Microbiology Department, School of Medicine, Universidad Complutense, Avda. Complutense s/n, 28040 Madrid, Spain.
Int J Antimicrob Agents. 2010 Feb;35(2):131-7. doi: 10.1016/j.ijantimicag.2009.09.021. Epub 2009 Dec 16.
This study explored the influence of vancomycin tolerance and protein binding on the bactericidal activity of vancomycin versus daptomycin (protein binding 36.9% vs. 91.7%, respectively) against four vancomycin-tolerant methicillin-resistant Staphylococcus aureus (MRSA) [minimum inhibitory concentration/minimum bactericidal concentration (MIC/MBC)=0.5/16, 1/32, 2/32 and 1/32microg/mL for vancomycin and 1/1, 1/2, 2/2 and 2/4microg/mL for daptomycin]. Killing curves were performed with vancomycin/daptomycin concentrations equal to serum peak concentrations (C(max)) (65.70/98.60microg/mL) and trough concentrations (C(min)) (7.90/9.13microg/mL) in the presence and absence of a physiological human albumin concentration (4g/dL), controlled with curves with the theoretical free drug fraction of vancomycin/daptomycin C(max) (41.45/8.18microg/mL) and C(min) (4.98/0.76microg/mL). Vancomycin C(max) and C(min) concentrations, regardless of the media, showed a bacteriostatic profile not reaching a reduction of 99% or 99.9% of the initial inocula during the 24-h experimental time period. Daptomycin antibacterial profiles significantly differed when testing C(max) and C(min). C(max) was rapidly bactericidal (< or =4h) with >5 log(10) reduction in the initial inocula for all strains, regardless of the presence or not of albumin or the use of concentrations similar to free C(max). C(min) exhibited similar final colony counts at 0h and 24h in curves with albumin, but with >3 log colony-forming units (CFU)/mL reduction at < or =4h for strains with an MIC of 1microg/mL and ca. 2 logCFU/mL reduction at < or =6h for strains with an MIC of 2microg/mL. This activity was significantly higher than the activity of the free C(min) fraction. The results of this study reinforce the idea that pharmacodynamics using concentrations calculated using reported protein binding are unreliable. Daptomycin exhibited rapid antibacterial activity against vancomycin-tolerant MRSA isolates even against those with high daptomycin MICs in the presence of physiological albumin concentrations.
本研究探讨了万古霉素耐药性和蛋白结合对万古霉素和达托霉素杀菌活性的影响（蛋白结合率分别为 36.9%和 91.7%），针对四种耐万古霉素的耐甲氧西林金黄色葡萄球菌（MRSA）[万古霉素的最小抑菌浓度/最小杀菌浓度（MIC/MBC）=0.5/16、1/32、2/32 和 1/32μg/mL，达托霉素的 MIC/MBC=1/1、1/2、2/2 和 2/4μg/mL]。在存在和不存在生理人白蛋白浓度（4g/dL）的情况下，用等于血清峰浓度（C(max)）（65.70/98.60μg/mL）和谷浓度（C(min)）（7.90/9.13μg/mL）的万古霉素/达托霉素浓度进行杀伤曲线实验，用万古霉素/达托霉素 C(max)（41.45/8.18μg/mL）和 C(min)（4.98/0.76μg/mL）的理论游离药物分数来控制曲线。无论介质如何，万古霉素的 C(max)和 C(min)浓度在 24 小时实验期间都表现出抑菌特性，未能使初始接种物减少 99%或 99.9%。达托霉素的抗菌谱在测试 C(max)和 C(min)时显著不同。C(max)在 4 小时内迅速杀菌（<或=4 小时），所有菌株的初始接种物减少>5 log(10)，无论是否存在白蛋白或使用类似于游离 C(max)的浓度。在含白蛋白的曲线中，C(min)在 0 小时和 24 小时的最终菌落计数相似，但对于 MIC 为 1μg/mL 的菌株，在<或=4 小时内减少了>3 log 菌落形成单位（CFU）/mL，对于 MIC 为 2μg/mL 的菌株，在<或=6 小时内减少了约 2 log CFU/mL。这种活性明显高于游离 C(min)部分的活性。本研究的结果加强了这样一种观点，即使用报告的蛋白结合计算浓度的药效动力学是不可靠的。达托霉素对耐万古霉素的 MRSA 分离株具有快速的抗菌活性，即使在存在生理白蛋白浓度的情况下，对达托霉素 MIC 较高的分离株也是如此。
