Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL, USA.
J Antimicrob Chemother. 2018 May 1;73(5):1295-1304. doi: 10.1093/jac/dkx537.
To characterize quantitatively the effect of avibactam in potentiating ceftazidime against MDR Pseudomonas aeruginosa by developing a mathematical model to describe the bacterial response to constant concentration time-kill information and validating it using both constant and time-varying concentration-effect data from in vitro and in vivo infection systems.
The time course of the bacterial population dynamics in the presence of static concentrations of ceftazidime and avibactam was modelled using a two-state pharmacokinetic/pharmacodynamic (PK/PD) model, consisting of active and resting states, to account for bactericidal activities, bacteria-mediated ceftazidime degradation and inhibition of degradation by avibactam. Ceftazidime's effect on the bacterial population was described as an enhancement of the death rate of the active population, with the effect of avibactam being to increase ceftazidime potency. Model validation was performed by comparing simulated time courses of bacterial responses with those from in vitro and in vivo experimental exposures of ceftazidime and avibactam that represented those predicted in an average patient dosed with 2 g/0.5 g ceftazidime/avibactam administered every 8 h as 2 h infusions.
The two-state model successfully described the bacterial population dynamics, ceftazidime degradation and its inhibition by avibactam. For external validation, the model correctly predicted the bacterial response of P. aeruginosa isolates evaluated in in vitro hollow-fibre and in vivo neutropenic mouse thigh and lung infection models.
The PK/PD model and modelled strains successfully replicated the spread in activity when compared with a large selection of P. aeruginosa strains reported in the literature.
通过建立一个数学模型来描述细菌对恒定浓度时间杀伤信息的反应，并使用来自体外和体内感染系统的恒定和时变浓度-效应数据对其进行验证，从而定量描述 avibactam 增强头孢他啶对多药耐药铜绿假单胞菌的作用。
使用由活性和静止状态组成的两状态药代动力学/药效学（PK/PD）模型来模拟存在静态浓度头孢他啶和 avibactam 时细菌群体动力学的时间过程，以解释杀菌活性、细菌介导的头孢他啶降解以及 avibactam 抑制降解的作用。头孢他啶对细菌群体的作用被描述为增加活性群体的死亡率，avibactam 的作用是增加头孢他啶的效力。通过将模拟的细菌反应时间过程与体外和体内实验暴露于头孢他啶和 avibactam 的时间过程进行比较来进行模型验证，这些实验暴露代表了在接受 2 g/0.5 g 头孢他啶/avibactam 每 8 小时给药的平均患者中预测的情况，作为 2 小时输注。
两状态模型成功描述了细菌群体动力学、头孢他啶降解及其被 avibactam 抑制的过程。对于外部验证，该模型正确预测了在体外中空纤维和体内中性粒细胞减少症小鼠大腿和肺感染模型中评估的铜绿假单胞菌分离株的细菌反应。
PK/PD 模型和模拟菌株成功复制了与文献中报道的大量铜绿假单胞菌菌株相比活性的扩散。
