Dandekar Prachi K, Tessier Pamela R, Williams Peter, Nightingale Charlie H, Nicolau David P
Center for Anti-infective Research and Development, Hartford Hospital, Hartford, CT 06102, USA.
J Antimicrob Chemother. 2003 Sep;52(3):405-11. doi: 10.1093/jac/dkg337. Epub 2003 Aug 13.
To describe the pharmacodynamic profile of daptomycin against methicillin-resistant Staphylococcus aureus (MRSA) and Enterococci species based on bacterial density in an immunocompromised mouse thigh infection model.
The pharmacodynamic (PD) profile of daptomycin was determined against two MRSA, one vancomycin-resistant Enterococcus faecium, and one vancomycin-susceptible Enterococcus faecalis using the immunocompromised murine thigh model. Efficacy was assessed by the change in log10 cfu in thighs after 24 h of drug treatment.
Daptomycin produced a maximal kill of 4.5-5 log10 cfu against the MRSA and 1.5-2 log10 for the Enterococcus species. AUC/MIC was the most predictive of the PD parameters. Utilizing MICs determined in serum or broth in the calculation of the PD parameters had minimal effect on this correlation. AUCfree/MICbroth required for static effects with MRSA and Enterococcus species were 12-36 and 5-13, whereas 99% of maximal kill was achieved at ratios of 171-442 and 38-157, respectively.
These data reveal the potent in vivo bactericidal activity of daptomycin against MRSA and Enterococcus species using clinically achievable drug exposures (dose 4-6 mg/kg per day) currently under investigation in man.
在免疫受损小鼠大腿感染模型中，基于细菌密度描述达托霉素对耐甲氧西林金黄色葡萄球菌（MRSA）和肠球菌属的药效学特征。
使用免疫受损小鼠大腿模型，测定达托霉素对两种MRSA、一种耐万古霉素屎肠球菌和一种对万古霉素敏感的粪肠球菌的药效学（PD）特征。通过药物治疗24小时后大腿中log10 cfu的变化评估疗效。
达托霉素对MRSA产生的最大杀菌效果为4.5 - 5 log10 cfu，对肠球菌属为1.5 - 2 log10 cfu。AUC/MIC是最能预测PD参数的指标。在计算PD参数时使用血清或肉汤中测定的MIC对这种相关性影响最小。MRSA和肠球菌属产生静态效应所需的AUCfree/MICbroth分别为12 - 36和5 - 13，而分别在171 - 442和38 - 157的比值时可实现99%的最大杀菌效果。
这些数据揭示了在目前人体正在研究的临床可达到的药物暴露水平（每日剂量4 - 6 mg/kg）下，达托霉素对MRSA和肠球菌属具有强大的体内杀菌活性。
