脓毒症患者在接受持续血液透析滤过时哌拉西林他唑巴坦的药代动力学研究

目的: 分析接受持续静脉-静脉血液透析滤过（CVVHDF）的脓毒症患者哌拉西林/他唑巴坦的药代动力学特点及其影响因素,为临床制定更加合理有效的给药方案提供参考。方法: 选取2014年6月到2016年5月间入住一综合性三级乙等医院重症监护病房接受持续肾脏替代治疗（CRRT）的脓毒症患者作为研究对象。30 min内给予患者首剂4.5 g哌拉西林/他唑巴坦后,采用高效液相色谱法分别对给药结束后0、15、30、45、60、90、120、180、240、360、480 min的静脉血样进行药物浓度测定,采用无房室方法进行药动学分析,DAS 3.2.1软件计算药代学参数,采用线性回归分析患者特征及CRRT参数与药代动力学的关系。以给药后8 h内血药浓度超过最小抑菌浓度（MIC）的时间大于50%（f%T_＞MIC＞50%）作为药效学达标的指标。结果: 总共纳入8名患者。CVVHDF均采用前稀释方式。哌拉西林和他唑巴坦的峰浓度（C _max）分别为116.11（98.03～152.29）和21.60（15.9～29.69） mg/L,分布容积（V _d）分别为1.05（0.70～1.56）和0.69（0.56～0.78）L/kg,清除半衰期（t _1/2）分别为4.79（3.30～8.27）和4.38（3.35～5.52）h,总清除率（CL）分别为7.67（5.66～9.71）和6.11（4.36～10.03）L/h。多因素分析提示哌拉西林的Cmax与置换液流速显著负相关（β：-0.854,95%CI：-0.148～-0.036,P=0.007）,CL与废液流速显著正相关（β：0.883,95%CI：0.133～0.433,P=0.004）。 假设MIC≤16 mg/L时所有患者均达到药效学目标,当16 mg/L＜MIC＜32 mg/L时,仅有5名患者（62.5%）达标,而当MIC≥64 mg/L,则所有患者均未能达标。结论: 哌拉西林/他唑巴坦在脓毒症患者接受CVVHDF时无论是哌拉西林还是他唑巴坦均表现为C _max明显降低、t _1/2明显延长、CL降低,哌拉西林和他唑巴坦的CL和t _1/2基本一致。对于行CVVHDF的脓毒症患者,当细菌的MIC＞32 mg/L,首剂给予哌拉西林/他唑巴坦4.5 g可能剂量不足。

Pharmacokinetic of piperacillin/tazobactam in patients with sepsis during continuous venovenous hemodiafiltration

AIM: To evaluate the pharmacokinetic of piperacillin/tazobactam in patients with sepsis during continuous venovenous hemodiafiltration and to analyse the influencing factors. METHODS: The patients with sepsis requiring CRRT in the intensive care units in a general hospital during June 2014 to May 2016 were enrolled as the subjects. First dose of piperacillin-tazobactam（4.5 g） was administered intravenously over 30 min. Blood samples were taken at 0, 15, 30, 45, 60, 90, 120, 180, 240, 360, 480 min after infusion.The concentrations of piperacillin and tazobactam were determined by high-performance liquid chromatography（HPLC）, PK analysis was conducted using a non-compartmental approach, the DAS 3.2.1 software was used to calculate pharmacokinetic parameters, Linear regression analysis was used to analyze the relationship between patient characteristics/CRRT parameters and pharmacokinetics.Blood concentration maintained above the minimum inhibitory concentration (MIC) for 50%(f%T_＞MIC＞50%) as a pharmacodynamic target. RESULTS: Eight patients with sepsis receiving CVVHDF were included in the investigation. The maximum concentration (C _max) of piperacillin and tazobactam was 116.11（98.03-152.29）and 21.60（15.9-29.69）mg/L,respectively; The volume of distribution (V_d) was 1.05（0.70-1.56）and 0.69（0.56-0.78）L/kg, respectively; The elimination half-time (t _1/2) was 4.79（3.30-8.27）and 4.38（3.35-5.52）h, respectively; The total clearance rate (CL) was 7.67（5.66-9.71）and 6.11（4.36-10.03）L/h, respectively. In the multivariate analysis, the most significant factor associated with Cmax of piperacillin was replacement flow rate (β：-0.854,95%CI：-0.148--0.036,P=0.007), the most significant factor associated with CL of piperacillin was effluent flow rate（β：0.883,95%CI：0.133-0.433,P=0.004）.When MIC≤16 mg/L, all patients reached pharmacodynamic target, when 16 mg/L＜MIC＜32 mg/L, just 5 patients (62.5%) reached the target, while MIC≥64 mg /L, no patient reached the target. CONCLUSION: Both piperacillin and tazobactam for patients with sepsis receiving CVVHDF show significantly lowerC _max, significantly longert _1/2, and decreased CL. CL andt _1/2 remain consistent. When germ's MIC＞32 mg/L, the first dosage of 4.5 g piperacillin/ tazobactam may be not enough.