What are the guidelines for antifungal escalation in sepsis?

Antifungal Escalation in Sepsis: Guideline-Based Approach

Empirical antifungal therapy should be initiated immediately in critically ill sepsis patients with septic shock—either from community-acquired infections or post-operative infections—using an echinocandin as first-line therapy. 1

When to Initiate Empirical Antifungal Therapy

High-Risk Scenarios Requiring Immediate Treatment

• Septic shock with intra-abdominal infection: Patients with septic shock complicating community-acquired or post-operative peritonitis require empirical antifungal therapy, as yeast in peritoneal fluid is an independent risk factor for death. 1

• ICU patients with multiple risk factors: Empirical antifungal therapy should be considered in critically ill patients with risk factors for invasive candidiasis (recent broad-spectrum antibiotics, multiple Candida colonization sites, central venous catheters, total parenteral nutrition, immunosuppression) and no other known cause of fever. 1

• Timing is critical: Empirical antifungal therapy must be started as soon as possible in patients with clinical signs of septic shock, as delayed therapy is associated with mortality approaching 100% without adequate source control. 1

First-Line Agent Selection

Preferred Agents by Clinical Scenario

• Echinocandins are first-line for critically ill patients: For nonneutropenic ICU patients with suspected invasive candidiasis, an echinocandin (caspofungin 70 mg loading dose then 50 mg daily; micafungin 100 mg daily; or anidulafungin 200 mg loading dose then 100 mg daily) is strongly recommended. 1

• Rationale for echinocandin preference: Candida glabrata (observed in 22% of intra-abdominal candidiasis cases) is resistant to azole agents, making echinocandins the safer empirical choice in critically ill patients. 1

• Fluconazole as alternative: Fluconazole 800 mg loading dose then 400 mg daily is acceptable only in patients without recent azole exposure and not colonized with azole-resistant Candida species. 1

• Consider local epidemiology: Selection should be tailored to local patterns of prevalent Candida species and any recent antifungal drug exposure. 1

Risk Stratification for Empirical Therapy

Patient-Level Risk Factors

• APACHE II score ≥17 on admission is independently associated with mortality in polymicrobial peritonitis with Candida isolation. 1

• Respiratory failure on admission, upper gastrointestinal tract origin of peritonitis, and positive direct examination of peritoneal fluid for Candida are additional independent mortality predictors. 1

• Multiple Candida colonization sites (≥3 sites), mechanical ventilation >3 days, urethral catheterization >3 days, and coexisting gram-positive and gram-negative bacterial infection increase IFI risk. 2

Critical Caveat on Source Control

• Source control is paramount: In patients with septic shock from intra-abdominal candidiasis, absence of adequate source control results in mortality rates above 60% regardless of appropriate antifungal therapy. 1

• Source control interventions (drainage, debridement, device removal) must be implemented as soon as possible, ideally within 12 hours when feasible. 3

Duration and De-escalation Strategy

Treatment Duration

• Candidemia without metastatic complications: Continue therapy for 2 weeks after documented clearance of Candida from bloodstream and resolution of attributable signs. 1

• Intra-abdominal candidiasis: Based on high rates of recurrence and relapse, experts recommend longer duration of 2-3 weeks. 1

• Empirical therapy in patients who improve: Continue for 2 weeks if clinical improvement occurs without documented IFI. 1

De-escalation Approach

• Daily reassessment is mandatory: Antimicrobial regimen should be reviewed daily for potential de-escalation once pathogen identification and sensitivities are available. 1, 4

• Early de-escalation is safe: In non-neutropenic ICU patients with documented or suspected invasive candidiasis, early antifungal therapy de-escalation at day 5 was not associated with increased 28-day mortality (RR 1.12,95% CI 0.76-1.66). 1

• Discontinue if no infection confirmed: For patients without clinical response at 4-5 days and no subsequent evidence of invasive candidiasis, strongly consider stopping antifungal therapy. 1

• Use biomarkers to guide discontinuation: Low procalcitonin levels or similar biomarkers can assist in discontinuing empirical antifungals in patients initially appearing septic but having no subsequent infection evidence. 1, 4

Common Pitfalls to Avoid

• Do not delay in septic shock: Failure to initiate appropriate antifungal therapy within the first hour of septic shock recognition dramatically increases mortality. 1

• Do not use fluconazole empirically in high-risk settings: Recent azole exposure or concern for C. glabrata infection mandates echinocandin use. 1

• Do not continue empirical therapy indefinitely: Without documented infection and with clinical improvement, prolonged empirical antifungal therapy is not indicated and should be discontinued. 1

• Do not neglect source control: Antifungal therapy alone without adequate source control in septic shock yields unacceptably high mortality. 1