Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Bundesstraße 45, 20146, Hamburg, Germany.
Clin Pharmacokinet. 2024 Jan;63(1):121-131. doi: 10.1007/s40262-023-01325-4. Epub 2023 Nov 26.
Ceftaroline fosamil is a β-lactam antibiotic approved as a 600 mg twice daily dose (≤1 h infusion, 'standard dosing') or a 600 mg thrice daily dose (2 h infusion) to treat complicated skin and soft tissue infections caused by Staphylococcus aureus (minimum inhibitory concentration [MIC] 2-4 mg/L). We sought to systematically evaluate the relative impact of the three key components of the intensified dosing regimen (i.e. shortened dosing interval, prolonged infusion duration and increased total daily dose [TDD]) on the pharmacokinetic/pharmacodynamic (PK/PD) target attainment given different grades of bacterial susceptibility.
A population PK model was developed using data from 12 healthy volunteers (EudraCT-2012-005134-11) receiving standard or intensified dosing. PK/PD target attainment (ƒT = 35% and 100%) after 24 h was compared following systematically varied combinations of the (1) dosing interval (every 12 h [q12h]→ every 8 h [q8h]); (2) infusion duration (1 h→2 h); and (3) individual and total daily dose (400→900 mg, i.e. TDD 1200→1800 mg), as well as for varying susceptibility of S. aureus (MIC 0.032-8 mg/L).
A two-compartment model with linear elimination adequately described ceftaroline concentrations (n = 274). The relevance of the dosing components dosing interval/infusion duration/TDD for ƒT systematically changed with pathogen susceptibility. For susceptible pathogens with MIC ≤1 mg/L, shortened dosing intervals appeared as the main driver of the improved target attainment associated with the intensified dosing regimen, followed by increased TDD and infusion duration. For less susceptible pathogens, the advantage of q8h dosing and 2 h infusions declined, and increased TDD improved ƒT the most.
The analysis calls to mind consideration of dose increases when prolonging the infusion duration in the case of low bacterial susceptibility.
头孢他美酯是一种β-内酰胺类抗生素，被批准用于治疗金黄色葡萄球菌引起的复杂性皮肤和软组织感染，其推荐剂量为 600mg，每日两次（≤1 小时输注，“标准剂量”）或 600mg，每日三次（2 小时输注）。我们旨在系统评估强化剂量方案的三个关键组成部分（即缩短给药间隔、延长输注时间和增加总日剂量[TDD]）对不同细菌敏感性程度下的药代动力学/药效学（PK/PD）目标实现的相对影响。
采用 12 名健康志愿者（EudraCT-2012-005134-11）接受标准或强化剂量的群体 PK 模型，对数据进行了开发。比较了 24 小时后不同剂量组合下（1）给药间隔（q12h→q8h）；（2）输注时间（1 小时→2 小时）；（3）单个和总日剂量（400→900mg，即 TDD 1200→1800mg），以及金黄色葡萄球菌（MIC 0.032-8mg/L）敏感性变化对 24 小时时头孢他美酯的药代动力学/药效学（PK/PD）目标实现（ƒT=35%和 100%）的影响。
头孢他美酯浓度（n=274）采用具有线性消除的两室模型进行了很好的描述。给药间隔/输注时间/TDD 等剂量组成部分对于 ƒT 的相关性随着病原体的敏感性而系统地变化。对于 MIC≤1mg/L 的敏感病原体，缩短给药间隔似乎是强化剂量方案相关的改善目标实现的主要驱动因素，其次是增加 TDD 和输注时间。对于敏感性较低的病原体，q8h 给药和 2 小时输注的优势降低，而增加 TDD 则最能提高 ƒT。
分析结果提示，在低细菌敏感性情况下，当延长输注时间时，需要考虑增加剂量。
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