替加环素脑室内注射治疗广泛耐药鲍曼不动杆菌颅内感染的PK/PD和神经毒性分析  

Analysis of pharmacokinetics/pharmacodynamics and neurotoxicity of tigecycline intraventricular injection for the treatment of extensively drug-resistant Acinetobacter baumannii intracranial infection

作　　者：黄琪 杨志玲 黄琪[2] 蒋宇[3] 张兴文[4] 贾爱军 Huang Qi;Yang Zhiling;Huang Qi;Jiang Yu;Zhang Xingwen;Jia Aijun(Department of Pharmacy,Hunan Provincial People’s Hospital(The First-Affiliated Hospital of Hunan Normal University),Changsha 410005;Department of Pharmacy,Xiangya Hospital,Central South University,Changsha 410031;Institute of Emergency Medicine,Hunan Provincial People's Hospital(The First-Affiliated Hospital of Hunan Normal University),Changsha 410005;Emergency Intensive Care Unit,Hunan Provincial People’s Hospital(The First-Affiliated Hospital of Hunan Normal University),Changsha 410005)

机构地区：[1]湖南省人民医院(湖南师范大学附属第一医院)药学部,长沙410005 [2]中南大学湘雅医院药学部,长沙410031 [3]湖南省人民医院(湖南师范大学附属第一医院)湖南省急救医学研究所,长沙410005 [4]湖南省人民医院(湖南师范大学附属第一医院)急诊ICU,长沙410005

出　　处：《中国抗生素杂志》2023年第8期953-959,共7页Chinese Journal of Antibiotics

基　　金：湖南省卫生健康委科研计划项目(No.202113011112)。

摘　　要：目的分析替加环素脑室内注射治疗广泛耐药鲍曼不动杆菌颅内感染的药动学/药效学(pharmacokinetics/pharmacodynamics,PK/PD)和神经毒性,预测临床有效性及安全性,为临床治疗方案提供可行的参考。方法对1例实施脑室内注射替加环素的广泛耐药(extensively drug-resistant,XDR)鲍曼不动杆菌(Acinetobacter baumannii,A.baumannii)颅内感染患者进行药物浓度监测(therapeutic drug monitoring,TDM),研究替加环素在脑脊液(cerebrospinal fluid,CSF)中的PK。浓度测定采用二维高效液相色谱法。结合最小抑菌浓度(minimum inhibitory concentration,MIC)评估替加环素的PD。用细胞计数试剂盒-8(cell counting kit-8,CCK-8)测替加环素对PC12细胞生长抑制、流式细胞术检测细胞凋亡评估替加环素的神经毒性。结果单次脑室内给药5 mg替加环素后,峰浓度(C_(max))为37.894 mg/L,远高于MIC值2 mg/L。AUC_(0-12h)为200.6 mg·h/L。半衰期为2.73 h,提示每日至少需要给药2次。模拟多剂给予替加环素的稳态C_(max)为55 mg/L。替加环素抑制PC12细胞生长并诱导PC12细胞凋亡,IC_(50)值约为51.35 mg/L。替加环素C_(max)接近40 mg/L,该浓度对PC12细胞生长抑制率和诱导凋亡率分别为41.33%和4.58%。结论脑室内注射替加环素是治疗鲍曼不动杆菌颅内感染的一种很有前景的方法。但高浓度替加环素可能存在潜在神经毒性,替加环素单次剂量最好不超过5 mg。脑室内注射替加环素必须谨慎选择,在TDM下进行。Objective To analyze the pharmacokinetics/pharmacodynamics(PK/PD)characteristics and neurotoxicity of tigecycline intraventricular injection and predict its clinical efficacy and safety to provide a feasible reference for a clinical therapeutic regimen.Methods The PK of tigecycline in cerebrospinal fluid(CSF)was investigated by performing therapeutic drug monitoring(TDM)for an extensively drug-resistant(XDR)Acinetobacter baumannii(A.baumannii)intracranial infection patients with intraventricular injecting tigecycline.The concentration of tigecycline was determined by two-dimensional high performance liquid chromatography(2D-HPLC).The PD of tigecycline was investigated with its minimum inhibitory concentration(MIC)against XDR A.baumannii.The CCK-8 assay was used to evaluate the cytotoxicity of different concentrations of tigecycline effect on PC12 cells,and the apoptosis assay was performed using flow cytometry.Results After a dose of 5 mg tigecycline,C_(max) in CSF was 37.894 mg/L which was high above the MIC value of 2 mg/L.The area under the curve of 0 to 12 hours(AUC_(0-12h))was 200.6 mg·h/L.The t_(1/2) of tigecycline was estimated to be 2.73 hours,indicating the intraventricular injection frequency at least twice daily.Steady-state C_(max) of simulated multi-dose tigecycline was 55 mg/L.Tigecycline significantly decreased cell viability as assessed and induced apoptosis of the PC12 cell.The IC_(50) value of PC12 cells treated with tigecycline was about 51.35 mg/L.When the concentration of tigecycline was 40 mg/L,close to C_(max),the growth inhibition rate and apoptosis induction rate of PC12 cells were 41.33%and 4.58%,respectively.Conclusion Intraventricular injection of tigecycline is a promising method for treating XDR A.baumannii intracranial infection.Since a high concentration of tigecycline in CSF may have potential neurotoxicity,each dose of tigecycline is better to be less than 5 mg.Intraventricular injection of tigecycline must be selected cautiously and best carried out under TDM.

关 键 词：替加环素 脑室内注射 广泛耐药鲍曼不动杆菌 颅内感染 治疗药物监测 

分 类 号：R978.1[医药卫生—药品]