应用UPLC研究亚胺培南在大鼠体内的药动学

目的 建立灵敏的超高效液相色谱法测定大鼠血浆中亚胺培南的浓度。方法 血浆样品采用乙腈蛋白沉淀方法,色谱柱为Dikma Diamonsil C₁₈;以0.1 mol·L^-1磷酸氢二钠(85%磷酸调pH至7.0)-甲醇(45∶55)为流动相;流速为1.0 mL·minL^-1;柱温为35 ℃;检测波长为295 nm。结果 亚胺培南血药浓度在0.5～100 μg·mL^-1内线性关系良好(r=0.999 7),最低检测限为0.5 μg·mL^-1;日内、日间RSD均≤10％,提取回收率在80.5％~81.2％之间。6只SD大鼠单剂量口服给予亚胺培南后药动学参数分别为：C_max(75.3±6.2)μg·mL^-1;t_1/2(6.72±1.58)h;AUC_0-t(694.1±28.3)h·μg·mLL^-1;AUC_0-∞(746.2±32.9) h·μg·mL^-1。结论 本方法简便、准确、灵敏、专属性强,同样适用于人血浆中亚胺培南浓度的测定及其药动学研究,对于评价亚胺培南疗效和安全性有重要意义。     

The Efficacy and Safety of Imipenem/Cilastatin in the Treatment of Severe Bacterial Infections

Summary

We have assessed the efficacy and safety of imipenem/cilastatin in a non-comparative study of 27 immunocompromised patients suffering from severe bacterial infections. Moreover, in two groups of 14 patients the efficacy of imipenem/cilastatin versus a standard broad spectrum antibiotic therapy has also been compared. Clinical and microbiological efficacy and side effects have been evaluated.     

Comparison of the Efficacy of Three Different Treatments with Imipenem Versus the Classical Clindamycin Plus Tobramycin in Experimental Peritonitis

Summary

This study compares the efficacy of three different treatment modalities of imipenem/cilastatin and the conventional clindamycin plus tobramycin in an experimental model of intra-abdominal sepsis. 145 Wistar rats were used. 40 served as control and 105 as study groups. A capsule with 0.5ml of inoculum was surgically implanted in the peritoneal cavity. The incoculum was prepared from human feces of healthy volunteers, with a composition of E. coli 10⁶, E. íaecalis 10⁶, B. fragils⁷, Clostridium sp 10⁵ to 10⁶ and anaerobic streptococci 10⁵ to 10⁶. Eighty animals were treated with imipenem/cilastatin and divided in 3 subgroups: “short pretreatment” — 29 animals treated 1 hour prior to surgery and 3 days after; “short” — 26 animals starting treatment 2 hours post-surgery and continuing it for 3 days; and “long” — 25 animals treated for 10 days, starting 2 hours post-surgery. 25 animals received clindamycin plus tobramycin for 10 days. Mortality and the presence of visceral and peritoneal abscesses were the end-points of the study.

The control group had 100% mortality. There were no statistically significant differences among the treated groups although lower mortality was obtained with “short pretreatment” and “long” treatment with imipenem. The presence of abscesses were statistically significant between the imipenem and the combination group. In the imipenem groups, the “short pretreatment” and the long treatment had fewer abscesses than the short one. We conclude that imipenem may be a good alternative monotherapy to conventional therapy with clindamycin plus tobramycin . The “short pretreatment” seemed as good as the long one and better than the short treatment.     

In Vitro Interactions of Aminoglycosides with Imipenem or Ciprofloxacin against Aminoglycoside Resistant Acinetobacter baumannii

Summary

The in vitro interactions between gentamicin, tobramycin, netilmicin and amikacin with imipenem and ciprofloxacin were evaluated by the killing curve technique against 20 clinical isolates of Acinetobacter baumannii highly resistant to aminoglycosides which were susceptible or moderately susceptible to imipenem and resistant or moderately susceptible to ciprofloxacin. Imipenem enhanced killing by gentamicin, tobramycin, netilmicin and amikacin in tests with 9, 12, 10 and 15 strains (45-75%) while ciprofloxacin with 3, 7, 5 and 6 strains (15-35%) respectively. Interaction results were influenced by the height of aminoglycoside minimum bactericidal concentrations (MBCs) but were independent of imipenem or ciprofloxacin MBCs and the presence of aminoglycoside modifying enzymes. It is concluded that enhanced killing after aminoglycoside interaction with imipenem or ciprofloxacin versus A. baumannii cannot be predicted but it should be carefully tested in vitro. The in vivo significance of the reported findings mandates clinical studies in humans.     

液相色谱-串联质谱法测定大鼠血浆中舒巴坦的浓度及其药动学研究

目的：建立测定大鼠血浆中舒巴坦血药浓度的液相色谱-串联质谱（LC-MS/MS）法,探讨美罗培南、亚胺培南对舒巴坦在大鼠体内的药动学影响。方法：将18只SD大鼠随机分为舒巴坦组、美罗培南+舒巴坦组和亚胺培南+舒巴坦组,分别静脉注射给药,按规定时间点采血,血浆样品经乙酸乙酯萃取,LC-MS/MS法测定血药浓度;采用负离子模式,多重反应监测（multiple reaction monitoring,MRM）,定量离子对为m/z 232.3→m/z 139.9（舒巴坦）和m/z 423.4→m/z 207.1（头孢呋辛,内标）。经DAS 2.0.1计算药动学参数,并进行统计学比较。结果：舒巴坦在0.250~200 μg·mL^-1范围内线性关系良好,方法学符合要求。药动学试验结果表明,合用美罗培南或亚胺培南后,舒巴坦在大鼠体内的主要药动学参数t_max、C_max、AUC、MRT、t_1/2z、CL_z和V_z与单用舒巴坦相比,无显著性差异。结论：和已报道的方法比较,本研究所建方法具有快速、高效,生物样品用量小的特点,适用于舒巴坦在大鼠体内药动学的研究;美罗培南、亚胺培南对舒巴坦在大鼠体内的药动学过程无明显影响,提示评价此类药物相互作用还需同时考虑药效学等方法。     

