PDF(Pubmed)
Abstract：
Background: While positive blood cultures are the gold standard for late-onset sepsis (LOS) diagnosis in premature and very low birth weight (VLBW) newborns, these results can take days, and early markers of possible treatment efficacy are lacking. The objective of the present study was to investigate whether the response to vancomycin could be quantified using bacterial DNA loads (BDLs) determined by real-time quantitative polymerase chain reaction (RT-qPCR). Methods: VLBW and premature neonates with suspected LOS were included in a prospective observational study. Serial blood samples were collected to measure BDL and vancomycin concentrations. BDLs were measured with RT-qPCR, whereas vancomycin concentrations were measured by LC-MS/MS. Population pharmacokinetic-pharmacodynamic modeling was performed with NONMEM. Results: Twenty-eight patients with LOS treated with vancomycin were included. A one-compartment model with post-menstrual age (PMA) and weight as covariates was used to describe the time PK profile of vancomycin concentrations. In 16 of these patients, time profiles of BDL could be described with a pharmacodynamic turnover model. The relationship between vancomycin concentration and first-order BDL elimination was described with a linear-effect model. Slope S increased with increasing PMA. In 12 patients, no decrease in BDL over time was observed, which corresponded with clinical non-response. Discussion: BDLs determined through RT-qPCR were adequately described with the developed population PKPD model, and treatment response to vancomycin using BDL in LOS can be assessed as early as 8 h after treatment initiation.
摘要：
背景：虽然血培养阳性是早产和极低出生体重（VLBW）新生儿迟发性败血症（LOS）诊断的金标准，这些结果可能需要几天的时间，缺乏可能的治疗效果的早期标志物。本研究的目的是研究是否可以使用通过实时定量聚合酶链反应（RT-qPCR）确定的细菌DNA载量（BDL）来定量对万古霉素的反应。方法：将VLBW和疑似LOS的早产儿纳入一项前瞻性观察性研究。收集系列血液样品以测量BDL和万古霉素浓度。用RT-qPCR测量BDL，而万古霉素浓度通过LC-MS/MS测量。使用NONMEM进行群体药代动力学-药效学建模。结果：28例LOS患者接受万古霉素治疗。以月经后年龄（PMA）和体重为协变量的一室模型用于描述万古霉素浓度的时间PK曲线。在其中16名患者中，BDL的时间曲线可以用药效学周转模型描述.用线性效应模型描述了万古霉素浓度与一级BDL消除之间的关系。斜率S随着PMA的增加而增加。在12名患者中，没有观察到BDL随时间的减少，这与临床无反应相对应。讨论：通过RT-qPCR确定的BDL用开发的群体PKPD模型充分描述，在LOS中使用BDL对万古霉素的治疗反应最早可以在治疗开始后8小时进行评估。
