title: Relationships of the area under the curve/MIC ratio to different integral endpoints of the antimicrobial effect: gemifloxacin pharmacodynamics in an in vitro dynamic model.
abstract: Most integral endpoints of the antimicrobial effect are determined over an arbitrarily chosen time period, such as the dosing interval (tau), regardless of the actual effect duration. Unlike the tau-related endpoints, the intensity of the antimicrobial effect (I(E)) does consider its duration-from time zero to the time when bacterial counts on the regrowth curve achieve the same maximal numbers as in the absence of the antimicrobial. To examine the possible impact of this fundamental difference on the relationships of the antimicrobial effect to the ratio of the area under the concentration-time curve (AUC) to the MIC, a clinical isolate of Staphylococcus aureus was exposed to simulated gemifloxacin pharmacokinetics over a 40-fold range of AUC/MIC ratios, from 11 to 466 h. In each run, I(E) and four tau-related endpoints, including the area under the time-kill curve (AUBC), the area above the curve (AAC), the area between the control growth and time-kill curves (ABBC), and the ABBC related to the area under the control growth curve (AUGC), were calculated for tau = 24 h. Unlike the I(E), which displayed pseudolinear relationships with the AUC/MIC ratio; each tau-related endpoint showed a distinct saturation at potentially therapeutic AUC/MIC ratios (116 to 466 h) when the antimicrobial effect persisted longer than tau. This saturation results from the underestimation of the true effect and may be eliminated if ABBC, AAC, and AUBC (but not AUGC) are modified and determined in the same manner as the I(E) to consider the actual effect duration. These data suggest a marginal value of the tau-related endpoints as indices of the total antimicrobial effect. Since all of them respond to AUC/MIC ratio changes less than the I(E), the latter is preferable in comparative pharmacodynamic studies.
authors.affiliation: Department of Pharmacokinetics, Centre of Science & Technology LekBioTech, Moscow, Russia. firsov@dol.ru
authors.forename: A A
authors.initials: AA
authors.lastname: Firsov
authors.forename: I Y
authors.initials: IY
authors.lastname: Lubenko
authors.forename: Y A
authors.initials: YA
authors.lastname: Portnoy
authors.forename: S H
authors.initials: SH
authors.lastname: Zinner
authors.forename: S N
authors.initials: SN
authors.lastname: Vostrov
mesh_terms: D000890:Anti-Infective Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D003198:Computer Simulation; D024841:Fluoroquinolones; D000077735:Gemifloxacin; D006801:Humans; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D009287:Naphthyridines / Q000493:pharmacokinetics* / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects*; D013997:Time Factors
chemical_list: D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D009287:Naphthyridines; D000077735:Gemifloxacin