title: Failure of empirical systemic antifungal therapy in mechanically ventilated critically ill patients.
abstract: BACKGROUND
  Systemic antifungal treatments are empirically administered to the sickest critically ill patients, often without documented invasive fungal infection.
  
  
  OBJECTIVE
  To estimate the impact of systemic antifungal treatment on 30-day survival of patients suspected to have invasive candidiasis.
  
  
  METHODS
  All nonneutropenic, nontransplant recipients managed in five intensive care units intubated for at least 5 days, and free of invasive candidiasis, were included. To account for differences in patients' characteristics recorded daily before study end point, a causal model for longitudinal data was used to assess benefits from antifungal treatment. The composite primary end point was hospital mortality or occurrence of invasive candidiasis.
  
  
  RESULTS
  Among 1,491 patients, 100 (6.7%) received antifungal treatment for a suspected infection. Patients treated with antifungals were more severely ill than untreated patients. Within the 30-day follow-up period, 363 (24.3%) patients died, and 22 (1.5%) exhibited documented invasive candidiasis. After adjustment on baseline and time-dependent confounders (underlying illness, severity, invasive procedures, Candida colonization), and using a marginal structural model for longitudinal data, treatment was not associated with a decreased risk of mortality or of occurrence of invasive candidiasis (hazard ratio, 1.05; 95% confidence interval, 0.56-1.96; P = 0.91).
  
  
  CONCLUSIONS
  This study failed to show outcome benefits for empirical systemic antifungal therapy in the sickest critically ill, nonneutropenic, nontransplanted patients. The post hoc power did not allow us to conclude to an absence of treatment effect especially for specific subgroups. Studies to refine indications for empirical treatment based on surrogate markers of invasive candidiasis are warranted.
authors.affiliation: 1 Grenoble 1 University, U823, La Tronche, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bailly
authors.forename: Lila
authors.initials: L
authors.lastname: Bouadma
authors.forename: Elie
authors.initials: E
authors.lastname: Azoulay
authors.forename: Maité Garrouste
authors.initials: MG
authors.lastname: Orgeas
authors.forename: Christophe
authors.initials: C
authors.lastname: Adrie
authors.forename: Bertrand
authors.initials: B
authors.lastname: Souweine
authors.forename: Carole
authors.initials: C
authors.lastname: Schwebel
authors.forename: Danièle
authors.initials: D
authors.lastname: Maubon
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hamidfar-Roy
authors.forename: Michael
authors.initials: M
authors.lastname: Darmon
authors.forename: Michel
authors.initials: M
authors.lastname: Wolff
authors.forename: Muriel
authors.initials: M
authors.lastname: Cornet
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Timsit
mesh_terms: D000368:Aged; D000935:Antifungal Agents / Q000008:administration & dosage; D058365:Candidiasis, Invasive / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality / Q000517:prevention & control; D016638:Critical Illness; D016208:Databases, Factual; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage*; D005602:France; D017052:Hospital Mortality; D006801:Humans; D007362:Intensive Care Units / Q000706:statistics & numerical data; D008137:Longitudinal Studies; D008297:Male; D008499:Medical Records / Q000706:statistics & numerical data; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D017063:Outcome Assessment, Health Care; D016016:Proportional Hazards Models; D012121:Respiration, Artificial / Q000009:adverse effects* / Q000401:mortality; D012720:Severity of Illness Index; D016019:Survival Analysis
chemical_list: D000935:Antifungal Agents; D015725:Fluconazole
keywords: antifungal; empirical treatment; intensive care unit; invasive candidiasis; marginal structural model