Mattioli Francesca, Fucile Carmen, Del Bono Valerio, Marini Valeria, Parisini Andrea, Molin Alexandre, Zuccoli Maria Laura, Milano Giulia, Danesi Romano, Marchese Anna, Polillo Marialuisa, Viscoli Claudio, Pelosi Paolo, Martelli Antonietta, Di Paolo Antonello
Department of Internal Medicine, Clinical Pharmacology and Toxicology Unit, University of Genoa, Viale Benedetto XV, n. 2, 16132, Genoa, Italy.
Infectious Diseases Clinics, IRCCS A.O.U San Martino-IST, University of Genoa, Largo R. Benzi, n. 10, 16132, Genoa, Italy.
Eur J Clin Pharmacol. 2016 Jul;72(7):839-48. doi: 10.1007/s00228-016-2053-x. Epub 2016 Apr 6.
Patients admitted to intensive care unit (ICU) with Klebsiella pneumoniae infections are characterized by high mortality. The aims of the present study were to investigate the population pharmacokinetics parameters and to assess the probability of target attainment of meropenem in critically ill patients to provide information for more effective regimens.
Twenty-seven consecutive patients were included in the study. Meropenem was administered as 3-h intravenous (i.v.) infusions at doses of 1-2 g every 8 or 12 h. Meropenem plasma concentrations were measured by a high-performance liquid chromatography (HPLC) method, and a population pharmacokinetics analysis was performed using NONMEM software. Meropenem plasma disposition was simulated for extended (3 h; 5 h) or continuous i.v. infusions, and the following parameters were calculated: time during which free drug concentrations were above minimum inhibitory concentration (MIC) (fT > MIC), free minimum plasma concentrations above 4× MIC (fCmin > 4× MIC), probability of target attainment (PTA), and cumulative fraction of response (CFR).
Gender and severity of sepsis affected meropenem clearance, whose typical population values ranged from 6.22 up to 12.04 L/h (mean ± standard deviation (SD) value, 9.38 ± 4.47 L/h). Mean C min value was 7.90 ± 7.91 mg/L, suggesting a high interindividual variability. The simulation confirmed that 88 and 97.5 % of patients achieved effective C min > 4× MIC values after 3- and 5-h i.v. infusions of meropenem 2 g × 3/day, respectively. On the contrary, the same total daily doses reached the target C min > 4× MIC values in 100 % of patients when administered as continuous i.v. infusions.
Several factors may influence meropenem pharmacokinetics in ICU patients. Continuous i.v. infusions of meropenem seem to be more effective than standard regimens to achieve optimal therapeutic targets.
因肺炎克雷伯菌感染入住重症监护病房（ICU）的患者死亡率较高。本研究的目的是调查群体药代动力学参数，并评估美罗培南在重症患者中达到靶目标的概率，以便为制定更有效的治疗方案提供信息。
本研究纳入了27例连续的患者。美罗培南采用3小时静脉输注给药，每8或12小时剂量为1 - 2克。采用高效液相色谱（HPLC）法测定美罗培南血浆浓度，并使用NONMEM软件进行群体药代动力学分析。模拟了美罗培南延长（3小时；5小时）或持续静脉输注的血浆处置情况，并计算了以下参数：游离药物浓度高于最低抑菌浓度（MIC）的时间（fT > MIC）、游离血浆最低浓度高于4×MIC（fCmin > 4×MIC）、达到靶目标的概率（PTA）和累积反应分数（CFR）。
性别和脓毒症严重程度影响美罗培南清除率，其典型群体值范围为6.22至12.04升/小时（平均值±标准差（SD）值，9.38±4.47升/小时）。平均Cmin值为7.90±7.91毫克/升，表明个体间变异性较高。模拟结果证实，分别给予美罗培南2克×3/天进行3小时和5小时静脉输注后，88%和97.5%的患者达到了有效的Cmin > 4×MIC值。相反，当作为持续静脉输注给药时，相同的每日总剂量在100%的患者中达到了靶目标Cmin > 4×MIC值。
多种因素可能影响ICU患者中美罗培南的药代动力学。美罗培南持续静脉输注似乎比标准方案更有效地实现最佳治疗目标。
