Management of Suspected Candidemia with Negative Beta-D-Glucan
A negative BDG result does not exclude candidemia and should not be used alone to withhold or discontinue antifungal therapy in critically ill patients with high clinical suspicion. 1, 2
Understanding BDG Limitations in Candidemia
Diagnostic Performance
- BDG has a sensitivity of only 65-89% for candidemia at the 80 pg/mL threshold, meaning 11-35% of true cases will be missed 1
- The negative predictive value is approximately 85%, which still leaves a 15% false-negative rate 1
- In real-world studies, 15.6-25% of patients with proven candidemia had BDG values <80 pg/mL 3, 2
- Blood cultures themselves only have 50-75% sensitivity for detecting Candida, so relying on either test alone is insufficient 1, 4
Factors Causing False-Negative BDG
- Echinocandin therapy can inhibit BDG-synthase enzyme activity, leading to false-negative results 1
- Certain Candida species may produce lower BDG levels 1
- Early infection stages may not yet generate detectable BDG levels 1
Clinical Decision Algorithm
Step 1: Assess Risk Factors and Clinical Context
Continue or initiate empiric antifungal therapy if the patient has:
- Clinical signs of septic shock with risk factors for invasive candidiasis 1
- Recent abdominal surgery with gastrointestinal perforation or anastomotic leak 1
- Central venous catheter, total parenteral nutrition, broad-spectrum antibiotics, or mechanical ventilation 1, 3
- Persistent fever despite 4-5 days of appropriate antibacterial therapy 1
Step 2: Obtain Additional Diagnostic Testing
Do not rely on BDG alone. Immediately collect:
- Two to three sets of blood cultures with 20 mL blood volume per set to maximize diagnostic yield 4
- Repeat BDG testing serially (twice weekly) as sensitivity improves with sequential specimens—one study showed BDG sensitivity increased from 80% to 90% with repeat testing 1, 5
- Consider mannan antigen and anti-mannan antibody testing, which can detect infection 6 days before blood cultures with 80% sensitivity and 85% specificity 1
- Culture specimens from any sterile sites (operative specimens, drains placed within 24 hours, CSF, peritoneal fluid) 1
Step 3: Empiric Antifungal Selection
Start or continue an echinocandin as first-line therapy:
- Caspofungin 70 mg loading dose, then 50 mg daily 1
- Micafungin 100 mg daily 1
- Anidulafungin 200 mg loading dose, then 100 mg daily 1
Rationale: Echinocandins are strongly recommended over fluconazole in critically ill patients, especially given increasing azole resistance and emergence of multidrug-resistant species like C. auris 1, 3, 2
Step 4: Reassessment at 4-5 Days
Only consider stopping antifungal therapy if ALL of the following are met:
- No clinical response improvement AND 1
- All blood cultures remain negative after 4-5 days AND 1
- Repeat BDG testing remains negative AND 1
- No subsequent evidence of invasive candidiasis develops AND 1
- Clinical condition has alternative explanation 1
If any uncertainty remains, continue therapy for the full 2-week empiric course 1
Critical Pitfalls to Avoid
- Never use a single negative BDG to rule out candidemia in high-risk ICU patients—the false-negative rate is too high (15-25%) 3, 2
- Do not delay antifungal therapy while awaiting repeat BDG or culture results in patients with septic shock and risk factors 1
- Avoid fluconazole as empiric therapy unless the patient has no recent azole exposure and local epidemiology confirms low azole resistance 1, 3, 2
- Do not stop antifungals prematurely based solely on negative biomarkers if clinical suspicion remains high 1
Species Identification and De-escalation
- Once cultures are positive, obtain species-level identification using MALDI-TOF MS or DNA sequencing 4
- Perform antifungal susceptibility testing on all isolates, particularly for C. auris which shows 100% fluconazole resistance 2
- Consider de-escalation to fluconazole 400 mg daily only after: clinical stability, blood culture clearance, and confirmed susceptibility 3, 2