Wenker Suzanne A M, Alabdulkarim Najla, Readman John B, Slob Elise M A, Satta Giovanni, Ali Shanom, Gadher Nishma, Shulman Rob, Standing Joseph F
Infection, Immunity and Inflammation Department, Great Ormond Street Institute of Child Health, University College London, London, UK.
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden University, Leiden, The Netherlands.
JAC Antimicrob Resist. 2024 Mar 12;6(2):dlae036. doi: 10.1093/jacamr/dlae036. eCollection 2024 Apr.
It is important to optimize dosing schemes of antibiotics to maximize the probability of therapeutic success. The recommended pharmacokinetic/pharmacodynamic (PK/PD) index for piperacillin/tazobactam therapy in clinical studies ranges widely (50%-100% ). Dosing schemes failing to achieve PK/PD targets may lead to negative treatment outcomes.
The first aim of this study was to define the optimal PK/PD index of piperacillin/tazobactam with a hollow-fibre infection model (HFIM). The second aim was to predict whether these PK/PD targets are currently achieved in critically ill patients through PK/PD model simulation.
A dose-fractionation study comprising 21 HFIM experiments was performed against a range of Gram-negative bacterial pathogens, doses and infusion times. Clinical data and dose histories from a case series of nine patients with a known bacterial infection treated with piperacillin/tazobactam in the ICU were collected. The PK/PD index and predicted plasma concentrations and therefore target attainment of the patients were simulated using R version 4.2.1.
was found to be the best-fitting PK/PD index for piperacillin/tazobactam. Bactericidal activity with 2 log cfu reduction was associated with 77% . Piperacillin/tazobactam therapy was defined as clinically 'ineffective' in ∼78% (7/9) patients. Around seventy-one percent (5/7) of these patients had a probability of >10% that 2 log cfu reduction was not attained.
Our dose-fractionation study indicates an optimal PK/PD target in piperacillin/tazobactam therapies should be 77% for 2 log kill. Doses to achieve this target should be considered when treating patients in ICU.
优化抗生素给药方案以最大化治疗成功的概率很重要。临床研究中推荐的哌拉西林/他唑巴坦治疗的药代动力学/药效学（PK/PD）指标范围广泛（50%-100%）。未达到PK/PD目标的给药方案可能导致负面治疗结果。
本研究的首要目的是通过中空纤维感染模型（HFIM）确定哌拉西林/他唑巴坦的最佳PK/PD指标。第二个目的是通过PK/PD模型模拟预测重症患者目前是否达到这些PK/PD目标。
针对一系列革兰氏阴性细菌病原体、剂量和输注时间进行了一项包含21次HFIM实验的剂量分割研究。收集了重症监护病房中9例已知细菌感染患者接受哌拉西林/他唑巴坦治疗的病例系列的临床数据和剂量史。使用R 4.2.1版模拟PK/PD指标以及预测的血浆浓度，从而模拟患者的目标达成情况。
发现是哌拉西林/他唑巴坦最合适的PK/PD指标。杀菌活性达到2 log cfu降低与77%相关。哌拉西林/他唑巴坦治疗在约78%（7/9）的患者中被定义为临床“无效”。这些患者中约71%（5/7）有超过10%的概率未达到2 log cfu降低。
我们的剂量分割研究表明，哌拉西林/他唑巴坦治疗的最佳PK/PD目标应为2 log杀灭率达到至77%。在治疗重症监护病房的患者时应考虑达到该目标的剂量。
