Therapeutic antibiotic dose monitoring can be particularly challenging in septic patients requiring renal replacement therapy. Our aim was to conduct an exploratory population pharmacokinetic (PK) analysis on PK of vancomycin following intermittent infusion in critically ill patients receiving continuous venovenous haemodiafiltration (CVVHDF); focussing on the influence of dialysis-related covariates. This was a retrospective single-centre tertiary level intensive care unit (ICU) study, which included patients treated concurrently with vancomycin and CVVHDF between January 2015 and July 2016. We extracted clinical, laboratory and dialysis data from the electronic healthcare record (EHR), using strict inclusion criteria. A population PK analysis was conducted with a one-compartment model using the PMetrics population PK modelling package. A base structural model was developed, with further analyses including clinical and dialysis-related data to improve model prediction through covariate inclusion. The final selected model simulated patient concentrations using probability of target attainment (PTA) plots to investigate the probability of different dosing regimens achieving target therapeutic concentrations. A total of 106 vancomycin dosing intervals (155 levels) in 24 patients were examined. An acceptable 1-compartment base model was produced (Plots of observed vs. population predicted concentrations (Obs–Pred) R2 = 0.78). No continuous covariates explored resulted in a clear improvement over the base model. Inclusion of anticoagulation modality and vasopressor use as categorical covariates resulted in similar PK parameter estimates, with a trend towards lower parameter estimate variability when using regional citrate anti-coagulation or without vasopressor use. Simulations using PTA plots suggested that a 2 g loading dose followed by 750 mg 12 hourly as maintenance dose, commencing 12 h after loading, is required to achieve adequate early target trough concentrations of at least 15 mg/L. PTA simulations suggest that acceptable trough vancomycin concentrations can be achieved early in treatment with a 2 g loading dose and maintenance dose of 750 mg 12 hourly for critically ill patients on CVVHDF.

中文翻译：

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探索连续静脉-静脉血液透析滤过 (CVVHDF) 期间接受万古霉素治疗的患者的群体药代动力学模型

在需要肾脏替代治疗的脓毒症患者中，治疗性抗生素剂量监测尤其具有挑战性。我们的目的是对接受连续静脉-静脉血液透析滤过 (CVVHDF) 的危重患者间断输注万古霉素后的 PK 进行探索性群体药代动力学 (PK) 分析；关注透析相关协变量的影响。这是一项回顾性单中心三级重症监护病房 (ICU) 研究，包括 2015 年 1 月至 2016 年 7 月期间同时接受万古霉素和 CVVHDF 治疗的患者。我们从电子医疗记录 (EHR) 中提取临床、实验室和透析数据，使用严格的纳入标准。使用 PMetrics 群体 PK 建模包通过单室模型进行群体 PK 分析。开发了一个基础结构模型，进一步分析包括临床和透析相关数据，以通过协变量包含改进模型预测。最终选择的模型使用目标达到概率 (PTA) 图模拟患者浓度，以研究不同给药方案达到目标治疗浓度的概率。共检查了 24 名患者的 106 次万古霉素给药间隔（155 个水平）。产生了一个可接受的 1 室基础模型（观察到的与总体预测浓度 (Obs–Pred) R2 = 0.78 的曲线图）。没有探索的连续协变量导致对基本模型的明显改进。将抗凝方式和血管加压药用作分类协变量导致相似的 PK 参数估计，当使用局部柠檬酸盐抗凝剂或不使用血管加压药时，参数估计变异性趋于降低。使用 PTA 图的模拟表明，为了达到至少 15 mg/L 的足够早期目标谷浓度，需要 2 g 负荷剂量，然后是 750 mg 12 小时作为维持剂量，从负荷后 12 小时开始。PTA 模拟表明，对于使用 CVVHDF 的危重患者，可以在治疗早期以 2 g 负荷剂量和 750 mg 维持剂量 12 小时达到可接受的万古霉素谷浓度。需要达到足够的早期目标谷浓度至少 15 mg/L。PTA 模拟表明，对于使用 CVVHDF 的危重患者，可以在治疗早期以 2 g 负荷剂量和 750 mg 维持剂量 12 小时达到可接受的万古霉素谷浓度。需要达到足够的早期目标谷浓度至少 15 mg/L。PTA 模拟表明，对于使用 CVVHDF 的危重患者，可以在治疗早期以 2 g 负荷剂量和 750 mg 维持剂量 12 小时达到可接受的万古霉素谷浓度。