【作者】 张雷；

【导师】 刘又宁；

【作者基本信息】 中国人民解放军军医进修学院 ， 呼吸系病， 2011， 博士

【摘要】 [目的]观察甲氧西林耐药的金黄色葡萄球菌(MRSA)临床分离株对多种抗菌药物的体外敏感性,分析利奈唑胺在中国健康人群及重症感染患者的群体药代/药效动力学(PPK/PPD)特性,了解利奈唑胺在呼吸重症监护病房(RICU)的使用情况并评价其安全性和有效性。旨在为临床合理使用利奈唑胺提供实验依据。[方法](1)采用琼脂平板稀释法测定利奈唑胺对98株MRSA的MIC。(2)采用棋盘法设计,微量肉汤稀释法测定不同浓度组合的抗菌药物对98株MRSA临床分离株的最低抑菌浓度(MIC),并计算联合抑菌指数(FICI),判定联合效应。(3)采用高效液相色谱法测定血浆利奈唑胺浓度,应用非线性混合效应模型法(NLME)分析其在中国健康人群及重症感染患者的PPK/PPD特征。(4)采用单中心、前瞻、无对照、描述性研究方法评价利奈唑胺对收住RICU临床证实或高度怀疑为耐药革兰阳性球菌(MR-GPC)感染患者的有效性和安全性。[结果](1)利奈唑胺对98株临床分离MRSA的MIC范围为0.5-2μg/mL, MIC50及MIC90均为2μg/mL。(2)米诺环素与夫西地酸体外联合应用,两药对98株临床分离MRSA的MIC50均显著降低。FICI≤0.5占57.14%；0.5<FICI≤4占42.86%；FICI>4为0。(3)中国健康志愿者单次给予利奈唑胺,其基础药代动力学(PK)模型为二房室线性消除模型；群体典型值：中央室表观分布容积(V)为26.99 L,外周室V为22.22 L,中央室表观清除率(CL)为7.99L/h,外周室CL为101.28 L/h；体重与其均值每相差1kg时外周室V值改变0.617L。(4)中国重症感染患者给予利奈唑胺达稳态时,其基础PK为一房室线性消除模型；群体典型值：V为38.85L,CL为4.70 L/h；体重与其均值每相差1kg时V值改变0.79L，CL值改变0.04L/h；年龄与其均值每相差1岁时CL值改变-0.045L/h；静脉滴注或口服给药下利奈唑胺对RICU中大部分MR-GPC的t>MIC百分比为100%,AUC0-24h/MIC90比值>100。(5)与静脉或口服给药相比,鼻饲给药表观分布容积(V)显著增大,血浆峰浓度(Cmax)和药-时曲线下面积(AUC)明显减小。(6)利奈唑胺治疗RICU住院患者MR-GPC感染,治愈率约85.7%,细菌清除或假定清除率约85.7%,血小板减少发生率约26.9%。[结论](1)98株临床分离MRSA对利奈唑胺的敏感率为100%。(2)体外米诺环素与夫西地酸联用对MRSA以协同作用为主。(3)利奈唑胺在中国人群的PK特征为：单次给药时为二房室线性模型,体重与表观分布容积(V)呈线性正相关；多次给药时为一房室线性模型；体重与V和表观清除率(CL)呈线性正相关,年龄与CL呈线性负相关；中国人群V和CL的群体典型值明显低于西方人群；与静脉或口服相比,鼻饲给药时V显著增大。(4)利奈唑胺对收住RICU的MR-GPC感染患者有效率高,但血小板减少发生率较高,且与疗程有关。更多还原

