title: Susceptibility breakpoints and target values for therapeutic drug monitoring of voriconazole and Aspergillus fumigatus in an in vitro pharmacokinetic/pharmacodynamic model.
abstract: BACKGROUND
  Although voriconazole reached the bedside 10 years ago and became the standard care in the treatment of invasive aspergillosis, reliable clinical breakpoints are still in high demand. Moreover, this has increased due to the recent emergence of azole resistance.
  
  
  METHODS
  Four clinical wild-type and non-wild-type A. fumigatus isolates with voriconazole CLSI MICs in the range of 0.125-2 mg/L were tested in an in vitro pharmacokinetic (PK)/pharmacodynamic (PD) model. Mouse PK was simulated and in vitro data were compared with in vivo outcome. Human PK was simulated and susceptibility breakpoints and trough levels required for optimal treatment were determined for the CLSI and EUCAST methods after 48 h and the gradient concentration MIC test strip (MTS) method after 24 h using the in vitro PK/PD relationship and Monte Carlo simulation.
  
  
  RESULTS
  The in vitro PK/PD target (95% CI) associated with 50% of the maximal antifungal activity (EC50) was 28.61 (16.18-50.61), close to the in vivo EC50 of 14.67 (9.31-21.58) fAUC0-24/CLSI MIC. When human PK was simulated, the EC50 was 24.7 (17.9-35.6) fAUC0-12/CLSI MIC and it was associated with 6 week survival in clinical studies of invasive pulmonary aspergillosis. Target attainment rates were ≤5% (0%-24%), 42% (16%-58%), 68% (54%-75%) and ≥79% (73%-86%) for isolates with CLSI MICs ≥2, 1, 0.5 and ≤0.25 mg/L, respectively. A trough/CLSI MIC ratio of 2 was required for optimal treatment. The susceptible/intermediate/resistant breakpoints were determined to be 0.25/0.5-1/2 mg/L for CLSI, 0.5/1-2/4 mg/L for EUCAST and 0.25/0.375-1/1.5 mg/L for MTS.
  
  
  CONCLUSIONS
  These susceptibility breakpoints and target values for therapeutic drug monitoring could be used to optimize voriconazole therapy against A. fumigatus.
authors.affiliation: Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Siopi
authors.affiliation: Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Weill Cornell Medical College of Cornell University, New York, New York, USA.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Mavridou
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Centre, Nijmegen, The Netherlands Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Johan W
authors.initials: JW
authors.lastname: Mouton
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Verweij
authors.affiliation: Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Loukia
authors.initials: L
authors.lastname: Zerva
authors.affiliation: Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece jmeletiadis@med.uoa.gr.
authors.forename: Joseph
authors.initials: J
authors.lastname: Meletiadis
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001228:Aspergillosis / Q000188:drug therapy*; D001232:Aspergillus fumigatus / Q000187:drug effects*; D004195:Disease Models, Animal; D016903:Drug Monitoring; D006801:Humans; D020714:Maximum Tolerated Dose; D051379:Mice; D008826:Microbial Sensitivity Tests; D015233:Models, Statistical; D065819:Voriconazole / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D065819:Voriconazole
keywords: A. fumigatus; azole resistance; trough levels