DataSheet1_Model-Informed Drug Development of New Cefoperazone Sodium and Sulbactam Sodium Combination (3:1): Pharmacokinetic/Pharmacodynamic Analysis and Antibacterial Efficacy Against Enterobacteriaceae.pdf

Objective: Cefoperazone/sulbactam is a commonly used antibiotic combination against the extended-spectrum beta-lactamases (ESBLs)-producing bacteria. The objective of this study was to evaluate the efficacy of a new cefoperazone/sulbactam combination (3:1) for Enterobacteriaceae infection via model-informed drug development (MIDD) approaches.Methods: Sulperazon [cefoperazone/sulbactam (2:1)] was used as a control. Pharmacokinetic (PK) data was collected from a clinical phase I trial. Minimum inhibitory concentrations (MICs) were determined using two-fold broth microdilution method. The percent time that the free drug concentration exceeded the minimum inhibitory concentration (%fT>MIC) was used as the pharmacokinetic/pharmacodynamic indicator correlated with efficacy. Models were developed to characterize the PK profile of cefoperazone and sulbactam. Monte Carlo simulations were employed to determine the investigational regimens of cefoperazone/sulbactam (3:1) for the treatment of infections caused by Enterobacteriaceae based on the probability of target attainment (PTA) against the tested bacteria.Results: Two 2-compartment models were developed to describe the PK profiles of cefoperazone and sulbactam. Simulation results following the single-dose showed that the regimens of cefoperazone/sulbactam combinations in the ratios of 3:1 and 2:1 achieved similar PTA against the tested bacteria. Simulation results from the multiple-dose showed that the dosing regimen of cefoperazone/sulbactam (4 g, TID, 3 g:1 g) showed slightly better antibacterial effect than cefoperazone/sulbactam (6 g, BID, 4 g:2 g) against the Escherichia coli (ESBL−) and Klebsiella pneumoniae (ESBL−). For the other tested bacteria, the above regimens achieved a similar PTA.Conclusions: Cefoperazone/sulbactam (3:1) showed similar bactericidal activity to sulperazon [cefoperazone/sulbactam (2:1)] against the tested bacteria. For the ESBL-producing and cefoperazone-resistant E. coli and K. pneumoniae, Cefoperazone/sulbactam (3:1) did not exhibit advantage as anticipated. Our study indicated that further clinical trials should be carried out cautiously to avoid the potential risks of not achieving the expected target.

研究目的：头孢哌酮/舒巴坦是一种针对广谱β-内酰胺酶（ESBLs）产生菌的常用抗生素组合。本研究旨在评估一种新型头孢哌酮/舒巴坦组合（3:1比例）针对肠杆菌科感染的疗效，通过模型引导的药物开发（MIDD）方法进行评估。研究方法：以舒巴坦[头孢哌酮/舒巴坦（2:1比例）]作为对照。从临床I期试验中收集了药代动力学（PK）数据。使用双倍稀释法确定最小抑菌浓度（MICs）。将药物浓度超过最小抑菌浓度的时间百分比（%fT>MIC）用作与疗效相关的药代动力学/药效学指标。开发了模型以描述头孢哌酮和舒巴坦的PK特征。采用蒙特卡洛模拟基于靶点达成概率（PTA）确定头孢哌酮/舒巴坦（3:1比例）针对肠杆菌科感染的研究方案。研究结果：开发了两个二室模型来描述头孢哌酮和舒巴坦的PK特征。单剂量模拟结果显示，头孢哌酮/舒巴坦组合（3:1和2:1比例）在针对测试细菌的PTA方面取得了相似的结果。多剂量模拟结果显示，头孢哌酮/舒巴坦（4克，每日三次，3克:1克）的剂量方案对大肠杆菌（ESBL-）和肺炎克雷伯菌（ESBL-）的抗菌效果略优于头孢哌酮/舒巴坦（6克，每日两次，4克:2克）。对于其他测试的细菌，上述方案达到了相似的PTA。研究结论：头孢哌酮/舒巴坦（3:1比例）在针对测试细菌的杀菌活性与舒巴坦[头孢哌酮/舒巴坦（2:1比例）]相似。对于产生ESBL和头孢哌酮耐药的大肠杆菌和肺炎克雷伯菌，头孢哌酮/舒巴坦（3:1比例）并未表现出预期的优势。我们的研究指出，应谨慎进行进一步的临床试验，以避免未能达到预期目标的风险。