Mukap Mispah, Sprod Corin, Yoo Okhee, Tefuarani Nakapi, Vince John, Laman Moses, Page-Sharp Madhu, Moore Brioni R, Batty Kevin T, Davis Timothy M E, Salman Sam, Manning Laurens
School of Medicine, University of Papua New Guinea, Port Moresby, Papua New Guinea.
Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea.
Antimicrob Agents Chemother. 2025 Apr 2;69(4):e0149124. doi: 10.1128/aac.01491-24. Epub 2025 Mar 4.
Amoxicillin plus gentamicin is the recommended first-line empiric therapy for neonates with infection. Guidelines vary widely in dose (mg/kg), dose frequency, and adjustments according to post-menstrual age (PMA) and post-natal age (PNA). We aimed to develop a population pharmacokinetic (PK) model for amoxicillin in neonates with clinical evidence of sepsis and design optimal dosing regimens. One hundred seventy-seven neonates receiving intravenous amoxicillin for infection were enrolled in a prospective, observational PK study in Papua New Guinea (PNG). The probability of PK-pharmacodynamic target attainment (PK-PD PTA) was determined based on minimum inhibitory concentrations (MIC) and the proportion of time concentrations that remained above these values (%T > MIC). Neonates with concentrations > 140 mg/L were considered to be at increased risk of amoxicillin neurotoxicity. A population PK model was developed. Simulations tested existing guidelines and proposed simplified regimens. The median PMA and PNA were 38 (37-40) weeks and 0 (0-2) days, respectively. From simulations, existing regimens with 50 or 100 mg/kg doses were associated with higher potential neurotoxic concentrations (24.9% and 84.5%, respectively). With the existing 30 mg/kg PNG regimen, neonates receiving twice-daily dosing between 3 and 7 days were systematically underdosed. A proposed 30 mg/kg regimen, with twice-daily dosing for the first 2 days PNA and three times daily from day 3, provides an optimal balance between the probability of PK-PD target attainment while minimizing toxicity. For fixed volume dosing, using 52 mg (0.25 mL of 250 mg in 1.2 mL) for those <3 kg and 104 mg (0.5 mL) for those ≥3 kg is proposed.
阿莫西林加庆大霉素是新生儿感染的推荐一线经验性治疗方案。指南在剂量（mg/kg）、给药频率以及根据月经龄（PMA）和出生后年龄（PNA）进行的调整方面差异很大。我们旨在建立一个针对有败血症临床证据的新生儿阿莫西林群体药代动力学（PK）模型，并设计最佳给药方案。在巴布亚新几内亚（PNG），177名因感染接受静脉注射阿莫西林的新生儿参加了一项前瞻性观察性PK研究。基于最低抑菌浓度（MIC）以及浓度保持高于这些值的时间比例（%T > MIC）来确定达到PK-药效学目标（PK-PD PTA）的概率。浓度>140 mg/L的新生儿被认为阿莫西林神经毒性风险增加。建立了一个群体PK模型。模拟测试了现有指南和提议的简化方案。PMA和PNA的中位数分别为38（37 - 40）周和0（0 - 2）天。通过模拟，50或100 mg/kg剂量的现有方案与更高的潜在神经毒性浓度相关（分别为24.9%和84.5%）。对于现有的30 mg/kg PNG方案，出生后3至7天接受每日两次给药的新生儿系统性给药不足。提议的30 mg/kg方案，出生后第1天和第2天每日两次给药，从第3天开始每日三次给药，在达到PK-PD目标的概率和最小化毒性之间提供了最佳平衡。对于固定体积给药，建议体重<3 kg的婴儿使用52 mg（1.2 mL中250 mg的0.25 mL），体重≥3 kg的婴儿使用104 mg（0.5 mL）。
