Empirical Micafungin Treatment and Survival Without Invasive Fungal Infection in Adults With ICU-Acquired Sepsis, Candida Colonization, and Multiple Organ Failure: The EMPIRICUS Randomized Clinical Trial.

Abstract

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.

• Authors: Jean-Francois Timsit, Elie Azoulay, Carole Schwebel, Pierre Emmanuel Charles, Muriel Cornet, Bertrand Souweine, Kada Klouche, Samir Jaber, Jean-Louis Trouillet, Fabrice Bruneel, Laurent Argaud, Joel Cousson, Ferhat Meziani, Didier Gruson, Adeline Paris, Michael Darmon, Maité Garrouste-Orgeas, Jean-Christophe Navellou, Arnaud Foucrier, Bernard Allaouchiche, Vincent Das, Jean-Pierre Gangneux, Stéphane Ruckly, Daniele Maubon, Vincent Jullien, Michel Wolff, EMPIRICUS Trial Group
• Journal: JAMA (JAMA) Vol. 316 Issue 15 Pg. 1555-1564 (Oct 18 2016) ISSN: 1538-3598 [Electronic] United States
• PMID: 27706483 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Antifungal Agents
• Echinocandins
• Lipopeptides
• Micafungin

Topics

• Aged
• Anti-Bacterial Agents (therapeutic use)
• Antifungal Agents (therapeutic use)
• Candidiasis (drug therapy, mortality)
• Candidiasis, Invasive (mortality, prevention & control)
• Critical Illness
• Cross Infection (drug therapy, microbiology, mortality)
• Disease-Free Survival
• Double-Blind Method
• Drug Administration Schedule
• Echinocandins (therapeutic use)
• Female
• Humans
• Lipopeptides (therapeutic use)
• Male
• Micafungin
• Middle Aged
• Multiple Organ Failure (mortality)
• Time Factors