Pharmacodynamic Model of the Dynamic Response of Pseudomonas aeruginosa Biofilms to Antibacterial Treatments.
Pharmacodynamic Model of the Dynamic Response of Pseudomonas aeruginosa Biofilms to Antibacterial Treatments.
复制标题
DOI：
10.3390/biomedicines11082316
复制
发表时间：
2023-08-21
期刊：
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
--
作者：
生物膜治疗的准确药代动力学-药效学（PK-PD）模型可用于指导制剂和给药策略，以更好地控制细菌性肺部感染。为此，我们开发了一种使用一线抗生素妥布霉素和粘菌素治疗铜绿假单胞菌的详细药效学模型，并在详细的杀伤动力学数据集上对其进行了验证。开发了一种房室模型结构，其中的关键特征是药物通过边界层扩散到细菌，与细菌的浓度依赖性相互作用，以及细菌在死亡前通过连续的过境状态。妥布霉素是一种核糖体抑制剂，其转运状态的数量大于粘菌素，而粘菌素会破坏细菌膜。对于这两种药物，实验观察到的药物暴露后细菌杀灭延迟与扩散时间和通过过渡状态的时间之和一致。对于每种药物，具有单组参数的PD模型描述了10倍浓度范围内的数据，以及连续和短暂暴露方案以及联合药物治疗的数据。在一系列给药方案中预测药物反应的能力允许该PD模型与PK描述整合，以描述体内抗生素反应动力学并预测用于改善细菌性肺部感染控制的药物递送策略。
Accurate pharmacokinetic–pharmacodynamic (PK-PD) models of biofilm treatment could be used to guide formulation and administration strategies to better control bacterial lung infections. To this end, we developed a detailed pharmacodynamic model of P. aeruginosa treatment with the front-line antibiotics, tobramycin and colistin, and validated it on a detailed dataset of killing dynamics. A compartmental model structure was developed in which the key features are the diffusion of the drug through a boundary layer to the bacteria, concentration-dependent interactions with bacteria, and the passage of the bacteria through successive transit states before death. The number of transit states employed was greater for tobramycin, which is a ribosomal inhibitor, than for colistin, which disrupts bacterial membranes. For both drugs, the experimentally observed delay in the killing of bacteria following drug exposure was consistent with the sum of the diffusion time and the time for passage through the transit states. For each drug, the PD model with a single set of parameters described data across a ten-fold range of concentrations and for both continuous and transient exposure protocols, as well as for combined drug treatments. The ability to predict drug response over a range of administration protocols allows this PD model to be integrated with PK descriptions to describe in vivo antibiotic response dynamics and to predict drug delivery strategies for the improved control of bacterial lung infections.
登录
查看更多内容
基于模型的肺部给药药物开发：治疗铜绿假单胞菌肺部感染的新候选药物的药代动力学分析。
影响因子：
3.8
作者：
Sou T;Kukavica-Ibrulj I;Soukarieh F;Halliday N;Levesque RC;Williams P;Stocks M;Cámara M;Friberg LE;Bergström CAS
通讯作者：
Bergström CAS
影响因子：
4.3
作者：
Angeles-Martinez L;Hatzimanikatis V
通讯作者：
Hatzimanikatis V
影响因子：
3.8
作者：
Janakiraman, Vijay;Englert, Derek;Baskaran, Harihara
通讯作者：
Baskaran, Harihara
影响因子：
6.4
作者：
Moustafa DA;Wu AW;Zamora D;Daly SM;Sturge CR;Pybus C;Geller BL;Goldberg JB;Greenberg DE
通讯作者：
Greenberg DE
影响因子：
3.2
作者：
Jung, Woo Jin;Park, Jung-Hyuck;Yun, Hwi-yeol
通讯作者：
Yun, Hwi-yeol