Department of Pharmacy Services, University of Kentucky HealthCare, Lexington, KY, USA.
Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, Lexington, KY, USA.
J Clin Pharmacol. 2024 Jul;64(7):860-865. doi: 10.1002/jcph.2425. Epub 2024 Mar 18.
Daptomycin is an antibiotic with Gram-positive activity, including methicillin-resistant Staphylococcus aureus, for which optimal pediatric dosing is unknown. This study aimed to evaluate daptomycin exposures achieved with package label dosing and to identify dosing regimens necessary to enhance efficacy and minimize toxicity in children with S. aureus bacteremia. Monte Carlo simulations were performed to determine probability of target attainment (PTA) for six pediatric age cohorts. Area under the curve to minimum inhibitory concentration ratio (AUC:MIC) ≥666 was used to determine the PTA for efficacy (PTA). Minimum concentration (C) ≥24.3 mg/L determined the PTA for toxicity (PTA). Acceptable dosing regimens were those which achieved the combined target of ≥90% PTA and ≤5% PTA. Package label dosing of daptomycin yielded insufficient efficacy with only 26.3% PTA in children 13-24 months, 39.5% PTA in children 2-6 years, 30.1% PTA in children 7-11 years, and 50.1% PTA in adolescents ≥12 years. To achieve the combined efficacy and safety target, doses of 18-24 mg/kg in children 3-12 months, 20-24 mg/kg in children 13-24 months, 19-24 mg/kg in children 2-6 years, 17-19 mg/kg in children 7-11 years, and 10-14 mg/kg in adolescents ≥12 years are necessary. Package label dosing resulted in suboptimal exposure for the majority of pediatric patients in all age groups evaluated. If targeting validated efficacy and safety endpoints, daily daptomycin doses of at least 20 mg/kg in children ≤6 years, 17 mg/kg in children 7-11 years, and 10 mg/kg in adolescents ≥12 years are necessary. Clinical studies evaluating these higher doses are needed.
达托霉素是一种具有革兰氏阳性活性的抗生素，包括耐甲氧西林金黄色葡萄球菌，其最佳儿科剂量尚不清楚。本研究旨在评估包装标签剂量下达托霉素的暴露情况，并确定在金黄色葡萄球菌菌血症患儿中增强疗效和降低毒性所需的剂量方案。进行蒙特卡罗模拟以确定六个儿科年龄组的目标达标概率（PTA）。曲线下面积与最小抑菌浓度比值（AUC：MIC）≥666 用于确定疗效的 PTA（PTA）。最小浓度（C）≥24.3mg/L 确定毒性的 PTA（PTA）。可接受的剂量方案是那些达到≥90%PTA 和≤5%PTA 的综合目标的方案。达托霉素的包装标签剂量在 13-24 个月的儿童中仅产生 26.3%的疗效 PTA，在 2-6 岁的儿童中产生 39.5%的疗效 PTA，在 7-11 岁的儿童中产生 30.1%的疗效 PTA，在≥12 岁的青少年中产生 50.1%的疗效 PTA。为了达到联合疗效和安全性目标，在 3-12 个月的儿童中需要 18-24mg/kg 的剂量，在 13-24 个月的儿童中需要 20-24mg/kg 的剂量，在 2-6 岁的儿童中需要 19-24mg/kg 的剂量，在 7-11 岁的儿童中需要 17-19mg/kg 的剂量，在≥12 岁的青少年中需要 10-14mg/kg 的剂量。在所有评估的年龄组中，包装标签剂量导致大多数儿科患者的暴露不足。如果以验证的疗效和安全性终点为目标，6 岁以下儿童至少需要每天 20mg/kg，7-11 岁儿童 17mg/kg，≥12 岁青少年 10mg/kg 的达托霉素剂量是必要的。需要开展评估这些更高剂量的临床研究。
