title: Concentration-dependent changes in the susceptibility and killing of Staphylococcus aureus in an in vitro dynamic model that simulates normal and impaired gatifloxacin elimination.
abstract: To demonstrate the impact of normal (NEK) and impaired elimination kinetics (IEK) of gatifloxacin on its ability to protect from losses in the susceptibility of Staphylococcus aureus, a clinical isolate of methicillin-resistant S. aureus at a starting inoculum of 10(8)cfu/ml was exposed to 3 days of quinolone dosing. A series of monoexponential pharmacokinetic profiles with half-lives of 7 h (NEK) and 31 h (IEK) were simulated over 32- and 8-fold ranges of the 24 h area under the concentration-time curve (AUC(24))-to-MIC ratio, respectively. The simulated AUC(24)/MICs were designed to provide peak concentrations (C(max)s) close to the MIC, between the MIC and the mutant prevention concentration (MPC), i.e., within the mutant selection window (MSW), and above the MPC. With both NEK and IEK simulations, significant increases in MIC were observed at those AUC(24)/MICs that correspond to gatifloxacin concentrations within the MSW over most of the dosing interval (>25%). No such increases were observed at the smallest AUC(24)/MIC (10h with NEK and 20 h with IEK) when the simulated C(max)s were close to the MIC, with minimal if any bacterial killing, and at the highest AUC(24)/MICs (310 and 160 h, respectively) when gatifloxacin concentrations exceeded the MPC over most of the dosing interval, with maximal antimicrobial effect. These 'protective' AUC(24)/MIC ratios correspond to 135% of the usual gatifloxacin clinical dose (400 mg NEK) and 60% of the loading and maintenance doses (400 mg, then 200 mg IEK). This study predicts different protective potentials of gatifloxacin in IEK and NEK against staphylococcal resistance and supports the MSW concept.
authors.affiliation: Department of Pharmacokinetics & Pharmacodynamics, Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 11 Bolshaya Pirogovskaya Street, Moscow 119021, Russia. firsov@dol.ru
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Firsov
authors.forename: Sergey N
authors.initials: SN
authors.lastname: Vostrov
authors.forename: Irene Yu
authors.initials: IY
authors.lastname: Lubenko
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Zinner
authors.forename: Yury A
authors.initials: YA
authors.lastname: Portnoy
mesh_terms: D024841:Fluoroquinolones / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077734:Gatifloxacin; D006801:Humans; D066298:In Vitro Techniques; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D013211:Staphylococcus aureus / Q000187:drug effects*
chemical_list: D024841:Fluoroquinolones; D000077734:Gatifloxacin