What antifungal therapy is recommended for a patient with a positive beta-D-glucan test on cefepime?

Management of Positive Beta-D-Glucan in Patients on Cefepime

Critical First Step: Do Not Treat Based on Beta-D-Glucan Alone

A positive beta-D-glucan test in a patient receiving cefepime should NOT automatically trigger antifungal therapy, as beta-lactam antibiotics (including cefepime) can cause false-positive results, and the test has limited positive predictive value (PPV) requiring clinical correlation and additional diagnostic workup. 1

Understanding the False Positive Risk

• Beta-lactam/beta-lactamase combinations (particularly piperacillin-tazobactam) are well-documented causes of false-positive galactomannan results, and similar concerns exist for beta-D-glucan testing with beta-lactam antibiotics 1
• The specificity of beta-D-glucan ranges from 65-95% in various studies, with PPV as low as 11.8-18% in some populations, meaning many positive results do not represent true invasive fungal infection 1, 2
• Additional causes of false positivity include: bacteremia, hemodialysis, administration of albumin or immunoglobulin products, hemolysis, exposure to surgical gauze, and gastrointestinal mucositis 1

Diagnostic Algorithm for Positive Beta-D-Glucan

Step 1: Repeat Testing (Days 1-3)

• Obtain serial beta-D-glucan measurements over 2-3 consecutive days 1, 3
• Two consecutive positive results significantly improve specificity and PPV compared to a single positive test 1, 4, 2
• A single negative result has extremely low sensitivity and should not rule out invasive fungal infection 1

Step 2: Assess Clinical Risk Factors

High-risk features that increase likelihood of true invasive fungal infection include:

• Neutropenia (absolute neutrophil count <500 cells/μL) 1
• Hematologic malignancy or hematopoietic stem cell transplantation 1
• Prolonged ICU stay with multiple risk factors (>7 days with central venous catheter, broad-spectrum antibiotics, parenteral nutrition, dialysis, surgery, pancreatitis, or immunosuppressive therapy) 1, 3
• Recent abdominal surgery with complications or tertiary peritonitis 1
• Persistent fever despite 4+ days of appropriate antibacterial therapy 1

Step 3: Obtain Complementary Diagnostic Tests

• Blood cultures: Minimum of two sets from different sites on consecutive days 1, 3
• High-resolution chest CT: Look for macronodules with halo sign (suggests invasive aspergillosis), cavitary lesions, or wedge-shaped peripheral infiltrates 1
• Galactomannan testing: If aspergillosis is suspected (detects only Aspergillus species, not Candida) 1
• Site-specific cultures: From normally sterile sites when clinically indicated (peritoneal fluid, abscess drainage, tissue biopsy) 1

Treatment Decision Framework

Initiate Antifungal Therapy When:

Echinocandins are the first-line empirical therapy for suspected invasive candidiasis in critically ill patients with positive beta-D-glucan plus clinical risk factors. 1

Specific indications for treatment initiation:

• Consecutive positive beta-D-glucan results (2+ tests) PLUS high-risk clinical features PLUS signs of sepsis unresponsive to antibiotics 1, 4, 3
• Positive blood cultures for Candida species (even a single positive culture constitutes candidemia requiring treatment) 1
• Radiographic findings suggestive of invasive fungal infection (halo sign, nodular lesions) PLUS positive beta-D-glucan 1
• Proven or probable invasive fungal infection by EORTC/MSG criteria 1

First-Line Antifungal Regimens:

For non-neutropenic critically ill patients:

• Echinocandin (preferred): Caspofungin 70 mg loading dose, then 50 mg daily; OR micafungin 100 mg daily; OR anidulafungin 200 mg loading dose, then 100 mg daily 1, 4, 5
• Alternative: Fluconazole 800 mg loading dose, then 400 mg daily (only if patient is hemodynamically stable and no prior azole exposure) 1

For neutropenic patients:

• Echinocandin OR liposomal amphotericin B (3-5 mg/kg daily) 1
• Voriconazole is considered a reliable alternative despite not meeting strict statistical noninferiority in some trials 1

Do NOT Initiate Antifungal Therapy When:

• Single positive beta-D-glucan with consecutive negative repeat tests 4, 3
• Candida isolated from respiratory secretions only (represents colonization, not infection) 1
• Low-risk patient without clinical signs of infection 1
• Fungal colonization at single site without systemic signs 1

Duration and Monitoring

Treatment Duration:

• For documented candidemia: Minimum 14 days after first negative blood culture AND resolution of clinical symptoms 6, 7
• Mandatory ophthalmologic examination to rule out endophthalmitis in all candidemia cases 6

Source Control (Critical):

• Remove infected central venous catheters within 24-48 hours 6, 7
• Drain abscesses or infected fluid collections 6, 7
• Surgical debridement of infected tissues when indicated 1

Special Considerations for Cefepime Context

• Cefepime itself is not specifically listed as causing false-positive beta-D-glucan (unlike piperacillin-tazobactam for galactomannan), but all beta-lactams carry theoretical risk 1
• If patient has bacteremia while on cefepime, this is an independent cause of false-positive beta-D-glucan 1
• Consider switching to non-beta-lactam antibiotic if feasible to clarify beta-D-glucan results, though this is rarely practical 1

Critical Pitfalls to Avoid

• Never treat based on single positive beta-D-glucan without supporting evidence 1, 4
• Do not ignore negative predictive value: Consecutive negative tests effectively rule out invasive fungal infection (NPV >90%) 1, 4, 8
• Beta-D-glucan does NOT detect mucormycosis (Zygomycetes) or Cryptococcus species 1
• Antifungal prophylaxis or treatment reduces test sensitivity, potentially causing false negatives 1, 4
• In lung transplant recipients, beta-D-glucan has particularly poor specificity (as low as 9%) and should not guide therapy 4

Preemptive vs. Empirical Strategy

• Preemptive therapy (treating only when biomarkers suggest infection) remains largely experimental and is not standard practice 1
• Empirical therapy for persistently febrile high-risk patients is still the standard approach, though serial beta-D-glucan monitoring can guide early discontinuation in patients with consecutive negative results 1, 3
• In one study, 75% of high-risk ICU patients discontinued empirical echinocandin on day 4 based on negative beta-D-glucan (days 1-3) with no subsequent candidemia through day 30 3