Leonard Steven N, Rybak Michael J
Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, and Detroit Receiving Hospital, Detroit, MI 48201, USA.
J Antimicrob Chemother. 2009 Jan;63(1):155-60. doi: 10.1093/jac/dkn439. Epub 2008 Nov 4.
Glycopeptides have historically been the drugs of choice for the treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA). However, the continued selective pressure has led to the emergence of non-susceptible strains including heterogeneously vancomycin-intermediate S. aureus (hVISA). Infections with hVISA have been associated with poor outcomes including vancomycin treatment failures. The objective of this study was to evaluate vancomycin and daptomycin against vancomycin-susceptible MRSA and hVISA in a pharmacokinetic/pharmacodynamic (PK/PD) model with simulated endocardial vegetations.
Six clinical isolates obtained from patients at the Detroit Medical Center were used: MRSA 494, MRSA 67, hVISA R1720, hVISS R2295, hVISA R3640 and hVISA R1629. All heteroresistant strains were confirmed by a population analysis profile ratio, with Mu3 as a control strain. Vancomycin regimens of 1 g every 12 h and 2 g every 12 h and daptomycin regimens of 6, 10 and 12 mg/kg daily were utilized in a PK/PD model over 72 h.
Against MRSA isolates, vancomycin displayed minimal activity and minimal-to-no activity against hVISA. In general, the use of high dose vancomycin over standard dose vancomycin did not improve activity except against one of six isolates (MRSA 494). Daptomycin was bactericidal against both MRSA and hVISA isolates, although the rate of kill was slower against hVISA.
Overall, daptomycin achieved rapid and effective kill against both MRSA and hVISA while vancomycin displayed slow and minimal kill against MRSA and minimal-to-no activity against hVISA, regardless of high dose exposure.
糖肽类药物一直是治疗耐甲氧西林金黄色葡萄球菌（MRSA）感染的首选药物。然而，持续的选择性压力导致了包括异质性万古霉素中介金黄色葡萄球菌（hVISA）在内的非敏感菌株的出现。hVISA感染与不良预后相关，包括万古霉素治疗失败。本研究的目的是在具有模拟心内膜赘生物的药代动力学/药效学（PK/PD）模型中评估万古霉素和达托霉素对万古霉素敏感的MRSA和hVISA的作用。
使用从底特律医疗中心患者分离得到的6株临床菌株：MRSA 494、MRSA 67、hVISA R1720、hVISS R2295、hVISA R3640和hVISA R1629。所有异质性耐药菌株均通过群体分析谱比进行确认，以Mu3作为对照菌株。在72小时的PK/PD模型中，采用每12小时1克和每12小时2克的万古霉素给药方案以及每日6、10和12毫克/千克的达托霉素给药方案。
对于MRSA菌株，万古霉素显示出最小活性，对hVISA显示出最小至无活性。一般来说，与标准剂量万古霉素相比，高剂量万古霉素的使用除了对6株菌株之一（MRSA 494）外，并未提高活性。达托霉素对MRSA和hVISA菌株均具有杀菌作用，尽管对hVISA的杀菌速率较慢。
总体而言，无论高剂量暴露情况如何，达托霉素对MRSA和hVISA均能实现快速有效的杀灭，而万古霉素对MRSA的杀灭缓慢且作用最小，对hVISA则几乎无活性。
