Abstract
BackgroundInvasive 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.MethodsPatients 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.ResultsSixty-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.ConclusionsBDG 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 RegistrationClinical Trials.gov NCT00672841
Highlights
Invasive candidiasis (IC) is associated with high mortality, prolonged hospitalization and excess costs [1,2,3]
Most invasive Candida infections are due to C. albicans followed in frequency by C. glabrata, a species that is often fluconazole resistant, and other non-albicans Candida species [4,5,6]
Empiric fluconazole based on the presence of fever has little clinical impact [8] and adequate empiric therapy is received by less than 30% of patients despite the availability of newer antifungal drugs with broad spectrum activity [9]
Summary
The protocol for this trial and supporting CONSORT checklist are available as supporting information; see Checklist S1 and Protocol S1. Active Surveillance/preemptive Therapy Group BDG testing was performed at baseline and twice weekly in the ICU. Results were reported within 24 hours, but baseline measurements were not used to inform initiation of preemptive therapy. Blood cultures were obtained prior to initiation of preemptive therapy, with additional collections based on clinical indicators of infection. To assess BDG kinetics on therapy, serum specimens were collected every other day while subjects were receiving anidulafungin. A feasible sample size of 100 subjects was projected based on the number of eligible patients expected to be admitted to the ICU over a 1 year period. The primary outcome measures of interest were the feasibility of preemptive antifungal therapy, BDG test performance and anidulafungin safety/tolerability in an ICU population.
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