title: Antifungal de-escalation was not associated with adverse outcome in critically ill patients treated for invasive candidiasis: post hoc analyses of the AmarCAND2 study data.
abstract: OBJECTIVE
  Systemic antifungal therapy (SAT) of invasive candidiasis needs to be initiated immediately upon clinical suspicion. Controversies exist about adequate time and potential harm of antifungal de-escalation (DE) in documented and suspected candidiasis in ICU patients. Our objective was to investigate whether de-escalation within 5 days of antifungal initiation is associated with an increase of the 28-day mortality in SAT-treated non-neutropenic adult ICU patients.
  
  
  METHODS
  From the 835 non-neutropenic adults recruited in the multicenter prospective observational AmarCAND2 study, we selected the patients receiving systemic antifungal therapy for a documented or suspected invasive candidiasis in the ICU and who were still alive 5 days after SAT initiation. They were included into two groups according to the occurrence of observed SAT de-escalation before day 6. The average causal SAT de-escalation effect on 28-day mortality was evaluated by using a double robust estimation.
  
  
  RESULTS
  Among the 647 included patients, early de-escalation at day 5 after antifungal initiation occurred in 142 patients (22%), including 48 (34%) patients whose SAT was stopped before day 6. After adjustment for the baseline confounders, early SAT de-escalation was the solely factor not associated with increased 28-day mortality (RR 1.12, 95% CI 0.76-1.66).
  
  
  CONCLUSIONS
  In non-neutropenic critically ill adult patients with documented or suspected invasive candidiasis, SAT de-escalation within 5 days was not related to increased day-28 mortality but it was associated with decreased SAT consumption. These results suggest for the first time that SAT de-escalation may be safe in these patients.
authors.affiliation: Inserm UMR 1137-IAME Team 5-DeSCID: Decision SCiences in Infectious Diseases, Control and Care INSERM/Paris Diderot, Sorbonne Paris Cité University, Paris, France. sbailly@chu-grenoble.fr.|Grenoble 1 University, U823, Rond-point de la Chantourne, 38700, La Tronche, France. sbailly@chu-grenoble.fr.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bailly
authors.affiliation: Medical ICU, Chatiliez Hospital, Tourcoing, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Leroy
authors.affiliation: Paris Diderot Sorbonne Cite University, and Anaesthesiology and Critical Care Medicine, Bichat-Claude Bernard University Hospital, APHP, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Montravers
authors.affiliation: Perioperative Medicine Department, Clermont-Ferrand University Hospital, Clermont-Ferrand, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Constantin
authors.affiliation: Surgical ICU, Amiens University Hospital, Amiens, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Dupont
authors.affiliation: Inserm UMR 1181 "Biostatistics, Biomathematics, Pharmacoepidemiology and Infectious Diseases" (B2PHI), 75015, Paris, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Guillemot
authors.affiliation: University Paris Descartes, Necker Pasteur Center for Infectious Diseases, Necker Enfants-Malades Hospital, IHU Imagine, Paris, France.|Pasteur Institute, National Reference Center for Invasive Mycoses and Antifungals, CNRS URA3012, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lortholary
authors.affiliation: Medical ICU, Cochin University Hospital, APHP, Paris, France.|Paris Descartes, Sorbonne Paris Cité University, Paris, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Mira
authors.affiliation: Medical-Surgical ICU, Montpellier University Hospital, Montpellier, France.
authors.forename: Pierre-François
authors.initials: PF
authors.lastname: Perrigault
authors.affiliation: Mycology, Rennes University Hospital, Rennes, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Gangneux
authors.affiliation: Medical ICU, Saint-Louis University Hospital, Paris, France.
authors.forename: Elie
authors.initials: E
authors.lastname: Azoulay
authors.affiliation: Inserm UMR 1137-IAME Team 5-DeSCID: Decision SCiences in Infectious Diseases, Control and Care INSERM/Paris Diderot, Sorbonne Paris Cité University, Paris, France. jean-francois.timsit@bch.aphp.fr.|Medical and Infectious Diseases ICU, Paris Diderot University/Bichat University Hospital, APHP, 46 rue Henri Huchard, Paris, 75018, France. jean-francois.timsit@bch.aphp.fr.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Timsit
mesh_terms: D000368:Aged; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D058365:Candidiasis, Invasive / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality / Q000517:prevention & control; D015897:Comorbidity; D016638:Critical Illness; D018450:Disease Progression; D054714:Echinocandins / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D005602:France / Q000453:epidemiology; D017052:Hospital Mortality; D006801:Humans; D007362:Intensive Care Units / Q000706:statistics & numerical data; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D019370:Observation; D010043:Outcome and Process Assessment, Health Care / Q000706:statistics & numerical data; D011446:Prospective Studies; D012720:Severity of Illness Index; D016019:Survival Analysis; D061665:Time-to-Treatment / Q000706:statistics & numerical data*
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D015725:Fluconazole
keywords: Antifungal; Causal inference; De-escalation; Intensive care unit; Invasive candidiasis; Outcome; Sepsis