title: Pharmacokinetic variability and exposures of fluconazole, anidulafungin, and caspofungin in intensive care unit patients: Data from multinational Defining Antibiotic Levels in Intensive care unit (DALI) patients Study.
abstract: BACKGROUND
  The objective of the study was to describe the pharmacokinetics (PK) of fluconazole, anidulafungin, and caspofungin in critically ill patients and to compare with previously published data. We also sought to determine whether contemporary fluconazole doses achieved PK/pharmacodynamic (PD; PK/PD) targets in this cohort of intensive care unit patients.
  
  
  METHODS
  The Defining Antibiotic Levels in Intensive care unit patients (DALI) study was a prospective, multicenter point-prevalence PK study. Sixty-eight intensive care units across Europe participated. Inclusion criteria were met by critically ill patients administered fluconazole (n = 15), anidulafungin (n = 9), and caspofungin (n = 7). Three blood samples (peak, mid-dose, and trough) were collected for PK/PD analysis. PK analysis was performed by using a noncompartmental approach.
  
  
  RESULTS
  The mean age, weight, and Acute Physiology and Chronic Health Evaluation (APACHE) II scores of the included patients were 58 years, 84 kg, and 22, respectively. Fluconazole, caspofungin, and anidulafungin showed large interindividual variability in this study. In patients receiving fluconazole, 33% did not attain the PK/PD target, ratio of free drug area under the concentration-time curve from 0 to 24 hours to minimum inhibitory concentration (fAUC(0-24)/MIC) ≥100. The fluconazole dose, described in milligrams per kilogram, was found to be significantly associated with achievement of fAUC(0-24)/MIC ≥100 (P = 0.0003).
  
  
  CONCLUSIONS
  Considerable interindividual variability was observed for fluconazole, anidulafungin, and caspofungin. A large proportion of the patients (33%) receiving fluconazole did not attain the PK/PD target, which might be related to inadequate dosing. For anidulafungin and caspofungin, dose optimization also appears necessary to minimize variability.
authors.affiliation: Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Australia. mahi716@yahoo.com.|School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia. mahi716@yahoo.com.|Therapeutics Research Centre, Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, Adelaide, Australia. mahi716@yahoo.com.
authors.forename: Mahipal G
authors.initials: MG
authors.lastname: Sinnollareddy
authors.affiliation: Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Australia. j.roberts2@uq.edu.au.|Royal Brisbane and Women's Hospital, Brisbane, Australia. j.roberts2@uq.edu.au.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Roberts
authors.affiliation: Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Australia. j.lipman@uq.edu.au.|Royal Brisbane and Women's Hospital, Brisbane, Australia. j.lipman@uq.edu.au.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lipman
authors.affiliation: School of Medicine, Hacettepe University, Ankara, Turkey. makova@hacettepe.edu.tr.
authors.forename: Murat
authors.initials: M
authors.lastname: Akova
authors.affiliation: Azienda Ospedaliera Universitaria Santa Maria della Misericordia, Udine, Italy. mattba@tin.it.
authors.forename: Matteo
authors.initials: M
authors.lastname: Bassetti
authors.affiliation: Ghent University Hospital, Ghent, Belgium. Jan.DeWaele@UGent.be.
authors.forename: Jan J
authors.initials: JJ
authors.lastname: De Waele
authors.affiliation: Helsinki University Central Hospital, Helsinki, Finland. maija.kaukonen@monash.edu.
authors.forename: Kirsi-Maija
authors.initials: KM
authors.lastname: Kaukonen
authors.affiliation: Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Australia. deskogr@yahoo.gr.|Attikon University Hospital, Athens, Greece. deskogr@yahoo.gr.
authors.forename: Despoina
authors.initials: D
authors.lastname: Koulenti
authors.affiliation: Hospital Nord, Marseille, France. claude.martin@mail.ap-hm.fr.|AzuRea Group, Antibes, France. claude.martin@mail.ap-hm.fr.
authors.forename: Claude
authors.initials: C
authors.lastname: Martin
authors.affiliation: Centre Hospitalier Universitaire Bichat-Claude Bernard, AP-HP, Université Paris VII, Paris, France. philippe.montravers@bch.ap-hop-paris.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Montravers
authors.affiliation: CIBERES, Vall d'Hebron Institute of Research, Universitat Autonoma de Barcelona, Barcelona, Spain. jrello@crips.es.
authors.forename: Jordi
authors.initials: J
authors.lastname: Rello
authors.affiliation: St George's Healthcare NHS Trust and St George's University of London, London, England. andrewrhodes@nhs.net.
authors.forename: Andrew
authors.initials: A
authors.lastname: Rhodes
authors.affiliation: Royal Brisbane and Women's Hospital, Brisbane, Australia. Therese.starr@health.qld.gov.au.
authors.forename: Therese
authors.initials: T
authors.lastname: Starr
authors.affiliation: Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Australia. s.wallis@uq.edu.au.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Wallis
authors.affiliation: Attikon University Hospital, Athens, Greece. gdimop@med.uoa.gr.
authors.forename: George
authors.initials: G
authors.lastname: Dimopoulos
mesh_terms: D000368:Aged; D000077612:Anidulafungin; D000935:Antifungal Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000077336:Caspofungin; D016638:Critical Illness / Q000628:therapy*; D016903:Drug Monitoring; D054714:Echinocandins / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005060:Europe; D005260:Female; D015725:Fluconazole / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D007362:Intensive Care Units; D055666:Lipopeptides; D008297:Male; D008875:Middle Aged
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D015725:Fluconazole; D000077612:Anidulafungin; D000077336:Caspofungin