Beijing Key Laboratory of Pediatric Respiratory Infection Diseases, Key Laboratory of Major Diseases in Children, Ministry of Education, National Clinical Research Center for Respiratory Diseases, National Key Discipline of Pediatrics (Capital Medical University), Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
Department of Neonatology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.
Int J Antimicrob Agents. 2019 Mar;53(3):347-351. doi: 10.1016/j.ijantimicag.2018.11.017. Epub 2018 Nov 22.
There has been recent renewed interest in historical antibiotics because of the increased antibiotic-resistant bacterial strains. Latamoxef, a semi-synthetic oxacephem antibiotic developed in 1980s, has recently been brought back into use for treatment of infections in newborns; however, it is still used off-label in neonatal clinical practice due to the lack of an evidence-based dosing regimen. This study was performed to evaluate the pharmacokinetics of latamoxef in neonates and young infants, and to provide an evidence-based dosing regimen for newborns based on developmental pharmacokinetics-pharmacodynamics (PK-PD).
Opportunistic blood samples from newborns treated with latamoxef were collected to determine the latamoxef concentration by high-performance liquid chromatography with UV detection. Population PK-PD analysis was conducted using NONMEM and R software. A total of 165 plasma samples from 128 newborns (postmenstrual age range 28.4-46.1 weeks) were available for analysis.
A two-compartment model with first-order elimination showed the best fit with the data. Current body weight, birth weight, and postnatal age were identified as significant covariates influencing latamoxef clearance. Simulation indicated that the current dosing regimen (30 mg/kg q12h) is adequate with an MIC of 1 mg/L. For an MIC of 4 mg/L, 30 mg/kg q8h was required to achieve a target rate of 70% of patients having a free antimicrobial drug concentration exceeding the MIC during 70% of the dosing interval.
Based on the developmental PK-PD analysis of latamoxef, a rational dosing regimen of 30 mg/kg q12h or q8h was required in newborns, depending on the pathogen.
由于抗生素耐药菌株的增加，最近人们对历史抗生素重新产生了兴趣。拉美莫头孢，一种 20 世纪 80 年代开发的半合成氧头孢烯抗生素，最近因其在新生儿感染治疗中的应用而重新受到关注；然而，由于缺乏基于证据的剂量方案，它仍在新生儿临床实践中被超适应证使用。本研究旨在评估拉美莫头孢在新生儿和婴儿中的药代动力学，并根据发育药代动力学-药效学（PK-PD）为新生儿提供基于证据的剂量方案。
从接受拉美莫头孢治疗的新生儿中采集机会性血样，通过高效液相色谱法（HPLC）结合紫外检测法测定拉美莫头孢的浓度。采用 NONMEM 和 R 软件进行群体 PK-PD 分析。共有 128 名新生儿（胎龄 28.4-46.1 周）的 165 个血浆样本可供分析。
数据拟合最佳的是一个具有一级消除的两室模型。当前体重、出生体重和出生后年龄被确定为影响拉美莫头孢清除率的显著协变量。模拟表明，当前的给药方案（30mg/kg，q12h）在 MIC 为 1mg/L 时是足够的。对于 MIC 为 4mg/L，需要 30mg/kg，q8h 才能使 70%的患者在 70%的给药间隔内有超过 MIC 的游离抗菌药物浓度达到目标率。
基于拉美莫头孢的发育 PK-PD 分析，新生儿需要根据病原体选择 30mg/kg，q12h 或 q8h 的合理给药方案。
