(1 → 3)-β-D-Glucan-guided antifungal therapy in adults with sepsis: the CandiSep randomized clinical trial

Bloos F et al. 2022; Intensive Care Medicine 48: 865 – 875

Clinical Question

  • In septic adults at high risk for invasive candida infection (ICI) does the use (1,3)-β-D-glucan (BDG) guided antifungal strategy, compared with standard treatment, reduce 28-day mortality compared to standard care?


  • The EUCANDICU project showed an incidence of ICI of ~7/1000 ICU admissions
    • C. Albicans was most frequently isolated (57%) followed by C. Glabrata (21%)
    • Crude 30-day mortality across all types of ICI (candidemia and intra-abdominal) was 42%
  • Similar mortality rates (~40%) were shown in the AMARCand2 study and EPICII study
  • The AMARCand2 study was a prospective observational study evaluating those with suspected or confirmed ICI
    • Of the ~50% with ultimately proven ICI, only 27% received systemic antifungals prior to mycological confirmation
    • Additionally, in those whom ICI was not proven, the median duration of systemic antifungals was 10 days
    • This prolonged duration of ultimately unnecessary antifungals could be due to diagnostic difficulties of ICI. These have been highlighted in the accompanying editorial.
  • The ESICM/ESCMID guidelines for ICI management in the critically ill recommend that empirical antifungal treatment only be considered in those with septic shock, MOF and at least 1 extra-digestive site with proven Candida colonisation
  • BDG, which is a fungal cell wall component, has been studied as a potential tool to help ameliorate some of these diagnostic uncertainties
    • Previous trials have shown its use to be safe, and that it might be helpful to identify those who benefit from empirical antifungal treatment
    • Guidelines don’t recommend it’s use to trigger antifungal treatment due to limited data, however the ESICM and ESCMID guidelines suggest that to improve specificity either a higher cut off (e.g. 200 pg/ml) or the requirement of two consecutive positive tests could be used


  • Open, randomized multicentre trial
  • Written, informed consent from patients or legal representative
  • Randomized in a 1:1 ratio using web-based software
    • Stratified by study centre
  • For BDG sampling:
    • BDG samples and blood cultures taken within 1 hour of enrolment and 24 hours following
    • Fungitell assay used to measure BDG concentrations in a central lab
  • Candida PCR sample also taken alongside microbiological samples from throat, skin, rectum/faeces, urine and trachea or bronchial secretions to determine the candida colonisation index (CCI)
    • PCR results not reported to physicians
  • Sample size based on estimated rates of 49.8% in control and 34.2% in BDG group
    • 348 patients required for 80% power, a two-sided alpha of 0.05 and 10% drop out rate
  • Registered at (NCT02734550)


  • 18 ICUs in Germany
  • September 2016 to September 2019


  • Inclusion:
    • Adult patient with sepsis (defined as proven or suspected infection and organ dysfunction)
    • Increased risk for IC
      • TPN, abdominal surgery within last 7 days, >48 hours of antibiotics within last 7 days, CRRT use
    • Within 24 hours of onset of sepsis
      • Initially was 12 hours but changed in January 2018
  • Exclusion:
    • Proven ICI
    • Ongoing or immediately planned systemic antifungal treatment
    • Child Pugh C cirrhosis
    • Cardiopulmonary bypass or treatment with immunoglobulins within last 4 weeks
    • Immunosuppression
    • Pregnancy or lactation
    • No commitment to full support (e.g. DNR) or imminent death
  • 2324 screened –> 342 randomised
    • 2 withdrew consent in control group –> n = 167
    • 1 withdrew consent in BDG group –> n = 172
  • Comparing baseline characteristics of BDG vs. control group
    • Age: 70 vs 71
    • Male: 67.6% vs 62.1%
    • APACHE II: 20.5 vs 20
    • SOFA: 12 vs 13
    • Lactate: 2.8 vs 2.7
    • Septic Shock: 87.9% vs 92.9%
    • On antimicrobials: 98.3% vs 97.6%
    • Mechanical Ventilation: 80.3% vs 82.1%
    • Time to randomisation: 13.9 vs 12.6 hours
    • Sepsis:
      • Pulmonary: 22% vs 24%
      • Abdominal: 60.1% vs 65.3%
    • Risk Factors for ICI:
      • TPN: 6.4% vs 7.7%
      • Abdominal Surgery: 67.6% vs 70.4%
      • Antimicrobials: 45.1% vs 43.2%
      • RRT: 8.7% vs 11.8%
    • Initial blood culture positive for candida: 4.6% vs 4.1%
    • ICI: 14.5% vs 13.8%
    • Baseline BDG (pg/ml): 73 vs 61
    • 24-hour BDG (pg/ml): 58 vs 56


