ICU patients have a higher incidence of invasive Candida
infection than do those on general medical/surgical wards 
. Antifungal prophylaxis has been proposed as a way to prevent IC in high-risk groups, but no consensus on the optimal strategy exists 
. In terms of drug selection, the polyenes are limited by drug-associated toxicities and the azoles have been suspected of promoting a shift toward resistant non-albicans Candida
species. Alternatively, the echinocandins have broad spectrum activity, are well tolerated with minimal drug interactions, and would likely be effective as prophylaxis in the ICU setting 
Identifying ICU populations that are most likely to benefit from early interventions (i.e. the likelihood of IC exceeds 10% 
) is difficult. Risk-factor based prediction rules and the “Candida
score” consistently identify high-risk patients, but they remain imprecise. Risk classification schemes predicated on Candida
colonization, for example, are potentially flawed by the inherent variability in culture acquisition. Previous ICU prophylaxis studies that based enrollment on multiple IC risk-factors closed prematurely due to difficulties identifying eligible subjects 
. In addition, there is a general reluctance to enroll high-risk patients into placebo-controlled trials and/or to withhold empiric treatment from febrile patients already receiving broad spectrum antibiotics. Novel strategies are clearly needed.
Assays that detect fungal cell wall components in the blood of patients with early IFI are commercially available and have been used in Japan for many years. Attractive features of the FungitellTM
BDG assay as a screening test are its sensitivity for the detection of early infection 
and high negative predictive value 
. A few studies have evaluated the utility of serial BDG monitoring in the ICU 
, but none have used biomarker surveillance to inform early treatment decisions. The most recent report by Mohr et al., using the FDA approved cut-off of ≥80 pg/ml and institution-specific definitions of proven/probable IC, observed a BDG sensitivity and specificity of 91% and 57%, respectively 
. When the number of positive specimens required to make a diagnosis of proven IC was increased to two or three, the specificity increased without affecting sensitivity. These observations are similar to ours, and when taken in the context of previous studies 
, serve to bolster the potential diagnostic value of sequential positive BDG results. A quantitative correlation between BDG levels and treatment response has also been reported 
, which suggests that sequential monitoring on therapy could have prognostic value. We were unable to draw definitive conclusions about glucan kinetics following the initiation of antifungal therapy, likely due to our small sample size and variability in number of BDG measurements obtained per subject.
Potential causes of false-positive BDG results have been identified and many of these factors are common in the ICU 
. Receipt of hemodialysis was associated with elevated BDG levels in this study as well as in an earlier report involving lung transplant recipients at our institution 
. These observations require further exploration given that renal elimination of BDG is not thought to be a major pathway of clearance and our dialysis membranes do not contain cellulose, a substance previously implicated in falsely elevated BDG levels 
. We waited at least 3 days to begin active surveillance in an attempt to avoid other BDG cross-reactive substances present in early in admission 
or following surgery 
. Using this delayed approach, significant proportions of subjects still had false-positive BDG results and were given anidulafungin. Changing the preemptive treatment threshold to require 2 sequential BDG values ≥80 pg/ml would reduce the number of patients treated by approximately half (a reduction from 59% [26/45] based on the current protocol to 24% [11/45]), without missing cases of proven/probable IC.
Overall adherence to the BDG surveillance protocol was good, with > 85% of preemptive subjects managed appropriately. Only 4 subjects assigned to the preemptive group received antifungal therapy despite negative BDG results and repeatedly negative results were used to safely withhold antifungal therapy in the majority of cases (78.9%, 15/19). Given the medical complexity of ICU patients, these observations suggest an acceptance of the BDG-driven strategy and a reliance on the negative predictive value of the test. BDG testing with present assays, however, is relatively expensive and labor intensive. Future studies incorporating biomarkers might consider alternative sampling schemes or the development of more facile assays that are amendable to the workflow of a routine clinical laboratory.
The main limitation of this study is the small number of subjects with proven/probable IC. Despite liberal inclusion criteria, we had a difficult time accruing patients not already receiving systemic antifungal therapy by day 3 of ICU admission. Targeted antifungal prophylaxis is routinely used for Duke solid organ transplant, peripheral blood stem transplant, high-risk leukemia/lymphoma and ventricular assist device patients. Reasons why potential subjects were already receiving systemic antifungal therapy was not documented as a part of the study screening process, however, we suspect that a significant proportion of ineligible ICU patients fell in to one of these categories. This may have biased study enrollment toward lower risk ICU subjects. In addition, we relied heavily on consent authorization obtained from patients’ legal representatives, but only half of all potentially eligible subjects had a designated surrogate available to discuss study participation during regular business hours. In the future, having the capacity to consent and screen both subjects in the evening and on weekends might modestly improve accrual. Perhaps more importantly, consideration should be given to initiating study enrollment/screening at the time of surgical or medical ICU admission, recognizing that some subjects will have a falsely elevated BDG level immediately following surgery. Antifungal therapy would then be withheld as a part of the protocol in selected subjects with a negative BDG test at baseline and during serial measurements.
In conclusion, this pilot study represents a first attempt at preemptive antifungal therapy based on the fungal biomarker BDG in busy tertiary care ICUs. Our results suggest that randomized studies of preemptive antifungal therapy in the ICU are feasible, but that these studies should ideally involve centers that do not routinely utilize fluconazole prophylaxis or employ protocols in which prophylaxis is held for selected patients with negative screening tests. Multicenter trials will ultimately be required to determine the efficacy, optimal algorithm, and cost-effectiveness of preemptive approaches for critically ill patients. Given the high mortality associated with delayed IC treatment and the ineffectiveness of empiric therapy based on fever, early preemptive approaches incorporating fungal biomarkers may have a substantial advantage.