What is the recommended diagnostic evaluation and empiric antifungal therapy, including source control, for a critically ill patient with a suspected systemic fungal infection such as candidemia or invasive aspergillosis?

Systemic Fungal Infection: Diagnostic Evaluation and Empiric Antifungal Therapy

Immediate Empiric Therapy Based on Patient Population

For critically ill nonneutropenic ICU patients with suspected systemic fungal infection, initiate an echinocandin immediately—this is the preferred first-line agent with strong evidence supporting improved outcomes in septic shock. 1

Critically Ill Nonneutropenic Patients (ICU Setting)

Preferred empiric regimen:

• Caspofungin: 70 mg IV loading dose, then 50 mg IV daily 1
• Micafungin: 100 mg IV daily 1
• Anidulafungin: 200 mg IV loading dose, then 100 mg IV daily 1

Alternative regimens (only if specific conditions met):

• Fluconazole 800 mg (12 mg/kg) loading dose, then 400 mg (6 mg/kg) daily—acceptable ONLY if no recent azole exposure AND not colonized with azole-resistant Candida species 1
• Lipid formulation amphotericin B 3-5 mg/kg daily—use only if intolerance to echinocandins and azoles 1

Critical timing consideration: Empiric therapy must be started as soon as possible in patients with clinical signs of septic shock and risk factors for invasive candidiasis 1

Neutropenic Patients with Prolonged Fever

For high-risk neutropenic patients with prolonged neutropenia (>10 days) who remain febrile despite broad-spectrum antibiotics:

Preferred options (all equally recommended):

• Lipid formulation amphotericin B: 3-5 mg/kg daily 1
• Echinocandin: Caspofungin 70 mg loading then 50 mg daily, OR micafungin 100 mg daily 1
• Voriconazole: 6 mg/kg IV q12h × 2 doses, then 4 mg/kg IV q12h 1

Do NOT use empiric antifungals if neutropenia expected <10 days unless other findings suggest invasive fungal infection. 1

Suspected Invasive Aspergillosis

Early initiation of antifungal therapy is warranted while diagnostic evaluation is conducted—do not delay treatment waiting for confirmation. 1

First-line therapy:

• Voriconazole: 6 mg/kg IV q12h × 2 doses, then 4 mg/kg IV q12h 2

Alternative first-line agents:

• Liposomal amphotericin B: 3 mg/kg/day IV 2
• Isavuconazole (dosing per package insert) 2

If breakthrough aspergillosis on azole prophylaxis: Switch to different drug class 1

Diagnostic Evaluation Strategy

Immediate Diagnostic Steps

Blood cultures:

• Obtain immediately from peripheral sites and central lines 1
• Repeat every 48-72 hours until clearance documented 1

Fungal biomarkers (use to guide therapy decisions):

• Serum (1→3)-β-D-glucan: High negative predictive value for invasive fungal infection 1
• Serum galactomannan (GM): For suspected aspergillosis 1
• BAL galactomannan: If pulmonary infiltrates present 1

The biomarker-driven preemptive approach can reduce unnecessary antifungal therapy without compromising survival and serves as an alternative to empiric therapy. 1

Risk Factor Assessment for Candidemia

Initiate empiric therapy if patient has:

• Critical illness with septic shock 1, 3
• Recent major abdominal surgery 1
• Central venous catheter with total parenteral nutrition 1
• Prolonged broad-spectrum antibiotic exposure 1
• Hemodialysis 1
• High-dose corticosteroids 1
• Multiple Candida colonization sites 1

Imaging Studies

CT chest with contrast: For suspected invasive aspergillosis—look for nodules with halo sign, cavitation, or wedge-shaped infiltrates 1

Abdominal/pelvic CT or ultrasound: If persistent candidemia to evaluate for hepatosplenic candidiasis or intra-abdominal abscess 1

Essential Source Control Measures

Remove all central venous catheters as early as feasible in nonneutropenic patients with candidemia—this is mandatory, not optional. 1, 3

Surgical debridement: Required for necrotizing soft tissue infections, intra-abdominal abscesses, or localized aspergillosis amenable to resection 1

Drainage procedures: Nephrostomy for renal aspergillosis with obstruction, drainage of peritoneal or pleural collections 1

Duration of Empiric Therapy

If clinical improvement without documented infection:

• Continue empiric therapy for 2 weeks (same duration as documented candidemia) 1

If no clinical response at 4-5 days AND:

• No subsequent evidence of invasive fungal infection, AND
• Negative biomarker with high negative predictive value
• STOP antifungal therapy 1

If documented candidemia:

• Continue for minimum 14 days AFTER first negative blood culture AND resolution of symptoms 1

If documented invasive aspergillosis:

• Continue for minimum 6-12 weeks depending on immunosuppression degree, disease site, and clinical improvement 2

Therapeutic Drug Monitoring

Voriconazole levels must be monitored—obtain trough levels after 5 days of therapy, target 1-5.5 mcg/mL. 2

Posaconazole levels: Monitor if used, target >1 mcg/mL 1

Critical Pitfalls to Avoid

Never delay antifungal therapy in septic shock waiting for culture confirmation—mortality increases with each hour of delay. 1, 3

Never use fluconazole empirically in critically ill patients—echinocandins have superior outcomes in this population. 1, 3

Never use echinocandins as primary therapy for suspected aspergillosis—they have inferior efficacy compared to voriconazole. 2

Never assume Candida in respiratory secretions represents infection—this is colonization and does not require antifungal therapy unless other criteria for invasive disease are met. 4

Never continue empiric therapy indefinitely without reassessment—stop if no evidence of infection by day 4-5 with negative biomarkers. 1

Never use amphotericin B deoxycholate as first-line in ICU patients—lipid formulations have equivalent efficacy with significantly less nephrotoxicity. 1

Adjunctive Immunomodulation

Reduce or eliminate immunosuppressive agents when feasible—this is a critical component of successful antifungal therapy. 2

For hepatosplenic candidiasis with persistent fever despite antifungals: Consider short-term (1-2 weeks) corticosteroids or NSAIDs to manage immune reconstitution inflammatory response 1