title: 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: 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.
  
  
  
  To determine whether empirical micafungin reduces invasive fungal infection (IFI)-free survival at day 28.
  
  
  
  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.
  
  
  
  Empirical treatment with micafungin (100 mg, once daily, for 14 days) (n = 131) vs placebo (n = 129).
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  clinicaltrials.gov Idenitfier: NCT01773876.
authors.affiliation: UMR1137-IAME Inserm, Paris Diderot University, Paris, France2Medical and Infectious Diseases ICU, Bichat-Claude Bernard University Hospital, Paris, France.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Timsit
authors.affiliation: Saint-Louis University Hospital, Medical ICU, Paris, France.
authors.forename: Elie
authors.initials: E
authors.lastname: Azoulay
authors.affiliation: Medical ICU, Albert Michallon University Hospital, Grenoble, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Schwebel
authors.affiliation: Medical ICU, François Mitterrand University Hospital, Dijon, France.
authors.forename: Pierre Emmanuel
authors.initials: PE
authors.lastname: Charles
authors.affiliation: UMR5525 CNRS-Grenoble Alpes University, Parasitology-Mycology, Grenoble Alpes University Hospital, Grenoble, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Cornet
authors.affiliation: Medical ICU, Gabriel Montpied University Hospital, Clermont-Ferrand, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Souweine
authors.affiliation: Medical ICU, Lapeyronie University Hospital, Montpellier, France.
authors.forename: Kada
authors.initials: K
authors.lastname: Klouche
authors.affiliation: Intensive Care Unit, Department of Anesthesia and Critical Care Medicine, University of Montpellier, Saint Eloi Teaching Hospital, Montpellier, France.
authors.forename: Samir
authors.initials: S
authors.lastname: Jaber
authors.affiliation: Medical ICU, Institut de Cardiologie, Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Trouillet
authors.affiliation: Medical ICU, André Mignot Hospital, Versailles, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Bruneel
authors.affiliation: Medical ICU, Edouard Herriot University Hospital, Lyon, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Argaud
authors.affiliation: Medical Surgical ICU, CHU de Reims, Reims France.
authors.forename: Joel
authors.initials: J
authors.lastname: Cousson
authors.affiliation: Service de Réanimation Médicale, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Ferhat
authors.initials: F
authors.lastname: Meziani
authors.affiliation: Medical ICU, Bordeaux University Hospital, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Gruson
authors.affiliation: Pharmacy Department, Grenoble Alpes University Hospital, Grenoble, France.
authors.forename: Adeline
authors.initials: A
authors.lastname: Paris
authors.affiliation: Medical ICU, Saint-Etienne University Hospital, Saint-Priest en Jarez, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Darmon
authors.affiliation: Medical-Surgical ICU, Saint-Joseph Hospital Network, Paris, France.
authors.forename: Maité
authors.initials: M
authors.lastname: Garrouste-Orgeas
authors.affiliation: Reanimation Médicale, CHU Jean Minjoz, Besancon, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Navellou
authors.affiliation: Surgical ICU, APHP, Beaujon Hospital, Clichy, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Foucrier
authors.affiliation: Surgical ICU, Edouard Heriot Hospital, Hospices Civils de Lyon, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Allaouchiche
authors.affiliation: Polyvalent ICU, CHI André Grégoire, Montreuil, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Das
authors.affiliation: Mycology Lab, Rennes University Hospital, Rennes, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Gangneux
authors.affiliation: ICUREsearch, Department of Biostatistics, Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Ruckly
authors.affiliation: UMR5525 CNRS-Grenoble Alpes University, Parasitology-Mycology, Grenoble Alpes University Hospital, Grenoble, France.
authors.forename: Daniele
authors.initials: D
authors.lastname: Maubon
authors.affiliation: Pharmacology Department, Georges Pompidou Hospital, Paris Descartes University, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Jullien
authors.affiliation: UMR1137-IAME Inserm, Paris Diderot University, Paris, France2Medical and Infectious Diseases ICU, Bichat-Claude Bernard University Hospital, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Wolff
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D000935:Antifungal Agents / Q000627:therapeutic use*; D002177:Candidiasis / Q000188:drug therapy / Q000401:mortality; D058365:Candidiasis, Invasive / Q000401:mortality* / Q000517:prevention & control*; D016638:Critical Illness; D003428:Cross Infection / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality*; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D054714:Echinocandins / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D055666:Lipopeptides / Q000627:therapeutic use*; D008297:Male; D000077551:Micafungin; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000401:mortality; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D000077551:Micafungin