title: Impact of fluconazole susceptibility on the outcome of patients with candidaemia: data from a population-based surveillance.
abstract: OBJECTIVE
  The clinical correlation of fluconazole antifungal susceptibility testing (AST) for Candida isolates and its integration with pharmacokinetics/pharmacodynamics (PK/PD) parameters is unclear. We analysed the impact of fluconazole minimum inhibitory concentration (MIC) values, 24-hour area under the concentration-time curve (AUC24) and AUC24/MIC ratio on the outcome of candidemic patients.
  
  
  METHODS
  We included 257 episodes of candidaemia treated with fluconazole monotherapy for ≥72 hours from a population-based surveillance conducted in 29 hospitals (CANDIPOP Project). AST was centrally performed by European Committee on Antimicrobial Susceptibility Testing (EUCAST) and Clinical and Laboratory Standards Institute (CLSI) microdilution methods. Primary outcome was clinical failure (30-day mortality and/or persistent candidaemia for ≥72 hours from initiation of therapy). Secondary outcomes included early (3-7 days) and late (3-30 days) mortality.
  
  
  RESULTS
  Rates of clinical failure, early and late mortality among evaluable episodes were 32.3% (80/248), 3.1% (8/257) and 23.4% (59/248). There was no relationship between fluconazole MIC values or PK/PD parameters and clinical failure. Although MIC values ≥2 mg/L by EUCAST (positive predictive value 32.1%, negative predictive value 68.7%) and ≥0.5 mg/L by CLSI (positive predictive value 34.8%, negative predictive value 74.4%) appeared to be optimal for predicting clinical failure, no significant associations remained after multivariate adjustment (odds ratio 1.67; 95% confidence interval 0.48-5.79; p 0.423). Lack of association was consistent for alternative thresholds (including proposed clinical breakpoints). The only association found for secondary outcomes was between an AUC24/MIC ratio >400 h by CLSI and early mortality (odds ratio 0.18; 95% confidence interval 0.04-0.98; p 0.026).
  
  
  CONCLUSIONS
  High fluconazole MIC values did not negatively impact outcome of patients with candidaemia treated with fluconazole. No effect of PK/PD targets on the risk of clinical failure was found.
authors.affiliation: Unit of Infectious Diseases, Hospital Universitario '12 de Octubre', Instituto de Investigación Hospital '12 de Octubre' (i+12), Universidad Complutense, Madrid, Spain. Electronic address: mario_fdezruiz@yahoo.es.
authors.forename: M
authors.initials: M
authors.lastname: Fernández-Ruiz
authors.affiliation: Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario 'Gregorio Marañón', Universidad Complutense, Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Guinea
authors.affiliation: Unit of Clinical Research, Hospital Universitario '12 de Octubre', Instituto de Investigación Hospital '12 de Octubre' (i+12), Madrid, Spain; CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Lora-Pablos
authors.affiliation: Department of Mycology, Spanish National Center for Microbiology, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain.
authors.forename: Ó
authors.initials: Ó
authors.lastname: Zaragoza
authors.affiliation: Department of Infectious Diseases, Hospital Universitari 'Vall d'Hebron', Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Puig-Asensio
authors.affiliation: Department of Infectious Diseases, Hospital Universitari 'Vall d'Hebron', Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Almirante
authors.affiliation: Department of Mycology, Spanish National Center for Microbiology, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Cuenca-Estrella
authors.affiliation: Unit of Infectious Diseases, Hospital Universitario '12 de Octubre', Instituto de Investigación Hospital '12 de Octubre' (i+12), Universidad Complutense, Madrid, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Aguado
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002175:Candida / Q000187:drug effects*; D058387:Candidemia / Q000188:drug therapy / Q000453:epidemiology / Q000382:microbiology*; D003430:Cross-Sectional Studies; D025141:Drug Resistance, Fungal; D005260:Female; D015725:Fluconazole / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D000935:Antifungal Agents; D015725:Fluconazole
keywords: Candidaemia; Fluconazole; Outcome; PK/PD parameters; Susceptibility