Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, Netherlands.
Antimicrob Agents Chemother. 2010 May;54(5):1734-41. doi: 10.1128/AAC.01696-09. Epub 2010 Feb 22.
Extracorporeal membrane oxygenation (ECMO) is used to temporarily sustain cardiac and respiratory function in critically ill infants but can cause pharmacokinetic changes necessitating dose modifications. Cefotaxime (CTX) is used to prevent and treat infections during ECMO, but the current dose regimen is based on pharmacokinetic data obtained for non-ECMO patients. The objective of this study was to validate the standard dose regimen of 50 mg/kg of body weight twice a day (postnatal age [PNA], <1 week), 50 mg/kg three times a day (PNA, 1 to 4 weeks), or 37.5 mg/kg four times a day (PNA, >4 weeks). We included 37 neonates on ECMO, with a median (range) PNA of 3.3 (0.67 to 199) days and a median (range) body weight of 3.5 (2.0 to 6.2) kg at the onset of ECMO. Median (range) ECMO duration was 108 (16 to 374) h. Plasma samples were taken during routine care, and pharmacokinetic analysis of CTX and its active metabolite, desacetylcefotaxime (DACT), was done using nonlinear mixed-effects modeling (NONMEM). A one-compartment pharmacokinetic model for CTX and DACT adequately described the data. During ECMO, CTX clearance (CL(CTX)) was 0.36 liter/h (range, 0.19 to 0.75 liter/h), the volume of distribution of CTX (V(CTX)) was 1.82 liters (0.73 to 3.02 liters), CL(DACT) was 1.46 liters/h (0.48 to 5.93 liters/h), and V(DACT) was 11.0 liters (2.32 to 28.0 liters). Elimination half-lives for CTX and DACT were 3.5 h (1.6 to 6.8 h) and 5.4 h (0.8 to 14 h). Peak CTX concentration was 98.0 mg/liter (33.2 to 286 mg/liter). DACT concentration varied between 0 and 38.2 mg/liter, with a median of 10 mg/liter in the first 12 h postdose. Overall, CTX concentrations were above the MIC of 8 mg/liter over the entire dose interval. Only 1 of the 37 patients had a sub-MIC concentration for over 50% of the dose interval. In conclusion, the standard cefotaxime dose regimen provides sufficiently long periods of supra-MIC concentrations to provide adequate treatment of infants on ECMO.
体外膜肺氧合（ECMO）用于暂时维持危重症婴儿的心脏和呼吸功能，但会导致药代动力学变化，需要调整剂量。头孢噻肟（CTX）用于预防和治疗 ECMO 期间的感染，但目前的剂量方案是基于非 ECMO 患者的药代动力学数据。本研究的目的是验证标准剂量方案，即每天两次 50mg/kg 体重（出生后年龄[PNA]，<1 周）、每天三次 50mg/kg 体重（PNA，1 至 4 周）或每天四次 37.5mg/kg 体重（PNA，>4 周）。我们纳入了 37 名接受 ECMO 的新生儿，中位（范围）PNA 为 3.3（0.67 至 199）天，中位（范围）体重为 3.5（2.0 至 6.2）kg，开始 ECMO 时。中位（范围）ECMO 持续时间为 108（16 至 374）小时。在常规护理期间采集血浆样本，并使用非线性混合效应建模（NONMEM）进行 CTX 及其活性代谢物去乙酰头孢噻肟（DACT）的药代动力学分析。CTX 和 DACT 的单室药代动力学模型能够很好地描述数据。在 ECMO 期间，CTX 清除率（CL(CTX)）为 0.36 升/小时（范围，0.19 至 0.75 升/小时），CTX 分布容积（V(CTX)）为 1.82 升（0.73 至 3.02 升），CL(DACT)为 1.46 升/小时（0.48 至 5.93 升/小时），V(DACT)为 11.0 升（2.32 至 28.0 升）。CTX 和 DACT 的消除半衰期分别为 3.5 小时（1.6 至 6.8 小时）和 5.4 小时（0.8 至 14 小时）。CTX 峰浓度为 98.0 毫克/升（33.2 至 286 毫克/升）。DACT 浓度在 0 至 38.2 毫克/升之间变化，首剂量后 12 小时的中位数为 10 毫克/升。总体而言，CTX 浓度在整个剂量间隔内均高于 8 毫克/升的 MIC。37 名患者中只有 1 名患者的亚 MIC 浓度超过 50%的剂量间隔。结论：标准头孢噻肟剂量方案可提供足够长的时间，使超 MIC 浓度，为 ECMO 婴儿提供充分的治疗。
