title: Correlation of MIC with outcome for Candida species tested against voriconazole: analysis and proposal for interpretive breakpoints.
abstract: Developing interpretive breakpoints for any given organism-drug combination requires integration of the MIC distribution, pharmacokinetic and pharmacodynamic parameters, and the relationship between the in vitro activity and outcome from both in vivo and clinical studies. Using data generated by standardized broth microdilution and disk diffusion test methods, the Antifungal Susceptibility Subcommittee of the Clinical and Laboratory Standards Institute has now proposed interpretive breakpoints for voriconazole and Candida species. The MIC distribution for voriconazole was determined using a collection of 8,702 clinical isolates. The overall MIC90 was 0.25 microg/ml and 99% of the isolates were inhibited at < or = 1 microg/ml of voriconazole. Similar results were obtained for 1,681 Candida isolates (16 species) from the phase III clinical trials. Analysis of the available data for 249 patients from six phase III voriconazole clinical trials demonstrated a statistically significant correlation (P = 0.021) between MIC and investigator end-of-treatment assessment of outcome. Consistent with parallel pharmacodynamic analyses, these data support the following MIC breakpoints for voriconazole and Candida species: susceptible (S), < or = 1 microg/ml; susceptible dose dependent (SDD), 2 microg/ml; and resistant (R), > or = 4 microg/ml. The corresponding disk test breakpoints are as follows: S, > or = 17 mm; SDD, 14 to 16 mm; and R, < or = 13 mm.
authors.affiliation: Medical Microbiology Division, C606 GH, Department of Pathology, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA. michael-pfaller@uiowa.edu
authors.forename: M A
authors.initials: MA
authors.lastname: Pfaller
authors.forename: D J
authors.initials: DJ
authors.lastname: Diekema
authors.forename: J H
authors.initials: JH
authors.lastname: Rex
authors.forename: A
authors.initials: A
authors.lastname: Espinel-Ingroff
authors.forename: E M
authors.initials: EM
authors.lastname: Johnson
authors.forename: D
authors.initials: D
authors.lastname: Andes
authors.forename: V
authors.initials: V
authors.lastname: Chaturvedi
authors.forename: M A
authors.initials: MA
authors.lastname: Ghannoum
authors.forename: F C
authors.initials: FC
authors.lastname: Odds
authors.forename: M G
authors.initials: MG
authors.lastname: Rinaldi
authors.forename: D J
authors.initials: DJ
authors.lastname: Sheehan
authors.forename: P
authors.initials: P
authors.lastname: Troke
authors.forename: T J
authors.initials: TJ
authors.lastname: Walsh
authors.forename: D W
authors.initials: DW
authors.lastname: Warnock
mesh_terms: D000935:Antifungal Agents / Q000008:administration & dosage*; D002175:Candida / Q000187:drug effects* / Q000302:isolation & purification; D002177:Candidiasis / Q000188:drug therapy / Q000382:microbiology; D003627:Data Interpretation, Statistical; D025141:Drug Resistance, Fungal; D023381:Endpoint Determination; D015725:Fluconazole / Q000008:administration & dosage; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests / Q000379:methods / Q000706:statistics & numerical data; D011743:Pyrimidines / Q000008:administration & dosage*; D014230:Triazoles / Q000008:administration & dosage*; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D015725:Fluconazole; D065819:Voriconazole