BACKGROUND Staphylococcus aureus is one of the major causes of bloodstream infections (BSI) worldwide, representing a major challenge for public health due to its resistance profile. Higher vancomycin minimum inhibitory concentrations (MIC) in S. aureus are associated with treatment failure and defining optimal empiric options for BSIs in settings where these isolates are prevalent is rather challenging. In silico pharmacodynamic models based on stochastic simulations (Monte Carlo) are important tools to estimate best antimicrobial regimens in different scenarios. We aimed to compare the pharmacodynamic profiles of different antimicrobials regimens for the treatment of S. aureus BSI in an environment with high vancomycin MIC. METHODS Steady-state drug area under the curve ratio to MIC (AUC/MIC) or the percent time above MIC (fT > MIC) were modeled using a 5000-patient Monte Carlo simulation to achieve pharmacodynamic exposures against 110 consecutive S. aureus isolates associated with BSI. RESULTS Cumulative fractions of response (CFRs) against all S. aureus isolates were 98% for ceftaroline; 79% and 92% for daptomycin 6 mg/kg q24h and for the high dose of 10 mg/kg q24h, respectively; 77% for linezolid 600 mg q12h when MIC was read according to CLSI M100-S26 instructions, and 64% when MIC was considered at the total growth inhibition; 65% and 86% for teicoplanin, three loading doses of 400 mg q12 h followed by 400 mg q24 h and for teicoplanin 400 mg q12 h, respectively; 61% and 76% for vancomycin 1000 mg q12 h and q8 h, respectively. CONCLUSIONS Based on this model, ceftaroline and high-dose daptomycin regimens delivered best pharmacodynamic exposures against S. aureus BSIs. Teicoplanin higher dose regimen achieved the best CFR (86%) among glycopeptides, although optimal threshold was not achieved, and vancomycin performance was critically affected by the S. aureus vancomycin MIC ≥2 mg/L. Linezolid effectiveness (CFR of 73%) is also affected by high prevalence of isolates with linezolid MIC ≥2 mg/L. These data show the need to continually evaluate the pharmacodynamic profiles of antimicrobials for empiric treatment of these infections.

中文翻译：

---

不同抗菌方案对万古霉素最低抑菌浓度升高的金黄色葡萄球菌血流感染的药效学比较。


背景技术金黄色葡萄球菌是全世界血流感染(BSI)的主要原因之一，由于其耐药性而对公共卫生构成了重大挑战。金黄色葡萄球菌中万古霉素最低抑菌浓度 (MIC) 较高与治疗失败相关，在这些分离株流行的环境中确定 BSI 的最佳经验选择相当具有挑战性。基于随机模拟（蒙特卡罗）的计算机药效学模型是估计不同情况下最佳抗菌方案的重要工具。我们的目的是比较在高万古霉素 MIC 环境中治疗金黄色葡萄球菌 BSI 的不同抗菌药物方案的药效学特征。方法 使用 5000 名患者蒙特卡罗模拟对稳态药物曲线下面积与 MIC 的比率 (AUC/MIC) 或高于 MIC 的时间百分比 (fT > MIC) 进行建模，以实现针对 110 个连续金黄色葡萄球菌分离株的药效学暴露与 BSI。结果 头孢洛林对所有金黄色葡萄球菌分离株的累积反应分数 (CFR) 为 98%；达托霉素 6 mg/kg q24h 和高剂量 10 mg/kg q24h 分别为 79% 和 92%；当根据 CLSI M100-S26 说明读取 MIC 时，利奈唑胺 600 mg q12h 为 77%，当考虑总生长抑制时 MIC 为 64%；对于替考拉宁，分别为 65% 和 86%，三个负荷剂量为 400 mg q12 h，随后为 400 mg q24 h，对于替考拉宁 400 mg q12 h，分别为 65% 和 86%；万古霉素 1000 mg 每 12 小时和每 8 小时分别为 61% 和 76%。结论 根据该模型，头孢洛林和高剂量达托霉素方案可提供针对金黄色葡萄球菌 BSI 的最佳药效学暴露。 替考拉宁较高剂量方案在糖肽类药物中实现了最佳 CFR (86%)，但未达到最佳阈值，并且万古霉素的性能受到金黄色葡萄球菌万古霉素 MIC ≥2 mg/L 的严重影响。利奈唑胺的有效性（CFR 为 73%）还受到利奈唑胺 MIC ≥2 mg/L 分离株高流行率的影响。这些数据表明需要不断评估用于经验性治疗这些感染的抗菌药物的药效学特征。