国产与原研利奈唑胺对革兰阳性菌体外PK/PD比较研究

Comparison of antibacterial efficacy of generic and branded linezolid against Gram-positive bacteria with in vitro pharmacokinetics/pharmacodynamics model

目的通过体外药动学(PK)/药效学(PD)研究,比较国产利奈唑胺(恒捷)及原研利奈唑胺(斯沃)对革兰阳性菌的抗菌效果。方法利用体外PK自动模拟系统PASS400持续24 h模拟国产及原研利奈唑胺(600mg iv.q12 h,静滴0.5 h)对金黄色葡萄球菌ATCC25923,耐甲氧西林金黄色葡萄球菌52118、耐甲氧西林表皮葡萄球菌54994、耐万古霉素屎肠球菌52820临床分离株的时间杀菌曲线及体外PD参数,使用GraphPad Prism 8.0分析数据。结果研究菌株对国产与原研利奈唑胺均敏感,最低抑菌浓度0.25~1μg/mL。在预设给药方式下,两种利奈唑胺对测定细菌均具有良好杀菌效应,且二者杀菌效果一致,24 h内二者时间杀菌曲线几乎重叠。PD参数中,两种利奈唑胺对4株细菌最大杀菌量(MKD)及24 h杀菌量(ΔlgN_(24))均接近2 lgCFU/mL,杀菌曲线下面积在23~33 lgCFU/(mL·h)之间,再生至初始菌量时间均大于24 h,54994菌株组杀菌曲线与空白对照对照曲线面积差接近13lgCFU/(mL·h),其余各组I_(E)(药物杀菌曲线与细菌生长空白对照曲线面积差)均在29~35 lgCFU/(mL·h)之间,两种药物对4株细菌杀菌速率浮动于约0.1~0.7 lgCFU/(mL·h)之间。国产与原研利奈唑胺各组间PD参数均无差异。结论国产利奈唑胺(恒捷)与原研利奈唑胺(斯沃)对常见革兰阳性菌具有相似的体外PK/PD特征及杀菌效应。

Objective To compare the antibacterial efficacy of generic and branded linezolid against Grampositive bacteria with in vitro pharmacokinetics(PK)/pharmacodynamics(PD)model.Methods The in vitro PK simulation system PASS400 was used to simulate the concentration-time curve after intravenous administration of linezolid at 600 mg q12 h for 24 hours(infusion time of 0.5 h).The bactericidal curves and PK/PD parameters of generic and branded linezolid against the reference strain of Staphylococcus aureus(ATCC25923),clinical strains of methicillin-resistant Staphylococcus aureus 52,118,methicillin-resistant coagulase-negative Staphylococcus epidermidis 54994 and vancomycin-resistant Enterococcus faecium 52,820 were compared.The GraphPad Prism 8.0 software was used for data analysis.Results All the four selected strains were susceptible to both generic and branded linezolid,and the minimum inhibitory concentrations were 0.25~1μg/mL.Both agents demonstrated outstanding and similar bactericidal effects,and their bacterial sterilization curves were almost unanimous.For the two agents,the maximum kill down was close to 2 lgCFU/mL,the area under kill curves was between 23~33 lgCFU/(mL·h),and the bacterial re-growth time was longer than 24 hours.The area difference between the control growth and bacterial killing curves against 54994 was around 13 lgCFU/(mL·h),and all against the others were 29~35 lgCFU/(mL·h),killing rate of the two agents against the four strains fluctuated between about 0.1~0.7 lgCFU/(mL·h).All PD parameters showed no difference between the generic and branded linezolid.Conclusion The generic and branded linezolid showed similar in vitro bactericidal ability and in vitro PK/PD effects against Gram positive bacteria.