多黏菌素E联用其他抗菌药物治疗鲍曼不动杆菌感染的药效学模型研究

Pharmacodynamic modeling for in vitro evaluation of colistin E⁃based combination treatments for Acinetobacter baumannii infection

目的建立药效学模型描述多黏菌素E(colistin E)与其他抗菌药联用对泛耐药鲍曼不动杆菌(XDR⁃AB)的体外杀菌作用。方法在前期工作中,我们筛选了对XDR⁃AB具有协同杀菌作用的抗菌药联合治疗方案,并选用基因型不同的菌株进行静态杀菌实验,考察药物联用对XDR⁃AB的杀菌效果。在此基础上建立数学模型,描述多黏菌素E与美罗培南、米诺环素或利福平联用对XDR⁃AB的静态杀菌曲线。细菌生长曲线用用非线性模型表述,细菌消亡曲线用一级动力学方程表述。药物对细菌生长和消亡过程的调节符合Emax模型,引入指数模型描述抗菌药对消亡过程促进作用的衰减。结果多黏菌素细菌生长速率kin为5.07 h^-1,消亡速率kout为4.34 h^-1。多黏菌素E对细菌生长过程的抑制作用较弱,对细菌消亡过程的促进作用较强,且该促进作用随时间推移呈指数衰减。结论所建立的药效学模型较好的描述了多黏菌素E对XDR⁃AB杀菌作用的特点,为抗菌药体外联用的药动学/药效学数据建模提供了范例。

Objective To establish a pharmacodynamic model to describe the in vitro antibacterial effect of colistin E⁃based combi⁃nation on extensive drug resistant Acinetobacter baumannii(XDR⁃AB).Methods In the preliminary work,we screened a combina⁃tion of antibacterial drugs that have a synergistic bactericidal effect on XDR⁃AB,and selected strains of different genotypes for stat⁃ic bactericidal experiments to investigate the bactericidal effect of the drug combination on XDR⁃AB.On this basis,a mathematical modeling was established to describe the time⁃kill curves that indicate the antibacterial effects of colistin E⁃based combination treat⁃ments,including colistin E/meropenem,colistin E/minocycline,colistin E/rifampicin,on XDR⁃AB strains.Bacterial growth curves were presented by nonlinear model and bacterial death curves were plotted using the first⁃order kinetic equation.The regulation of antimicrobials on the bacterial growth and death process was in accordance with the Emax model;exponential decay model was intro⁃duced to describe the decay of the antibacterial’s promoting effect on bacterial death.Results The bacterial growth rate kin was 5.07 h-1 and the death rate kout was 4.34 h-1.The inhibitory effect of colistin E on bacterial growth was weak,while its promoting ef⁃fect on bacterial death was relatively strong,and this promoting effect was exponentially decaying over time.Conclusion The phar⁃macodynamic model satisfactorily describes the characteristics of the antibacterial effect of colistin E on XDR⁃AB,and provides an example for the pharmacokinetic/pharmacodynamic data modeling of in vitro drug combination of antimicrobial agents.