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Published on: November 6, 2020
Empirical Micafungin Treatment and Survival Without Invasive Fungal Infection in Adults With ICU-Acquired Sepsis,
Jean-Francois Timsit1, Elie Azoulay2, Carole Schwebel3
1UMR1137-IAME Inserm, Paris Diderot University, Paris, France2Medical and Infectious Diseases ICU, Bichat-Claude Bernard University Hospital, Paris, France.
Importance:
Although frequently used in treating intensive care unit (ICU) patients with sepsis, empirical antifungal therapy, initiated for suspected fungal infection, has not been shown to improve outcome.
Objective:
To determine whether empirical micafungin reduces invasive fungal infection (IFI)-free survival at day 28.
Design, Setting, And Participants:
Multicenter double-blind placebo-controlled study of 260 nonneutropenic, nontransplanted, critically ill patients with ICU-acquired sepsis, multiple Candida colonization, multiple organ failure, exposed to broad-spectrum antibacterial agents, and enrolled between July 2012 and February 2015 in 19 French ICUs.
Interventions:
Empirical treatment with micafungin (100 mg, once daily, for 14 days) (n = 131) vs placebo (n = 129).
Main Outcomes And Measures:
The primary end point was survival without proven IFI 28 days after randomization. Key secondary end points included new proven fungal infections, survival at day 28 and day 90, organ failure, serum (1-3)-β-D-glucan level evolution, and incidence of ventilator-associated bacterial pneumonia.
Results:
Among 260 patients (mean age 63 years; 91 [35%] women), 251 (128, micafungin group; 123, placebo group) were included in the modified intent-to-treat analysis. Median values were 8 for Sequential Organ Failure Assessment (SOFA) score, 3 for number of Candida-colonized sites, and 99 pg/mL for level of (1-3)-β-D-glucan. On day 28, there were 82 (68%) patients in the micafungin group vs 79 (60.2%) in the placebo group who were alive and IFI free (hazard ratio [HR], 1.35 [95% CI, 0.87-2.08]). Results were similar among patients with a (1-3)-β-D-glucan level of greater than 80 pg/mL (n = 175; HR, 1.41 [95% CI, 0.85-2.33]). Day-28 IFI-free survival in patients with a high SOFA score (>8) was not significantly different when compared between the micafungin vs placebo groups (HR, 1.69 [95% CI, 0.96-2.94]). Use of empirical micafungin decreased the rate of new invasive fungal infection in 4 of 128 patients (3%) in the micafungin group vs placebo (15/123 patients [12%]) (P = .008).
Conclusions And Relevance:
Among nonneutropenic critically ill patients with ICU-acquired sepsis, Candida species colonization at multiple sites, and multiple organ failure, empirical treatment with micafungin, compared with placebo, did not increase fungal infection-free survival at day 28.
Trial Registration:
clinicaltrials.gov Idenitfier: NCT01773876.
Insights
Empirical micafungin did not improve survival without invasive fungal infection (IFI) in critically ill patients with sepsis. However, micafungin did reduce the incidence of new IFIs in this patient population.
Area of Science:
- Critical Care Medicine
- Infectious Diseases
- Clinical Pharmacology
Background:
- Empirical antifungal therapy is common in intensive care unit (ICU) patients with sepsis but lacks proven outcome benefits.
- Invasive fungal infections (IFIs) pose a significant threat to critically ill patients, particularly those with sepsis and multiple organ failure.
Purpose of the Study:
- To evaluate the efficacy of empirical micafungin in improving IFI-free survival at day 28 in critically ill patients with ICU-acquired sepsis.
- To assess the impact of empirical micafungin on the incidence of new IFIs and other clinical outcomes.
Main Methods:
- A multicenter, double-blind, placebo-controlled study involving 260 nonneutropenic, critically ill patients with ICU-acquired sepsis and multiple Candida colonization.
- Patients received either empirical micafungin (100 mg daily for 14 days) or a placebo.
- The primary endpoint was survival without proven IFI at 28 days; secondary endpoints included new IFIs, survival rates, organ failure, and biomarker levels.
Main Results:
- Empirical micafungin did not significantly increase IFI-free survival at day 28 compared to placebo (68% vs 60.2%).
- Results were consistent across subgroups, including those with elevated (1-3)-β-D-glucan levels or high Sequential Organ Failure Assessment (SOFA) scores.
- However, micafungin significantly reduced the incidence of new IFIs (3% vs 12%, P=.008).
Conclusions:
- Empirical micafungin treatment did not improve IFI-free survival at day 28 in critically ill patients with sepsis, multiple Candida colonization, and multiple organ failure.
- Despite not improving the primary outcome, empirical micafungin demonstrated a significant reduction in the development of new invasive fungal infections.
- Further research may be needed to identify specific patient subgroups who might benefit from empirical antifungal therapy.
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