(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 https://doi.org/10.1007/s00134-022-06733-x

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?

Background

• 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

Design

• 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 ClinicalTrials.gov (NCT02734550)

Setting

• 18 ICUs in Germany
• September 2016 to September 2019

Population

• 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

Intervention

• 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

Control

• 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

Outcome

• 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

Strengths

• 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

Weaknesses

• 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

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

Metadata

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

Picture by: Pexels/Emily Ranquist