Smirnova Maria V, Lubenko Irene Yu, Portnoy Yury A, Zinner Stephen H, Firsov Alexander A
Department of Pharmacokinetics and Pharmacodynamics, Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 11 Bolshaya Pirogovskaya Street, Moscow 119021, Russia.
Int J Antimicrob Agents. 2007 Feb;29(2):165-9. doi: 10.1016/j.ijantimicag.2006.09.011. Epub 2007 Jan 4.
The abilities of different indices of bacterial killing to ensure reasonable concentration-response relationships have been compared only in studies in vitro with fluoroquinolones. To ascertain the relevance of conclusions drawn in these studies to other antibiotic classes, five widely used indices that reflect the rate of initial killing (time to reduce the initial inoculum 10- and 100-fold-T(90%) and T(99%), respectively), the extent of killing (minimal number of surviving organisms-N(min)), and the entire antimicrobial effect (number of surviving organisms (N(t)) at the time t close to the end of the observation period (48 h in most experiments), and area between the control growth curve and the time-kill curve from zero point to t-ABBC) were examined with daptomycin (DAP)- and vancomycin (VAN)-exposed Staphylococcus aureus. To compare the pharmacodynamics of DAP and VAN and examine different parameters, killing kinetics of differentially susceptible S. aureus were studied over a wide range of ratios of area under the curve (AUC) to MIC. Killing kinetics of two clinical isolates, S. aureus 866 (MIC(DAP) 0.35 mg/L and MIC(VAN) 0.70 mg/L) and S. aureus 10 (MIC(DAP) 1.1mg/L and MIC(VAN) 1.3mg/L), were studied in an in vitro dynamic model that simulates human pharmacokinetics of DAP (as a single dose) and VAN (as two 12-h doses). Mono-exponential concentration decays were mimicked with half-lives of 9h (DAP) and 6h (VAN) at AUC/MIC ratios varying from 33 to 1150 h. T(90%), T(99%) and N(t) (at t=48 h) exhibited loose, if any, correlations with log AUC/MIC. Both ABBC (a direct measure of the antimicrobial effect) and N(min) (an inverse measure of the effect) correlated well with log AUC/MIC (r(2)=0.8-0.9). Based on the ABBC-log AUC/MIC relationships, the effects of DAP on S. aureus were predicted to be slightly greater than those of VAN at a given AUC/MIC ratio. The better abilities of ABBC and N(min) and the inability of T(90%) and T(99%) to provide reasonable AUC/MIC relationships with DAP and VAN support earlier findings reported with fluoroquinolones.
仅在氟喹诺酮类药物的体外研究中比较了不同细菌杀灭指标确保合理浓度-反应关系的能力。为确定这些研究得出的结论与其他抗生素类别的相关性，对反映初始杀灭速率（分别将初始接种物减少10倍和100倍的时间——T(90%)和T(99%)）、杀灭程度（存活生物体的最小数量——N(min)）以及整个抗菌效果（在接近观察期结束时（大多数实验中为48小时）时间t时存活生物体的数量（N(t)）以及从零点到t的对照生长曲线与时间-杀灭曲线之间的面积——ABBC）的五个广泛使用的指标，用达托霉素（DAP）和万古霉素（VAN）处理金黄色葡萄球菌进行了研究。为比较DAP和VAN的药效学并检查不同参数，在曲线下面积（AUC）与最低抑菌浓度（MIC）的广泛比例范围内研究了不同敏感性金黄色葡萄球菌的杀灭动力学。在一个模拟DAP（单剂量）和VAN（两剂12小时剂量）人体药代动力学的体外动态模型中，研究了两种临床分离株金黄色葡萄球菌866（MIC(DAP) 0.35 mg/L和MIC(VAN) 0.70 mg/L）和金黄色葡萄球菌10（MIC(DAP) 1.1mg/L和MIC(VAN) 1.3mg/L）的杀灭动力学。在AUC/MIC比值从33到1150小时变化时，模拟了半衰期为9小时（DAP）和6小时（VAN）的单指数浓度衰减。T(90%)、T(99%)和N(t)（在t = 48小时时）与log AUC/MIC呈松散（如果有的话）相关性。ABBC（抗菌效果的直接测量指标）和N(min)（效果的反向测量指标）均与log AUC/MIC有良好相关性（r(2)=0.8 - 0.9）。基于ABBC - log AUC/MIC关系，在给定的AUC/MIC比值下，预计DAP对金黄色葡萄球菌的作用略大于VAN。ABBC和N(min)的较好能力以及T(90%)和T(99%)无法与DAP和VAN建立合理的AUC/MIC关系，支持了先前关于氟喹诺酮类药物的研究结果。
