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Original Investigation
Caring for the Critically Ill Patient
October 18, 2016

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

Author Affiliations
  • 1UMR1137-IAME Inserm, Paris Diderot University, Paris, France
  • 2Medical and Infectious Diseases ICU, Bichat-Claude Bernard University Hospital, Paris, France
  • 3Saint-Louis University Hospital, Medical ICU, Paris, France
  • 4Medical ICU, Albert Michallon University Hospital, Grenoble, France
  • 5Medical ICU, François Mitterrand University Hospital, Dijon, France
  • 6UMR5525 CNRS-Grenoble Alpes University, Parasitology-Mycology, Grenoble Alpes University Hospital, Grenoble, France
  • 7Medical ICU, Gabriel Montpied University Hospital, Clermont-Ferrand, France
  • 8Medical ICU, Lapeyronie University Hospital, Montpellier, France
  • 9Intensive Care Unit, Department of Anesthesia and Critical Care Medicine, University of Montpellier, Saint Eloi Teaching Hospital, Montpellier, France
  • 10Medical ICU, Institut de Cardiologie, Hôpital de la Pitié–Salpêtrière, Assistance Publique–Hôpitaux de Paris, Paris, France
  • 11Medical ICU, André Mignot Hospital, Versailles, France
  • 12Medical ICU, Edouard Herriot University Hospital, Lyon, France
  • 13Medical Surgical ICU, CHU de Reims, Reims France
  • 14Service de Réanimation Médicale, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
  • 15Medical ICU, Bordeaux University Hospital, France
  • 16Pharmacy Department, Grenoble Alpes University Hospital, Grenoble, France
  • 17Medical ICU, Saint-Etienne University Hospital, Saint-Priest en Jarez, France
  • 18Medical-Surgical ICU, Saint-Joseph Hospital Network, Paris, France
  • 19Reanimation Médicale, CHU Jean Minjoz, Besancon, France
  • 20Surgical ICU, APHP, Beaujon Hospital, Clichy, France
  • 21Surgical ICU, Edouard Heriot Hospital, Hospices Civils de Lyon, France
  • 22Polyvalent ICU, CHI André Grégoire, Montreuil, France
  • 23Mycology Lab, Rennes University Hospital, Rennes, France
  • 24ICUREsearch, Department of Biostatistics, Paris, France
  • 25Pharmacology Department, Georges Pompidou Hospital, Paris Descartes University, Paris, France
JAMA. 2016;316(15):1555-1564. doi:10.1001/jama.2016.14655
Key Points

Question  Does empirical antifungal therapy increase invasive fungal infection–free survival at day 28 in nonneutropenic critically ill patients with sepsis, multiple Candida colonization, and multiple organ failure exposed to broad-spectrum antibacterials?

Findings  In this randomized clinical trial of 260 adults, there was no significant difference in the rate of survivors without any fungal infection at day 28 between micafungin-treated (87/128 [68%]) and placebo-treated (74/123 [60.2%]) groups.

Meaning  The use of micafungin as a routine empirical treatment in critically ill patients with suspected fungal infection did not improve fungal infection–free survival at 28 days.


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