【Abstract】 [OBJECTIVES] To investigate the in vitro sensitivity of clinically isolated methicillin-resistant Staphylococcus aureus (MRSA) to antibiotics. To analyze the population pharmacokinetic and pharmacodynamic profiles of linezolid in Chinese healthy volunteers and critically ill patients. To investigate the application of linezolid in respiratory intensive care unit (RICU), and assess its efficacy and safety. On the whole, to provide some laboratory evidences for the rational use of linezolid in clinic.[METHODS] (1) A agar plate dilution method was applied to determine the MIC of linezolid against 98 strains of clinically isolated MRSA. (2) A checkerboard method that adhered to the recommendations of Clinical Laboratory Standards Institute (CLSI) was applied to assess the synergism effect of minocycline and fosidic acid on 98 strains of MRSA. The Fraction Inhibitory Concentration Index (FICI) was calculated according to the results. (3) High performance liquid chromatography was applied to determine the plasma concentration of linezolid. Nonlinear mixed-effects modeling method was applied to analyze the PPK/PPD profiles of linezolid in Chinese healthy volunteers and critically ill patients. (4) A single-centre, prospective, non-controlled descriptive study was performed to assess the efficacy and safety of linezolid in critically ill patients that proven or highly suspected of multi-resistant gram-positive cocci (MR-GPC) infection in RICU.[RESULTS] (1) The MIC range of linezolid against 98 strains of MRSA was 0.5-2μg/mL, and the MIC50, as well as MIC90 was 2μg/mL. (2) The MIC50 of minocycline and fosidic acid against 98 strains of MRSA was significantly decreased when the two antibiotics were combined in vitro. The percentage of FICI≤0.5 was 57.14%,0.5< FICI≤4 was 42.86%, FICI> 4 was 0. (3) Single dose of linezolid was administrated to Chinese healthy volunteers. A 2-compartment with linear elimination model was the most appropriate structural pharmacokinetic (PK) model. The population typical value of apparent volume (V) of central compartment was 26.99 L, V of peripheral compartment was 22.22 L, apparent clearance (CL) of central compartment was 7.99 L/h, and CL of peripheral compartment was 101.28 L/h. For each 1 kg deviation of weight from the mean value,0.617 L of V of peripheral compartment was correlated. (4) Multiple doses of linezolid were administered to Chinese critically ill patients to achieve steady state. A 1-compartment with linear elimination model was the most appropriate structural PK model. The population typical value of apparent volume (V) was 38.85 L, apparent clearance (CL) was 4.70 L/h. For each 1 kg deviation of weight from the mean value,0.79 L of V, as well as 0.04 L/h of CL was correlated. For each 1 year deviation of age from the mean value,-0.045 L/h of CL was correlated. When linezolid was administrated intravenously or orally, the percentage of t>MIC was 100%, and the ratio of AUC0-24h/MIC90 was>100 for most MR-GPC in RICU. (5) Compared with intravenous or orally administration, nasal feeding of ground linezolid resulted in an obvous increase of V, thus, the maximal plasma concentration (Cmax) and the area under the concentration-time curve (AUC) were decreased significantly. (6) When linezolid was administrated to patients with MR-GPC infection in RICU, the cure rate was approximately 85.7%, the bacterial elimination (actual and presumable) rate was 85.7%, and the rate of thrombocytopenia was 26.9%.[CONCLUSION] (1) The sensitivity of 98 strain of clinically isolated MRSA to linezolid is 100%. (2) The in vitro combination of minocycline and fosidic acid mainly presents synergistic effect on MRSA. (3) The PK profiles of linezolid in Chinese simulate a 2-compartment with linear elimination model when single dose is administrated, and the weight is linearly positive-correlated to V. While a 1-compartment with linear elimination model is appropriate when multiple doses are administrated, and the weight is linearly positive-correlated to V and CL, the age is linearly negative-correlated to CL. The typical value of V and CL of Chinese population is significantly lower than that of Western population. Compared with intravenous or orally administration, nasal feeding of ground linezolid results in an obvous increase of apparent volume. (4) Linezolid has satisfying efficacy in treating patients with MR-GPC infection in RICU. Nevertheless, the rate of thrombocytopenia is high, which is correlated to the duration of therapy.更多还原