Rayner Craig R, Forrest Alan, Meagher Alison K, Birmingham Mary C, Schentag Jerome J
Department of Pharmacy Practice, Victorian College of Pharmacy, Monash University, Parkville, Victoria, Australia.
Clin Pharmacokinet. 2003;42(15):1411-23. doi: 10.2165/00003088-200342150-00007.
To characterise the pharmacokinetic-pharmacodynamic relationships for linezolid efficacy.
Retrospective nonblinded analysis of severely debilitated adult patients with numerous comorbid conditions and complicated infections enrolled under the manufacturer's compassionate use programme.
Patients received intravenous or oral linezolid 600 mg every 12 hours. Plasma concentrations were obtained and a multicompartmental pharmacokinetic model was fitted. Numerical integration of the fitted functions provided the area under the concentration-time curve over 24 hours (AUC), the ratio of AUC to minimum inhibitory concentration (AUC/MIC) and the percentage of time that plasma concentrations exceeded the MIC (%T>MIC).
Modelled pharmacodynamic outcomes of efficacy included probabilities of eradication and clinical cure (multifactorial logistic regression, nonparametric tree-based modelling, nonlinear regression) and time to bacterial eradication (Kaplan-Meier and Cox proportional hazards regression). Factors considered included AUC/MIC, %T>MIC, site of infection, bacterial species and MIC, and other medical conditions.
There were 288 cases evaluable by at least one of the efficacy outcomes. Both %T>MIC and AUC/MIC were highly correlated (Spearman r2 = 0.868). In our analyses, within specific infection sites, the probability of eradication and clinical cure appeared to be related to AUC/MIC (eradication: bacteraemia, skin and skin structure infection [SSSI], lower respiratory tract infection [LRTI], bone infection; clinical cure: bacteraemia, LRTI) and %T>MIC (eradication: bacteraemia, SSSI, LRTI; clinical cure: bacteraemia, LRTI). Time to bacterial eradication for bacteraemias appeared to be related to the AUC, %T>MIC and AUC/MIC. For most sites, AUC/MIC and %T>MIC models performed similarly.
Higher success rates for linezolid may occur at AUC/MIC values of 80-120 for bacteraemia, LRTI and SSSI. Chance of success in bacteraemia, LRTI and SSSI also appear to be higher when concentrations remain above the MIC for the entire dosing interval.
描述利奈唑胺疗效的药代动力学-药效学关系。
对在制造商的同情用药计划下登记的患有多种合并症和复杂感染的严重虚弱成年患者进行回顾性非盲分析。
患者每12小时接受600mg静脉或口服利奈唑胺。获取血浆浓度并拟合多室药代动力学模型。对拟合函数进行数值积分可得出24小时内浓度-时间曲线下面积（AUC）、AUC与最低抑菌浓度之比（AUC/MIC）以及血浆浓度超过MIC的时间百分比（%T>MIC）。
疗效的模拟药效学结果包括根除概率和临床治愈率（多因素逻辑回归、基于非参数树的建模、非线性回归）以及细菌根除时间（Kaplan-Meier和Cox比例风险回归）。考虑的因素包括AUC/MIC、%T>MIC、感染部位、细菌种类和MIC以及其他医疗状况。
至少有一项疗效结果可评估的病例有288例。%T>MIC和AUC/MIC均高度相关（Spearman r2 = 0.868）。在我们的分析中，在特定感染部位，根除概率和临床治愈率似乎与AUC/MIC（根除：菌血症、皮肤及皮肤结构感染[SSSI]、下呼吸道感染[LRTI]、骨感染；临床治愈：菌血症、LRTI）和%T>MIC（根除：菌血症、SSSI、LRTI；临床治愈：菌血症、LRTI）有关。菌血症的细菌根除时间似乎与AUC、%T>MIC和AUC/MIC有关。对于大多数部位，AUC/MIC和%T>MIC模型的表现相似。
对于菌血症、LRTI和SSSI，当AUC/MIC值为80-120时，利奈唑胺的成功率可能更高。当在整个给药间隔内浓度保持高于MIC时，菌血症、LRTI和SSSI的成功机会似乎也更高。
