应用蒙特卡罗模拟优化革兰阳性球菌感染时达托霉素的给药方案

Application of Monte Carlo simulation in optimization of dosing regimens of daptomycin for treatment of gram-positive cocci infections

  • 摘要: 目的 基于达托霉素的药代动力学/药效学参数、利用蒙特卡罗(MCS)模拟评价达托霉素治疗葡萄球菌和肠球菌感染的给药方案,为临床合理使用达托霉素提供参考。方法 收集山东第一医科大学附属省立医院细菌耐药监测数据,使用肉汤稀释法测定达托霉素对致病菌的最小抑菌浓度(MIC);通过MCS模拟预测7种不同给药方案的目标获得概率(PTA)和累积反应评分(CFR),给药方案分别为4 mg/(kg·d)、5 mg/(kg·d)、6 mg/(kg·d)、500 mg/d、7 mg/(kg·d)、8 mg/(kg·d)和9 mg/(kg·d)。结果 针对金黄色葡萄球菌感染,7种给药方案的CFR值均>90%,表明在经验性治疗过程中,所有给药方案均可获得理想疗效。对于粪肠球菌感染,则需剂量达到8 mg/(kg·d)及以上,其CFR值方可>90%。对于表皮葡萄球菌感染,尽管其PTA值与金黄色葡萄球菌相同,但因MIC分布不同,仍需8 mg/(kg·d)及以上的给药方案才可使CFR>90%。结论 达托霉素用于治疗不同的革兰阳性球菌感染时所需的给药方案需根据感染菌种及MIC值进行个体化调整,经验性治疗方案的制定需参考本地流行病学数据,以优化抗感染效果并延缓耐药发生。

     

    Abstract: OBJECTIVE To evaluate the dosing regimens of daptomycin for treatment of Staphylococcus and Enterococcus faecalis infections by Monte Carlo simulation (MCS) based on pharmacokinetic/pharmacodynamic (PK/PD) parameters of daptomycin so as to provide reference for reasonable clinical use of daptomycin. METHODS The data regarding bacterial resistance surveillance were collected from Shandong Provincial Hospital Affiliated to Shandong First Medical University, and the minimum inhibitory concentrations (MIC) of daptomycin against pathogenic bacteria were determined by broth dilution method. The probability of target attainment (PTA) and cumulative fraction of response (CFR) of 7 dosing regimens were predicated through MCS; the dosing regimens were 4 mg/(kg·d), 5 mg/(kg·d), 6 mg/(kg·d), 500 mg/d, 7 mg/(kg·d), 8 mg/(kg·d) and 9 mg/(kg·d), respectively. RESULTS The CFRs of all the 7 dosing regimens were greater than 90% for Staphylococcus aureus infection, indicating that all of the dosing regimens could acquired satisfied effect during the process of empirical therapy. The dosage needed to be 8 mg/(kg·d) or more for Enterococcus faecalis infection, then its CFR could be greater than 90%. Although the PTA of Staphylococcus epidermidis infection was as same as that of the S. aureus infection, the dosing regimen with no less than 8 mg/(kg·d) could make the CFR greater than 90% due to the different distributions of MIC. CONCLUSION The dosing regimens of daptomycin for treatment of the gram-positive bacteria infection need to be adjusted individually based on the species of pathogens and MICs, the empirical therapeutic regimen should be formulated based on the epidemiological data so as to optimize the anti-infection effect and postpone the drug resistance.

     

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