β-D-glucan surveillance with preemptive anidulafungin for invasive candidiasis in intensive care unit patients: a randomized pilot study

Abstract

Background: Invasive candidiasis (IC) is a devastating disease. While prompt antifungal therapy improves outcomes, empiric treatment based on the presence of fever has little clinical impact. Β-D-Glucan (BDG) is a fungal cell wall component detectable in the serum of patients with early invasive fungal infection (IFI). We evaluated the utility of BDG surveillance as a guide for preemptive antifungal therapy in at-risk intensive care unit (ICU) patients.

Methods: Patients admitted to the ICU for ≥ 3 days and expected to require at least 2 additional days of intensive care were enrolled. Subjects were randomized in 3:1 fashion to receive twice weekly BDG surveillance with preemptive anidulafungin in response to a positive test or empiric antifungal treatment based on physician preference.

Results: Sixty-four subjects were enrolled, with 1 proven and 5 probable cases of IC identified over a 2.5 year period. BDG levels were higher in subjects with proven/probable IC as compared to those without an IFI (117 pg/ml vs. 28 pg/ml; p<0.001). Optimal assay performance required 2 sequential BDG determinations of ≥ 80 pg/ml to define a positive test (sensitivity 100%, specificity 75%, positive predictive value 30%, negative predictive value 100%). In all, 21 preemptive and 5 empiric subjects received systemic antifungal therapy. Receipt of preemptive antifungal treatment had a significant effect on BDG concentrations (p< 0.001). Preemptive anidulafungin was safe and generally well tolerated with excellent outcome.

Conclusions: BDG monitoring may be useful for identifying ICU patients at highest risk to develop an IFI as well as for monitoring treatment response. Preemptive strategies based on fungal biomarkers warrant further study.

Trial registration: Clinical Trials.gov NCT00672841.

Figure 1. Study Subject Disposition.

Abbreviations: RX = treatment; TX = transplant; LFTs = liver function tests; ULN = upper limit of the normal reference range; IC = invasive candidiasis; IFI = invasive fungal infection; IA = invasive aspergillosis; BDG = β-D-Glucan; medical vs. surgical = ICU location.*5 subjects in the preemptive group had a positive BDG test(s) but did not receive anidulafungin; 2 were BDG positive only at baseline/screening, 2 were transitioned to comfort care and 1 was treated empirically with antifungal therapy before development of a single positive test. All 5 subjects in the empiric therapy group that received systemic antifungal therapy had at least 1 positive BDG test around the time antifungal treatment.

Figure 2. β-D-Glucan Positive Predictive Value as a function of varying Disease Prevalence.

The positive predictive value of two sequential β-D-Glucan test results ≥80 pg/ml is plotted relative to increasing invasive candidiasis prevalence. Sensitivity and specificity have been fixed at 100% and 75%, respectively.

Figure 3. β-D-Glucan Concentrations Over Time in Subjects Receiving Preemptive versus No Antifungal Therapy.

The antifungal treatment effect on glucan concentration over time was modeled as a linear trend. Abbreviations: 0 = subjects in the standard care group with at least one positive BDG test, but no systemic antifungal treatment; 2 = subjects in active surveillance group that were treated with preemptive anidulafungin; SE = standard error of the estimated glucan concentration slope.