Concentration-dependent changes in the susceptibility and killing of Staphylococcus aureus in an in vitro dynamic model that simulates normal and impaired gatifloxacin elimination

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• 作者：Firsov ; Alexander A. ; Vostrov ; Sergey N. ; Lubenko ; Irene Yu. ; Zinner ; Stephen H. ; Portnoy ; Yury A.
• 关键词：Bacterial resistance ; Fluoroquinolones ; Pharmacokinetics
• 刊名：International Journal of Antimicrobial Agents
• 出版年：2004
• 出版时间：January, 2004
• 年：2004
• 卷：23
• 期：1
• 页码：60-66
• 全文大小：262 K

文摘

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 10⁸cfu/ml was exposed to 3 days of quinolone dosing. A series of monoexponential pharmacokinetic profiles with half-lives of 7h (NEK) and 31h (IEK) were simulated over 32- and 8-fold ranges of the 24h area under the concentration-time curve (AUC₂₄)-to-MIC ratio, respectively. The simulated AUC₂₄/MICs were designed to provide peak concentrations (C_maxs) 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 AUC₂₄/MICs that correspond to gatifloxacin concentrations within the MSW over most of the dosing interval (>25 % ). No such increases were observed at the smallest AUC₂₄/MIC (10h with NEK and 20h with IEK) when the simulated C_maxs were close to the MIC, with minimal if any bacterial killing, and at the highest AUC₂₄/MICs (310 and 160h, respectively) when gatifloxacin concentrations exceeded the MPC over most of the dosing interval, with maximal antimicrobial effect. These ‘protective’ AUC₂₄/MIC ratios correspond to 135 % of the usual gatifloxacin clinical dose (400mg NEK) and 60 % of the loading and maintenance doses (400mg, then 200mg IEK). This study predicts different protective potentials of gatifloxacin in IEK and NEK against staphylococcal resistance and supports the MSW concept.