Pharmacodynamics of Glycopeptides in the Mouse Peritonitis Model of Streptococcus pneumoniae or Staphylococcus aureus Infection

The emergence of resistance to various antibiotics in pneumococci leaves the glycopeptides as the only antibiotics against which pneumococci have no resistance mechanism. This situation has led to a renewed interest in the use of glycopeptides. It has not yet been possible to conclude which one or more of the pharmacokinetic or pharmacodynamic (PK/PD) parameters are the most important and best predictors for the effects of treatment with glycopeptides in animal models or in humans. We used the mouse peritonitis model with immunocompetent mice and with Staphylococcus aureus and Streptococcus pneumoniae as infective organisms. A wide spectrum of different treatment regimens with vancomycin and teicoplanin was tested to study the pharmacodynamics of these drugs. In studies in which the single dose that protected 50% of lethally infected mice (ED(50)) was given as one dose or was divided into two doses, survival was significantly decreased when the dose was divided. The only statistically significant correlations between the percentage of survival of the mice after 6 days and each of the PK/PD parameters were for peak concentration (C(max))/MIC and S. aureus and for the free fraction of C(max) (C(max-free))/MIC and S. pneumoniae. For S. pneumoniae, the ED(50) for different dosing regimens increased with the number of doses given; e.g., the single-dose ED(50)s for vancomycin and teicoplanin were 0.65 and 0.45 mg/kg, respectively, but the ED(50)s for dosing regimens with 2-h doses given for 48 h were 6.79 and 5.67 mg/kg, respectively. In experiments with 39 different vancomycin dosing regimens and 40 different teicoplanin dosing regimens against S. pneumoniae, the different PK/PD parameters were analyzed using logistic regression. The C(max-free)/MIC was one of two parameters that best explained the effect for both drugs; for vancomycin, the other important parameter was the AUC/MIC, and for teicoplanin, the other parameter was the time the free fraction of the drug is above the MIC. The effect analyzed as a function of C(max-free)/MIC disclosed thresholds with shifts from almost no effect to full effect at ratios of five to six for vancomycin and two to three for teicoplanin.

肺炎链球菌（pneumococci）对各类抗生素产生耐药性，使得糖肽类抗生素（glycopeptides）成为目前唯一未被该菌产生耐药机制的抗菌药物。这一现状使得糖肽类抗生素的临床应用重新受到关注。目前尚无定论，在动物模型或人体中，哪些药代动力学/药效动力学（pharmacokinetic or pharmacodynamic，PK/PD）参数可最精准、最优地预测糖肽类抗生素的治疗效果。本研究采用免疫健全小鼠腹膜炎模型（mouse peritonitis model），以金黄色葡萄球菌（Staphylococcus aureus）与肺炎链球菌（Streptococcus pneumoniae）作为感染菌，通过万古霉素（vancomycin）与替考拉宁（teicoplanin）的多种给药方案，探究这两种药物的药效动力学特征。在相关研究中，若将保护50%致死感染小鼠的单剂量给药方案（半数有效剂量，ED₅₀）分为单次给药或两次给药，拆分给药组的小鼠存活率显著降低。小鼠6天存活率与各PK/PD参数间仅存在两项具有统计学意义的相关性：针对金黄色葡萄球菌，为峰浓度（Cmax）与最低抑菌浓度（MIC）的比值（Cmax/MIC）；针对肺炎链球菌，为游离峰浓度（Cmax-free）与MIC的比值（Cmax-free/MIC）。对于肺炎链球菌而言，不同给药方案下的ED₅₀随给药次数增加而升高：例如万古霉素与替考拉宁的单剂量ED₅₀分别为0.65 mg/kg与0.45 mg/kg，但采用2小时/次、持续给药48小时的方案时，二者的ED₅₀分别升至6.79 mg/kg与5.67 mg/kg。在针对肺炎链球菌的实验中，共测试了39种不同的万古霉素给药方案与40种替考拉宁给药方案，并通过逻辑回归分析各PK/PD参数与药效的关联。结果显示，Cmax-free/MIC是两种药物药效的最优解释参数之一：对于万古霉素，另一关键参数为药时曲线下面积（AUC）与MIC的比值（AUC/MIC）；对于替考拉宁，另一关键参数为游离药物浓度高于MIC的持续时间。以Cmax-free/MIC为自变量分析药效时，可观察到效应阈值：万古霉素的阈值为5~6，此时药效从几乎无效应转变为完全效应；替考拉宁的阈值为2~3。