Pai Manjunath P, Cojutti Piergiorgio, Pea Federico
Albany College of Pharmacy and Health Sciences, Albany, NY, USA.
Clin Pharmacokinet. 2015 Sep;54(9):933-41. doi: 10.1007/s40262-015-0266-2.
Meropenem is an anti-Gram-negative antimicrobial, the time-dependent activity of which may be maximized through administration by continuous infusion.
The objectives of this study were to characterize the pharmacokinetics of continuous infusion meropenem in relation to body size and Cockcroft-Gault estimated creatinine clearance (CLCR) in overweight and obese patients with stable and unstable kidney function with the intent of creating a nomogram for optimal dosing.
Patients from a single institution with a body mass index ≥25 kg/m(2) receiving meropenem by continuous infusion with measurement of meropenem steady-state concentrations (C ss) were identified. Individual Bayesian estimates of meropenem volume of distribution of the central compartment (V c) and clearance (CL) were calculated and relationships to body size descriptors and CLCR estimated using these body size descriptors were defined by regression. Kidney function stability was defined based on median absolute deviation, stratification by the ratio of maximum to minimum serum creatinine (SCr) and individual patient-level regression of SCr over time. The influence of kidney function stability on meropenem CL estimation by CLCR was tested.
A total of 375 patients (77.9 % male) with 846 C ss values (62.4 % of patients with ≥2 measurements) were identified. The median daily dose of meropenem and frequency of infusion bag changes were 2000 mg/day and four times per day, respectively. The meropenem C ss values were ≥16, ≥8, ≥4, and ≥2 mg/L for 41.1, 76.1, 97.4, and 99.9 % of observations, respectively. The median (range) age, weight, and BMI were 66 (24-90) years, 90 (70-250) kg, and 30.8 (25.1-81.6) kg/m(2), respectively. The mean [standard deviation (SD)] serum creatinine at baseline was 1.57 (1.37) mg/dL. The mean (SD) V c was 28.1 (1.36) L and not related to body size, while CL was 8.85 (6.40) L/h and best related to CLCR estimated using adjusted body weight (ABW). The meropenem CL to CLCR relationship was not significantly impacted by the presence or absence of kidney function stability. The user-friendly dosing nomogram based on CLCR estimated using ABW showed that optimal drug exposure [Css ≥ minimum inhibitory concentration (MIC)] may be obtained even against multi-drug resistant (MDR) pathogens when considering dosages up to 1250 mg every 6 h by continuous infusion.
Meropenem CL is best estimated using CLCR with ABW in patients with a BMI ≥25 kg/m(2) and this relationship is not altered by unstable kidney function. Application of our dosing nomogram may improve the care of overweight and obese patients with severe MDR Gram-negative infections treated with meropenem by continuous infusion.
美罗培南是一种抗革兰氏阴性菌的抗菌药物，其时间依赖性活性可通过持续输注给药使其最大化。
本研究的目的是描述在肾功能稳定和不稳定的超重及肥胖患者中，持续输注美罗培南的药代动力学与体型和Cockcroft - Gault估计的肌酐清除率（CLCR）之间的关系，旨在创建一个用于优化给药的列线图。
确定来自单一机构、体重指数≥25 kg/m²且通过持续输注接受美罗培南治疗并测量美罗培南稳态浓度（Css）的患者。计算美罗培南中央室分布容积（Vc）和清除率（CL）的个体贝叶斯估计值，并通过回归定义其与体型描述符以及使用这些体型描述符估计的CLCR之间的关系。基于中位数绝对偏差、最大与最小血清肌酐（SCr）比值分层以及个体患者水平的SCr随时间的回归来定义肾功能稳定性。测试肾功能稳定性对通过CLCR估计美罗培南CL的影响。
共确定了375例患者（77.9%为男性），有846个Css值（62.4%的患者有≥2次测量值）。美罗培南的每日中位剂量和输液袋更换频率分别为2000 mg/天和每天4次。美罗培南Css值分别在41.1%、76.1%、97.4%和99.9%的观察值中≥16、≥8、≥4和≥2 mg/L。年龄、体重和BMI的中位数（范围）分别为66（24 - 90）岁、90（70 - 250）kg和30.8（25.1 - 81.6）kg/m²。基线时平均[标准差（SD）]血清肌酐为1.57（1.37）mg/dL。平均（SD）Vc为28.1（1.36）L，与体型无关，而CL为8.85（6.40）L/h，与使用调整体重（ABW）估计的CLCR最相关。肾功能稳定与否对美罗培南CL与CLCR的关系没有显著影响。基于使用ABW估计的CLCR的用户友好型给药列线图显示，当考虑每6小时持续输注高达1250 mg的剂量时，即使针对多重耐药（MDR）病原体也可能获得最佳药物暴露[Css≥最低抑菌浓度（MIC）]。
对于体重指数≥25 kg/m²的患者，使用ABW的CLCR能最好地估计美罗培南的CL，且这种关系不会因肾功能不稳定而改变。应用我们的给药列线图可能会改善超重和肥胖的严重MDR革兰氏阴性感染患者接受持续输注美罗培南治疗的护理。