  • BDG guided
    • First BDG result available within 24 hours, and treating physicians informed of result via phone and fax
    • If any BDG serum concentration ≥ 80 pg/ml then antifungals commenced in accordance with European guidelines
    • If one BDG concentration > 80 pg/ml and cultures negative, then antifungals could be ceased
    • If culture results for candida spp. negative, then antifungal treatment still continued if both BDG concentrations ≥ 80 pg/ml


  • Standard care – diagnosis of ICI and subsequent antifungal from culture-based methods only
  • BDG levels taken but not expedited and not used to guide management

Management common to both groups

  • No specific management stated


  • Primary outcome: 28-day mortality
    • 33.7% (BDG) vs 30.5% (standard care)
      • RR 1.1 95% CI 0.80–1.51; p = 0.53
    • No differences in any subgroups: number of +ve BDG results, sepsis severity, number of ICI risk factors, blood culture result, candida PCR result and CCI index
  • Secondary outcomes:
  • Comparing BDG vs standard care group
    • No significant difference in
      • Hospital mortality: 34.5% vs 35.9%
      • Hospital LOS: 25.5 vs 28 days
      • ICU LOS: 11 vs 11 days
      • Ventilator Free Days: 16 vs 15
      • Vasopressor Free Days:20 vs 20
      • Cost: 4451 vs 2800 (Euros)
    • Significant difference in:
      • % of patients receiving antifungals: 57.6% vs 27.5%
      • Time to antifungal: 1.1 vs 4.4 days

Authors’ Conclusions

  • Early antifungal therapy guided by BDG concentrations did not improve 28-day mortality compared to standard care in critically ill septic patients


  • Aims to answer a question about a potentially important diagnostic strategy for a condition with high associated mortality
  • Randomised, multicentre
    •  All centres were in Germany so this may limit more generalised external validity
  • Well balanced baseline characteristics
  • Intention to treat analysis
  • Separation achieved with regards to timing and frequency of antifungal administration


  • Time window for enrolment changed during trial due to poor recruitment
  • Lower mortality than accounted for in power calculation (expected 49%, observed 30%)
  • High rates of protocol violations
    • 57 in BDG group:
      • 42 were due to antifungal therapy stopping before 2 weeks, in 14 no antifungal therapy initiated and in 1 antifungal therapy initiated immediately despite a BDG < 80 pg/ml
    • The per-protocol analysis trended to improved mortality in the BDG group, however this was not significant
  • High rates (~85%) of patients screened were not enrolled
    • Of those excluded ~6% were for other “reasons” and ~17% were already on antifungal therapy or therapy was imminent
    • This may introduce a selection bias
  • Low rates of ICI: Only 15% of those included were diagnosed with ICI so the inclusion criteria may not reflect truly high-risk patients

The Bottom Line

  • Until further evidence becomes available, I will not use BDG alone to commence empirical antifungals in patients within 24 hours of sepsis and at risk of ICI
  • It would be interesting to see studies that increase BDG specificity with the use of a higher cut off given that in this study the baseline median BDG values were 170.5 pg/ml in patients with ultimately confirmed ICI compared to 62 pg/ml in patients without confirmed ICI

External Links


Summary author: George Walker @hgmwalker89
Summary date: 2nd August 2022
Peer-review editor: David Slessor

Picture by: Pexels/Emily Ranquist


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