Anesthésie Réanimation, CHU Rangueil, Toulouse, France.
Clin Ther. 2013 Oct;35(10):1603-12. doi: 10.1016/j.clinthera.2013.08.014. Epub 2013 Oct 1.
Ceftazidime dosage regimen recommendations based on pharmacokinetic/pharmacodynamic approaches are not available for burn patients.
The goal of this study was to propose a continuous dosage regimen of ceftazidime in burn patients, taking into account different MICs and pharmacokinetic covariates.
The population pharmacokinetic analysis was conducted by using software dedicated to the analysis of nonlinear mixed effects models. The population pharmacokinetic model was first developed and validated in 70 adult burn patients. Taking into account various MICs of pathogens, 3 Monte Carlo simulation trials were conducted by using target concentration intervals (10-100, 20-100, and 40-100 mg/L). The recommended dosages were defined as the minimum dose leading to the highest percentage of patients whose ceftazidime concentrations were included in the target interval.
Serum creatinine and age were identified as covariates of ceftazidime clearance. Age was also involved in volume of distribution. The simulations showed that a dose of 6 g/d did not allow achievement of the target interval in most patients. Regardless of dosage regimen, age, and serum creatinine, the mean percentage of patients reaching the 10- to 100-mg/L and the 20- to 100-mg/L target intervals were 99.4% (0.3%) and 96.1% (0.8%), respectively. For the 40- to 100-mg/L target interval, this percentage was only 76.4% (2.1%) (range, 65%-80%).
Age and serum creatinine level can be used at the bedside to determine the initial doses of ceftazidime. These Monte Carlo simulations highlight the need of a reappraisal of ceftazidime's use in burn patients. Doses between 3 and 16 g/d are proposed, taking into account the pathogens' MICs. However, for sepsis caused by a pathogen with an MIC ≥ 8 mg/L, an insufficient percentage of burn patients will reach the therapeutic target with the recommended dosages.
目前针对烧伤患者，尚未有基于药代动力学/药效学方法的头孢他啶剂量方案推荐。
本研究旨在针对烧伤患者，提出一种头孢他啶的持续剂量方案，同时考虑不同的 MIC 值和药代动力学协变量。
使用专门用于非线性混合效应模型分析的软件进行群体药代动力学分析。首先在 70 例成年烧伤患者中开发和验证群体药代动力学模型。考虑到不同病原体的 MIC 值，通过 3 次蒙特卡罗模拟试验，使用目标浓度范围（10-100、20-100 和 40-100mg/L）进行研究。推荐剂量定义为导致最高比例的患者头孢他啶浓度处于目标范围内的最小剂量。
血清肌酐和年龄被确定为头孢他啶清除率的协变量。年龄也参与了分布容积。模拟结果表明，每天 6g 的剂量不能使大多数患者达到目标范围。无论剂量方案、年龄和血清肌酐如何，达到 10-100mg/L 和 20-100mg/L 目标范围的患者平均百分比分别为 99.4%（0.3%）和 96.1%（0.8%）。对于 40-100mg/L 的目标范围，该百分比仅为 76.4%（2.1%）（范围为 65%-80%）。
年龄和血清肌酐水平可用于床边确定头孢他啶的初始剂量。这些蒙特卡罗模拟强调需要重新评估烧伤患者中头孢他啶的使用。考虑到病原体的 MIC 值，建议使用 3-16g/d 的剂量。然而，对于由 MIC≥8mg/L 的病原体引起的败血症，推荐剂量下，只有不足 76.4%（2.1%）的烧伤患者能够达到治疗目标。
