Department of Pharmacy, Children's Hospital Colorado, Aurora.
University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora.
J Pediatric Infect Dis Soc. 2019 Sep 25;8(4):297-302. doi: 10.1093/jpids/piy040.
Metronidazole is traditionally dosed every 6-8 hours even though in adults it has a long half-life, concentration-dependent killing, and 3-hour postantibiotic effect. Based on this logic, some pediatric hospitals adopted once-daily dosing for appendicitis, despite limited pharmacokinetics-pharmacodynamics (PK/PD) in children. We studied pediatric patients with appendicitis given metronidazole once daily to determine whether this dosing would meet target area under the curve (AUC)/minimum inhibitory concentration (MIC) ratio of ≥70 for Bacteroides fragilis.
One hundred pediatric patients aged 4-17 years had an average of 3 blood draws per patient during the first 24 hours after a 30 mg/kg per dose of intravenous metronidazole. Concentrations of drug were determined using validated liquid chromatography and tandem mass spectrometry. A NONMEM model was constructed for determining PK, followed by Monte Carlo simulations to generate a population of plasma concentration-time AUC of metronidazole and hydroxy-metronidazole.
Simulated AUC values met target attainment (AUC/MIC ratio of ≥70 to B fragilis MICs) for 96%-100% of all patients for an MIC of 2 mcg/mL. For MICs of 4 and 8 mcg/mL, target attainment ranged from 61% to 97% and 9% to 71%, respectively. Areas under the curve were similar to that of adults receiving 1000 mg and 1500 mg q24, or 500 mg q8 hours.
Metronidazole, 30 mg/kg per dose, once daily achieved AUC target attainment for B fragilis with an MIC of 2 mcg/mL or less in pediatric appendicitis patients. Based on this and studies in adults, there does not seem to be any PK/PD advantage of more frequent dosing in this population.
尽管甲硝唑在成年人中具有较长的半衰期、浓度依赖性杀菌作用和 3 小时的抗生素后效应，但传统上仍每 6-8 小时给药一次。基于这一逻辑，尽管儿童的药代动力学-药效学（PK/PD）数据有限，一些儿科医院仍将甲硝唑用于阑尾炎的一日一次给药。我们研究了接受甲硝唑一日一次给药的阑尾炎儿科患者，以确定这种给药方案是否能达到针对脆弱拟杆菌的目标 AUC/MIC 比值≥70。
100 名 4-17 岁的儿科患者在接受 30mg/kg 剂量的静脉甲硝唑后 24 小时内平均每人进行 3 次采血。使用经过验证的液相色谱和串联质谱法测定药物浓度。建立了一个 NONMEM 模型来确定 PK，然后进行蒙特卡罗模拟，以生成甲硝唑和羟基甲硝唑的群体血浆浓度-时间 AUC。
模拟 AUC 值达到了目标（AUC/MIC 比值≥70 与脆弱拟杆菌 MIC 的比值），所有患者的 MIC 为 2 mcg/mL 的比例为 96%-100%。对于 MIC 为 4 和 8 mcg/mL，目标达标率分别为 61%-97%和 9%-71%。AUC 与接受 1000mg 和 1500mg q24 或 500mg q8 小时的成人相似。
在儿科阑尾炎患者中，30mg/kg 剂量，一日一次，对于 MIC 为 2 mcg/mL 或更低的脆弱拟杆菌，可达到 AUC 目标。基于这一点以及成人的研究，在该人群中，更频繁的给药似乎没有任何 PK/PD 优势。
Zotero 插件