论文部分内容阅读
目的了解去甲万古霉素在感染患者中群体药代动力学(PPK)和药效学(PD)。方法药代动力学(PK)分析在诊断或拟诊为革兰阳性菌感染的146例患者中进行,收集患者的临床资料,以NONMEM程序建立并验证去甲万古霉素PK模型。PD分析在同组感染者中进行,收集病原菌,以琼脂对倍稀释法测定去甲万古霉素对细菌最低抑菌浓度(MIC)。根据患者的PK参数和MIC测定结果,计算患者的PK/PD参数,分析其与去甲万古霉素临床和细菌学疗效的关系,制定最佳给药方案。结果去甲万古霉素基础PK模型为线性二房室模型,PK参数个体间变异为指数模型,个体内变异为加法模型。患者内生肌酐清除率(Ccr)的变化对去甲万古霉素清除率(CL)的影响不同,当患者肾功能减退时(Ccr≤85mL/min),CL=2.54×(Ccr/50)~(1.20),Ccr的变化影响该药在体内清除速率,当患者肾功能正常时(Ccr>85 mL/min),CL=5.66×(体质量/60)~(0.52),患者Ccr的变化并不影响药物的廓清率。患者合并使用利尿剂后,去甲万古霉素周边室分布容积(V_2)增大。CL、中央室分布容积(V_1)、室间清除率(Q)和V_2的患者个体间变异分别为35.92%、11.40%、0和79.75%,残差误差为3.05 mg/L。葡萄球菌及肠球菌感染者经去甲万古霉素治疗后治愈组和未治愈组比较,在葡萄球菌感染苦中两组间给药剂量、年龄、药时曲线下面积(AUC)_(24)和AUC_(24)/MIC的差异具有统计学意义(P<0.05)。肠球菌感染者两组间AUC_(24)和AUC_(24)/MIC的差异亦具有统计学意义(P<0.05)。多因素回归分析显示,仅AUC_(24)/MIC是影响治愈率的因素。当葡萄球菌感染组和肠球菌感染组的AUC_(24)/MIC平均值分别为579.90和637.67时,去甲万古霉素对患者的治愈率可达95%。结论AUC_(24)/MIC可作为去甲万古霉素治疗耐药革兰阳性菌感染时预测临床和细菌学疗效的指标,据此制定适用于不同感染患者群体的最佳给药方案。
Objective To understand the population pharmacokinetics (PPK) and pharmacodynamics (PD) of norvancomycin in infected patients. Methods Pharmacokinetic (PK) analyzes were performed in 146 patients diagnosed or diagnosed as Gram-positive bacterial infections. Clinical data were collected and the norvancomycin PK model was established and validated using the NONMEM program. PD analysis was carried out in the same group of infected persons, and pathogenic bacteria were collected. The minimum inhibitory concentration (MIC) of norvancomycin against bacteria was determined by agar dilution method. According to the patient’s PK parameters and the MIC measurement results, the patients’ PK / PD parameters were calculated, and their clinical and bacteriological effects on norvancomycin were analyzed to determine the optimal dosage regimen. Results The baseline PK model of norvancomycin was a linear two-compartment model. The variation of PK parameters was an exponential model, and the intra-individual variation was additive model. The changes of endogenous creatinine clearance (Ccr) had different effects on the clearance of norvancomycin (CL). When the patients had renal dysfunction (Ccr≤85mL / min), CL = 2.54 × (Ccr / 50) (1.20), Ccr changes in vivo clearance rate of the drug, when patients with normal renal function (Ccr> 85 mL / min), CL = 5.66 × (body mass /60))(0.52), changes in patients with Ccr and Does not affect the clearance rate of drugs. Patients combined with diuretics, norvancomycin peripheral volume (V_2) increased. The individual variation of CL, central volume distribution (V_1), interventricular clearance (Q) and V_2 were 35.92%, 11.40%, 0 and 79.75%, and the residual error was 3.05 mg / L, respectively. Staphylococcus aureus and enterococci infection by norvancomycin treatment after treatment compared with the untreated group, staphylococcus aureus infection bitterness between the two groups administered dose, age, drug area under the curve (AUC) _ (24) And AUC_ (24) / MIC were statistically significant (P <0.05). The differences of AUC_ (24) and AUC_ (24) / MIC between the two groups were also statistically significant (P <0.05). Multivariate regression analysis showed that only AUC_ (24) / MIC was the factor that affected the cure rate. When the average AUC_ (24) / MIC of staphylococcal and enterococcal infections were 579.90 and 637.67 respectively, the response rate of norvancomycin to patients was 95%. Conclusion AUC 24 / MIC can be used as an indicator of clinical and bacteriological efficacy in the treatment of gram-positive gram-negative infections with norvancomycin. Therefore, the optimal dosage regimen for different infected patients can be formulated.