terminated after 12 months. Until this time-point, 41 patients had been included. In the intervention group (n = 19), AT was stopped in only two patients because all others showed either positive BDG and/or mannan levels. One of these two patients developed candidemia and AT had to be restarted. There was no significant difference in the primary and secondary endpoints. In summary, the strategy of using two negative BDG and mannan levels to stop AT failed to reduce antifungal consumption in our cohort. Indeed, there will inevitably be patients with invasive candidiasis in whom necessary AT is discontinued. The optimal patient population, biomarker set, and termination criteria are critical to the success of biomarker-based termination strategies.

Evaluation of a Biomarker-Guided Strategy for Discontinuation of Antifungal Therapy in ICU Patients

• Introduction:
  • Large point-prevalence studies show that ICU patients frequently receive antifungal therapy (AT) despite most detections representing colonization.
  • Antifungal overtreatment can lead to undesirable side effects, resistance, and increased expenses.
  • Biomarkers like β-(1→3)-D-glucan (BDG) and mannan have been evaluated for their diagnostic performance in candidemia.
  • Targeted use of biomarkers may help reduce antifungal consumption.
• Study Design:
  • Prospective, randomized intervention study conducted in three ICUs.
  • Included adult patients with newly started systemic AT but without fungal infection.
  • Patients randomized into intervention and control groups.
  • BDG and mannan levels measured on days 1 and 2 of AT.
  • Antifungal therapy discontinued in intervention group if all measurements were negative.
• Results:
  • 41 patients included until study termination after 12 months.
  • In the intervention group, AT was stopped in only two patients due to positive BDG and/or mannan levels.
  • No significant difference in antifungal use and other endpoints between intervention and control groups.
• Conclusion:
  • Biomarker-guided discontinuation of AT did not reduce antifungal consumption in the cohort.
  • Optimal patient population, biomarker set, and termination criteria are critical for successful biomarker-based termination strategies.
• Study Background:
  • Prospective, randomized intervention study
  • Evaluate a biomarker-guided strategy for early termination of antifungal therapy in ICU patients
• Patient Enrollment and Randomization:
  • Study enrolled 41 patients, randomized into intervention and control group
  • Baseline characteristics showed no significant differences between study groups
• Biomarker Results:
  • BDG and mannan positive in 73.2% and 45.5% of patients, respectively
  • 78.0% of patients had positive biomarkers on first and/or second day of therapy
• Study Endpoints:
  • Primary endpoint: no significant difference in consumption of antifungal drugs until day 28
  • Secondary outcomes: no significant differences in mortality, length of stay, and dialysis/ventilation support
  • Length of vasopressor support and costs for antifungal drugs/biomarker testing were higher in intervention group
• Importance of Additional Biomarker Measurement:
  • Determination on days 1 and 2 alone not sufficient
  • Additional measurement on day 3 would have prevented incorrect discontinuation of therapy
  • Two patients with first-time positive biomarkers on day 3 developed proven IC
• Comparison with Previous Studies:
  • In contrast to previous studies, biomarker-guided strategy did not lead to significant differences in endpoints
  • Previous studies showed reduced antifungal duration without increased IC or mortality
• Study Limitations:
  • Small sample size (41 patients)
  • Reasons for unexpected results and differences from previous studies unclear
  • Duration of vasopressor use significantly higher in intervention group
• Conclusion:
  • Biomarker-guided strategy did not result in significant differences in antifungal therapy and clinical outcomes
  • Further research needed to understand the reasons behind unexpected results
• High Positivity Rate of Biomarkers:
  • The high positivity rate of BDG (73%) and mannan (46%) biomarkers contributed to the failure of the diagnostic strategy to reduce antifungal consumption.
  • BDG levels can be elevated due to parenterally applied drugs, blood fractionation products, and the use of BDG-containing materials during surgery.
  • Long-term ICU patients and patients with serious underlying diseases and conditions also tend to have elevated BDG levels.
• Comparison with Existing Studies:
  • The study criteria for discontinuation of antifungal therapy in this research included two BDG and two mannan measurements for two consecutive days, different from previous studies.
  • The inclusion of classical diagnostic methods, like blood cultures, along with biomarkers is critical for the success of biomarker-based termination strategies.
• Limitations:
  • The study was conducted at a single center, and physicians in the intervention group were not blinded.
  • The study population was diverse, without specific restrictions on high risk for IC or sepsis.
  • A substantial number of excluded patients had previous BDG and mannan measurements, and some patients with putative IC were unnecessarily excluded.