头孢氨苄基于模型的重症感染给药建议：从婴儿期到成年期的汇总药代动力学分析。
完整摘要 · 中文译文
背景：头孢氨苄越来越多地用于严重感染的初始治疗和口服转换治疗，但在这种情形下的最佳给药剂量仍不确定。方法：汇总了涵盖早产新生儿至年轻成人的四个头孢氨苄药代动力学（PK）数据集，以建立一个统一的群体PK模型。模拟估算了在不同fT > MIC目标（游离药物浓度高于最低抑菌浓度的时间）、甲氧西林敏感金黄色葡萄球菌（MSSA）和肠杆菌目细菌的MIC分布以及多种给药方案下，目标达成概率（PTA）和累积达标率（CFR，按病原菌MIC分布加权的目标达成率）。结果：71名受试者（年龄9天–29岁）贡献了360份血浆样本，最佳描述为具有一级吸收和滞后时间的一室模型。表观容积和清除率随去脂体重缩放，清除率随经后龄增加而升高。新生儿吸收较慢。头孢氨苄25 mg/kg/剂，最大1000 mg，每8小时一次，对MSSA达到1-log杀灭目标（在MIC = 4 mg/L时，35% fT > MIC目标的PTA ≥ 98%）；当MIC = 8 mg/L时需要每6小时给药。对于肠杆菌目细菌，仅在2个月以下的婴儿中达到了60% fT > MIC目标。然而，当cefazolin MIC≤2 mg/L时，较高剂量方案（37.5–50 mg/kg，最大1500 mg，每6小时一次）对40%–50% fT > MIC目标实现了> 90%的CFR。结论：头孢氨苄的PK随年龄变化，但可通过统一的体型和成熟度缩放模型很好地描述。这些数据支持在FDA批准的范围内给药。 针对全身性甲氧西林敏感金黄色葡萄球菌（MSSA）感染的用药范围。对于肠杆菌目细菌，需要更高剂量方案才能充分达到目标浓度。适当给药剂量的头孢氨苄是治疗某些特定严重感染的可行选择，包括口服转换治疗。
完整摘要 · 英文原文
BACKGROUND: Cephalexin is increasingly used as initial and oral transition therapy for severe infections, but optimal dosing in this setting remains uncertain. METHODS: Four cephalexin pharmacokinetic (PK) datasets spanning preterm neonates through young adults were pooled to develop a unified population PK model. Simulations estimated probability of target attainment (PTA) and cumulative fractional response (CFR, target attainment weighted across the pathogen MIC distribution) across fT > MIC targets (free drug time above the minimum inhibitory concentration), MIC distributions for methicillin-susceptible Staphylococcus aureus (MSSA) and Enterobacterales, and multiple dosing regimens. RESULTS: Seventy-one subjects (age 9 days-29 years) contributed 360 plasma samples, best described by a 1-compartment model with first-order absorption and lag time. Apparent volume and clearance scaled with fat-free mass, and clearance increased with postmenstrual age. Absorption was slower in neonates. Cephalexin 25 mg/kg/dose, maximum 1000 mg, every 8 hours, achieved 1-log kill targets for MSSA (PTA ≥ 98% for 35% fT > MIC at MIC = 4 mg/L); every 6-hour dosing was needed at MIC = 8 mg/L. For Enterobacterales, a 60% fT > MIC target was achieved only in infants < 2 months. However, higher-dose regimens (37.5-50 mg/kg, maximum 1500 mg, every 6 hours) achieved CFRs > 90% for 40%-50% fT > MIC targets when cefazolin MICs were ≤2 mg/L. CONCLUSIONS: Cephalexin PK varies with age but is well-captured by a unified size- and maturation-scaled model. These data support dosing within the FDA-approved range for systemic MSSA infections. Higher-dose regimens are necessary for adequate target attainment against Enterobacterales. Appropriately dosed cephalexin represents a viable option for selected severe infections, including oral transition therapy.