Abstract：
OBJECTIVE: Predictions of antimicrobial effects typically rely on plasma-based pharmacokinetic-pharmacodynamic (PK-PD) targets, ignoring target-site concentrations and potential differences in tissue penetration between antibiotics. In this study, we applied PK-PD modelling to compare target site-specific effects of antibiotics by integrating clinical microdialysis data, in vitro time-kill curves, and antimicrobial susceptibility distributions. As a case study, we compared the effect of lefamulin and ceftaroline against methicillin-resistant Staphylococcus aureus (MRSA) at soft-tissue concentrations.
METHODS: A population PK model describing lefamulin concentrations in plasma, subcutaneous adipose and muscle tissue was developed. For ceftaroline, a similar previously reported PK model was adopted. In vitro time-kill experiments were performed with six MRSA isolates and a PD model was developed to describe bacterial growth and antimicrobial effects. The clinical PK and in vitro PD models were linked to compare antimicrobial effects of ceftaroline and lefamulin at the different target sites.
RESULTS: Considering minimum inhibitory concentration (MIC) distributions and standard dosages, ceftaroline showed superior anti-MRSA effects compared to lefamulin both at plasma and soft-tissue concentrations. Looking at the individual antibiotics, lefamulin effects were highest at soft-tissue concentrations, while ceftaroline effects were highest at plasma concentrations, emphasising the importance of considering target-site PK-PD in antibiotic treatment optimisation.
CONCLUSIONS: Given standard dosing regimens, ceftaroline appeared more effective than lefamulin against MRSA at soft-tissue concentrations. The PK-PD model-based approach applied in this study could be used to compare or explore the potential of antibiotics for specific indications or in populations with unique target-site PK.
METHODS: A population PK model describing lefamulin concentrations in plasma, subcutaneous adipose and muscle tissue was developed. For ceftaroline, a similar previously reported PK model was adopted. In vitro time-kill experiments were performed with six MRSA isolates and a PD model was developed to describe bacterial growth and antimicrobial effects. The clinical PK and in vitro PD models were linked to compare antimicrobial effects of ceftaroline and lefamulin at the different target sites.
RESULTS: Considering minimum inhibitory concentration (MIC) distributions and standard dosages, ceftaroline showed superior anti-MRSA effects compared to lefamulin both at plasma and soft-tissue concentrations. Looking at the individual antibiotics, lefamulin effects were highest at soft-tissue concentrations, while ceftaroline effects were highest at plasma concentrations, emphasising the importance of considering target-site PK-PD in antibiotic treatment optimisation.
CONCLUSIONS: Given standard dosing regimens, ceftaroline appeared more effective than lefamulin against MRSA at soft-tissue concentrations. The PK-PD model-based approach applied in this study could be used to compare or explore the potential of antibiotics for specific indications or in populations with unique target-site PK.
摘要：
目的：抗菌作用的预测通常依赖于基于血浆的药代动力学-药效学（PK-PD）目标，忽略靶部位浓度和抗生素之间组织渗透的潜在差异。在这项研究中,我们应用PK-PD模型通过整合临床微透析数据来比较抗生素的靶部位特异性效应，体外时间-杀伤曲线，和抗菌药物敏感性分布。作为一个案例研究，我们比较了lefamulin和头孢洛林在软组织浓度下对抗耐甲氧西林金黄色葡萄球菌(MRSA)的效果.
方法：描述血浆中lefamulin浓度的群体PK模型，发展皮下脂肪和肌肉组织。对于头孢洛林，采用了以前报道的类似PK模型.用6种MRSA分离物进行了体外时间杀伤实验，并开发了PD模型来描述细菌生长和抗菌作用。将临床PK和体外PD模型相关联以比较头孢洛林和lefamulin在不同靶位点处的抗微生物作用。
结果：考虑到最小抑制浓度（MIC）分布和标准剂量，在血浆和软组织浓度下，头孢洛林均显示出比lefamulin更好的抗MRSA作用。看看单独的抗生素，lefamulin在软组织浓度下效果最高，虽然头孢洛林在血浆浓度下效果最高，强调在抗生素治疗优化中考虑靶位PK-PD的重要性。
结论：给定标准给药方案，在软组织浓度下，头孢洛林比lefamulin对MRSA更有效。本研究中应用的基于PK-PD模型的方法可用于比较或探索抗生素在特定适应症或具有独特靶位PK的人群中的潜力。
方法：描述血浆中lefamulin浓度的群体PK模型，发展皮下脂肪和肌肉组织。对于头孢洛林，采用了以前报道的类似PK模型.用6种MRSA分离物进行了体外时间杀伤实验，并开发了PD模型来描述细菌生长和抗菌作用。将临床PK和体外PD模型相关联以比较头孢洛林和lefamulin在不同靶位点处的抗微生物作用。
结果：考虑到最小抑制浓度（MIC）分布和标准剂量，在血浆和软组织浓度下，头孢洛林均显示出比lefamulin更好的抗MRSA作用。看看单独的抗生素，lefamulin在软组织浓度下效果最高，虽然头孢洛林在血浆浓度下效果最高，强调在抗生素治疗优化中考虑靶位PK-PD的重要性。
结论：给定标准给药方案，在软组织浓度下，头孢洛林比lefamulin对MRSA更有效。本研究中应用的基于PK-PD模型的方法可用于比较或探索抗生素在特定适应症或具有独特靶位PK的人群中的潜力。
