Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Germany.
Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Knappschaftskrankenhaus Bochum, Ruhr-University Bochum, Germany.
Clin Microbiol Infect. 2020 Sep;26(9):1255.e1-1255.e8. doi: 10.1016/j.cmi.2020.02.013. Epub 2020 Feb 21.
Pharmacokinetic-pharmacodynamic (PK-PD) considerations are at the heart of defining susceptibility breakpoints for antibiotic therapy. However, current approaches follow a fragmented workflow. The aim of this study was to develop an integrative pharmacometric approach to define MIC-based breakpoints for killing and suppression of resistance development for plasma and tissue sites, integrating clinical microdialysis data as well as in vitro time-kill curves and heteroresistance information, exemplified by moxifloxacin against Staphylococcus aureus and Escherichia coli.
Plasma and target site samples were collected from ten patients receiving 400 mg moxifloxacin/day. In vitro time-kill studies with three S. aureus and two E. coli strains were performed and resistant subpopulations were quantified. Using these data, a hybrid physiologically based (PB) PK model and a PK-PD model were developed, and utilized to predict site-specific breakpoints.
For both bacterial species, the predicted MIC breakpoint for stasis at 400 mg/day was 0.25 mg/L. Less reliable killing was predicted for E. coli in subcutaneous tissues where the breakpoint was 0.125 mg/L. The breakpoint for resistance suppression was 0.06 mg/L. Notably, amplification of resistant subpopulations was highest at the clinical breakpoint of 0.25 mg/L. High-dose moxifloxacin (800 mg/day) increased all breakpoints by one MIC tier.
An efficient pharmacometric approach to define susceptibility breakpoints was developed; this has the potential to streamline the process of breakpoint determination. Thereby, the approach provided additional insight into target site PK-PD and resistance development for moxifloxacin. Application of the approach to further drugs is warranted.
药代动力学-药效学（PK-PD）的考虑因素是确定抗生素治疗敏感性折点的核心。然而，目前的方法采用的是碎片化的工作流程。本研究的目的是开发一种综合的药剂学方法，为血浆和组织部位的杀菌和抑制耐药发展定义基于 MIC 的折点，整合临床微透析数据以及体外时间杀伤曲线和异质耐药信息，以莫西沙星为例，用于金黄色葡萄球菌和大肠杆菌。
从每天接受 400 毫克莫西沙星治疗的 10 名患者中采集血浆和靶部位样本。对三种金黄色葡萄球菌和两种大肠杆菌菌株进行了体外时间杀伤研究，并对耐药亚群进行了定量。利用这些数据，开发了一种混合生理基础（PB）PK 模型和 PK-PD 模型，并用于预测部位特异性折点。
对于两种细菌，每天 400 毫克的停滞预测 MIC 折点为 0.25 毫克/升。在皮下组织中，大肠杆菌的预测杀菌效果较差，折点为 0.125 毫克/升。耐药抑制的折点为 0.06 毫克/升。值得注意的是，耐药亚群的扩增在临床折点 0.25 毫克/升时最高。高剂量莫西沙星（800 毫克/天）将所有折点提高了一个 MIC 梯级。
开发了一种有效定义药敏折点的药剂学方法；这有可能简化折点确定的过程。因此，该方法为莫西沙星的靶部位 PK-PD 和耐药发展提供了更多的见解。有必要将该方法应用于其他药物。
