Objectives

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.

Methods

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.

Results

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.

Conclusions

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.

中文翻译：

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结合微生物透析，时间杀灭曲线和异抗性数据的药理学方法，用于确定细菌杀灭和耐药性抑制的目标位点特异性断点：莫西沙星的案例研究。

目标

药代动力学-药效学（PK-PD）的考虑是定义抗生素治疗敏感性临界点的核心。但是，当前的方法遵循零散的工作流程。这项研究的目的是开发一种综合药理学方法，以定义基于MIC的断点来杀死和抑制血浆和组织部位的耐药性发展，整合临床微透析数据以及体外时间-杀伤曲线和异抗性信息，例如莫西沙星对金黄色葡萄球菌和大肠埃希菌。

方法

从每天接受400 mg莫西沙星的10名患者中收集血浆和目标部位样品。对三个金黄色葡萄球菌和两个大肠杆菌菌株进行了体外时间杀灭研究，并对耐药亚群进行了定量。利用这些数据，开发了基于生理的混合（PB）PK模型和PK-PD模型，并用于预测位点特异性断点。

结果

对于这两种细菌，预计停滞在400 mg / day的MIC断裂点均为0.25 mg / L。预测断点为0.125 mg / L的皮下组织中对大肠杆菌的杀灭可靠性较低。电阻抑制的临界点为0.06 mg / L。值得注意的是，耐药亚群的扩增在临床断点为0.25 mg / L时最高。大剂量莫西沙星（800毫克/天）将所有断点提高了一个MIC层。

结论

开发了一种定义药敏断点的有效药理学方法。这有可能简化断点确定的过程。因此，该方法提供了对靶位点PK-PD和莫西沙星耐药性发展的更多见解。有必要将该方法应用于其他药物。