title: Bacterial strain-to-strain variation in pharmacodynamic index magnitude, a hitherto unconsidered factor in establishing antibiotic clinical breakpoints.
abstract: Antibiotic pharmacodynamic modeling allows variations in pathogen susceptibility and human pharmacokinetics to be accounted for when considering antibiotic doses, potential bacterial pathogen targets for therapy, and clinical susceptibility breakpoints. Variation in the pharmacodynamic index (area-under-the-concentration curve to 24 h [AUC(24)]/MIC; maximum serum concentration of drug in the serum/MIC; time the serum concentration remains higher than the MIC [T > MIC]) is not usually considered. In an in vitro pharmacokinetic model of infection using a dose-ranging design, we established the relationship between AUC(24)/MIC and the antibacterial effect for moxifloxacin against 10 strains of Staphylococcus aureus. The distributions of AUC(24)/MIC targets for 24-h bacteriostatic effect and 1-log, 2-log, and 3-log drops in bacterial counts were used to calculate potential clinical breakpoint values, and these were compared with those obtained by the more conventional approach of taking a single AUC(24)/MIC target. Consideration of the AUC(24)/MIC as a distribution rather than a single value resulted in a lower clinical breakpoint.
authors.affiliation: Bristol Centre for Antimicrobial Research and Evaluation, University of Bristol, North Bristol NHS Trust, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol, United Kingdom. alasdair.macgowan@nbt.nhs.uk
authors.forename: Alasdair P
authors.initials: AP
authors.lastname: MacGowan
authors.forename: Rosy
authors.initials: R
authors.lastname: Reynolds
authors.forename: Alan R
authors.initials: AR
authors.lastname: Noel
authors.forename: Karen E
authors.initials: KE
authors.lastname: Bowker
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001372:Aza Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology; D024841:Fluoroquinolones; D006801:Humans; D008826:Microbial Sensitivity Tests; D008962:Models, Theoretical; D000077266:Moxifloxacin; D011804:Quinolines / Q000493:pharmacokinetics* / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D000077266:Moxifloxacin