亚胺培南血药浓度测定方法改进及其在血浆中稳定性考察

目的:建立高效液相色谱法测定人血浆中亚胺培南浓度,并重点考察亚胺培南血浆样品的稳定性。方法:采用Venusil XBP C₁₈ (5μm,4.6mm×250 mm)色谱柱,以10 mmol·L^-1磷酸二氢钾-含四丁基溴化铵(0.3 mmol·L^-1)甲醇液(96:4,V:V)为流动相,调节pH至7.2,柱温为30℃,内标为5-羟基吲哚-3-醋酸,检测波长300 nm。稳定剂0.5mol·L^-1 3-吗啉丙磺酸缓冲液(pH6.8)-乙二醇-水,体积比2:1:1。结果:低、中、高3个浓度提取回收率分别为(89.6±1.7)%,(93.9±2.2)%,(91.4±0.4)%,批内、批间RSD均小于15%;血浆中亚胺培南在0.1~100 μg·ml^-1浓度范围内线性关系良好(r=0.995~0.996),定量下限为0.1μg·ml^-1;不加稳定剂时,含亚胺培南的血浆样品在室温、4℃、-30℃条件下分别可以稳定2,6,8 h,加入稳定剂后分别为6,12,48 h。结论:本试验建立的分析方法线性范围宽,操作简便,准确度高,可用于亚胺培南血药浓度的测定,适用于重症感染患者治疗药物监测。     

亚胺培南联合磷霉素对多重耐药鲍曼不动杆菌的试验研究

目的 探索以亚胺培南为基础用药,对临床分离多重耐药鲍曼不动杆菌(MDR-AB)的体内外抗菌方法。方法 用微量肉汤稀释法及棋盘法测定7株临床分离的MDR-AB对亚胺培南、磷霉素、阿米卡星、替加环素、多粘菌素B 5种抗菌药物的最低抑菌浓度(MIC)及联合MIC,并计算部分抑菌浓度指数(FICI)。用时间杀菌曲线法判断亚胺培南联合磷霉素的杀菌效果。选取菌株AB6624、AB0153构建体外生物膜模型,结晶紫染色法半定量生物膜。激光共聚焦显微镜观察使用亚胺培南联合磷霉素对生物膜细菌的杀伤作用。流式细胞仪检测亚胺培南及磷霉素单药与联合用药对细菌活性氧(ROS)表达的影响。建立大蜡螟感染模型,记录亚胺培南及磷霉素单药与联合用药时大蜡螟存活率。结果 亚胺培南联合磷霉素对5株MDR-AB具有协同作用;亚胺培南联合磷霉素对菌株AB6624、AB0153分别在4、8 h的菌落数较单药组降低>2log₁₀ CFU/mL;亚胺培南联合磷霉素抑制菌株生物膜形成并对菌株AB0153生物膜结构具有破坏作用;亚胺培南联合磷霉素可以提高菌株AB0153胞内ROS水平,差异具有统计学意义(P&...     

亚胺培南西司他丁与莫西沙星对重症肺炎患者CRP、PCT水平及OI的改善效果比较

目的 比较亚胺培南西司他丁与莫西沙星对重症肺炎患者CRP、PCT水平及OI的改善效果.方法 以2019年3月至2021年3月我院收治的150例重症肺炎患者为研究对象,根据用药方案不同将其分为对照组(n=75,莫西沙星)和试验组(n=75,亚胺培南西司他丁).比较两组的治疗效果.结果 试验组的治疗总有效率及细菌清除率显著...     

肺炎克雷伯菌外膜蛋白与亚胺培南耐药性的关系研究

目的　探讨肺炎克雷伯菌外膜蛋白缺失与亚胺培南耐药性的关系。方法　对 2株临床分离的耐亚胺培南肺炎克雷伯菌进行传代,用肉汤稀释法检测其最低抑菌浓度(MIC),并提取外膜蛋白(OMP)进行SDS-PAGE。结果　2株多重耐药的肺炎克雷伯菌经传 9代后除对亚胺培南恢复为敏感以外,对其余抗生素的耐药性不变;经SDS- PAGE发现对亚胺培南耐药肺炎克雷伯菌与敏感株相比,缺少分子量 35 000~45 000之间的一条带,从位置判断该条带可能为OMPk36或OMPk37的一种膜蛋白。结论　肺炎克雷伯菌OMP缺失可能与对亚胺培南的耐药密切相关,细菌经传代修复膜蛋白后可恢复对亚胺培南的敏感性。     

亚胺培南/西司他丁致中枢神经系统不良反应的文献分析

目的 进一步了解亚胺培南/西司他丁中枢神经系统不良反应(ADR)的发生情况及危险因素,为临床合理用药提供参考.方法 检索中国知网(CNKI)、万方数据库(Wanfang)、中国生物医学文献数据库(CBM)及维普数据库(VIP)中亚胺培南/西司他丁致中枢神经系统ADR的病例报道,并进行统计分析.检索时间为自该药上市以来至...