Burns Trauma and Critical Care Research Centre, The University of Queensland, Level 3, Ned Hanlon Building, Royal Brisbane and Women's Hospital, Butterfield St., Brisbane, Queensland, Australia 4029.
Antimicrob Agents Chemother. 2011 Jun;55(6):2704-9. doi: 10.1128/AAC.01708-10. Epub 2011 Mar 14.
Despite the development of novel antibiotics active against Gram-positive bacteria, vancomycin generally remains the first treatment, although rapidly achieving concentrations associated with maximal efficacy provides an unresolved challenge. The objective of this study was to conduct a population pharmacokinetic analysis of vancomycin in a large population of critically ill patients. This was a retrospective data collection of 206 adult septic critically ill patients who were administered vancomycin as a loading dose followed by continuous infusion. The concentration-versus-time data for vancomycin in serum was analyzed by a nonlinear mixed-effects modeling approach using NONMEM. Monte Carlo simulations were performed using the final covariate model. We found that the best population pharmacokinetic model consisted of a one-compartment linear model with combined proportional and additive residual unknown variability. The volume of distribution of vancomycin (1.5 liters/kg) was described by total body weight and clearance (4.6 liters/h) by 24-hour urinary creatinine clearance (CrCl), normalized to body surface area. Simulation data showed that a 35-mg/kg loading dose was necessary to rapidly achieve vancomycin concentrations of 20 mg/liter. Daily vancomycin requirements were dependent on CrCl, such that a patient with a CrCl of 100 ml/min/1.73 m² would require at least 35 mg/kg per day by continuous infusion to maintain target concentrations. In conclusion, we have found that higher-than-recommended loading and daily doses of vancomycin seem to be necessary to rapidly achieve therapeutic serum concentrations in these patients.
尽管已经开发出了针对革兰氏阳性菌的新型抗生素，但万古霉素通常仍然是首选治疗药物，尽管迅速达到与最大疗效相关的浓度仍然是一个尚未解决的挑战。本研究的目的是对大量重症感染患者的万古霉素进行群体药代动力学分析。这是对 206 例接受万古霉素负荷剂量后持续输注的成年脓毒症重症患者进行的回顾性数据收集。采用 NONMEM 非线性混合效应模型分析方法对血清中万古霉素的浓度-时间数据进行分析。使用最终协变量模型进行 Monte Carlo 模拟。我们发现，最佳的群体药代动力学模型由一个具有组合比例和加性残留未知变异性的单室线性模型组成。万古霉素的分布容积（1.5 升/千克）由总体重描述，清除率（4.6 升/小时）由 24 小时尿肌酐清除率（CrCl）归一化至体表面积表示。模拟数据表明，需要 35 毫克/千克的负荷剂量才能迅速达到 20 毫克/升的万古霉素浓度。万古霉素的每日需求量取决于 CrCl，因此，CrCl 为 100 ml/min/1.73 m²的患者每天至少需要 35 毫克/千克的连续输注才能维持目标浓度。总之，我们发现，为了在这些患者中迅速达到治疗血清浓度，万古霉素的负荷剂量和每日剂量似乎需要高于推荐剂量。
