抗菌药物在胆汁中药物代谢动力学特点的实验研究及杀菌效力评价

目的 探讨6种抗菌药物在胆汁中的药物代谢动力学特点,并评估其杀菌效力.方法 实验用健康家兔36只,随机分为6组,每组6只.行胆总管造瘘术后,分别静脉注射头孢曲松、头孢哌酮/舒巴坦钠、哌拉西林/他唑巴坦、美罗培南、左氧氟沙星、甲硝唑,于注射后不同时间收集家兔胆汁标本,采用高效液相色谱法测定各抗菌药物的浓度,并计算出药物代谢动力学参数.结合最低抑菌浓度(MIC)评估各抗菌药物在胆汁中的杀菌效力.结果 各抗菌药物在胆汁中的峰浓度和半衰期分别为:哌拉西林(7 950 ±3 023) mg/L和(1.97±1.23)h,头孢曲松(1 104±248) mg/L和(3.14±0.57)h,头孢哌酮(5 215 ±2 225) mg/L和(0.89 ±0.13)h,美罗培南(31.97 ±12.44) mg/L和(0.36±0.11)h,左氧氟沙星(66.3±36.9) mg/L和(3.32±2.57)h,甲硝唑(28.2±10.2) mg/L和(0.81 ±0.33)h.哌拉西林/他唑巴坦和头孢哌酮/舒巴坦的杀菌指数最大,分别为(62.1±23.6) ～(993.8±377.9)和(164.8 ±69.0) ～ (659.3 ±275.9),其药物浓度持续在MIC以上的时间(T＞MIC)最长,两药的T＞MIC分别为(6.00±2.53)～(8.00±0.00)h和(6.33±1.97) ～ (8.00±0.00)h;左氧氟沙星的杀菌指数[(2.1±1.2)～(8.3±4.6)]和T＞MIC[(0.54±0.25)～(2.67±1.03)h]最小,头孢曲松和美罗培南居中,其杀菌指数和T＞MIC分别为(4.3±1.0) ～ (69.2±15.5)、(1.42±0.65)～(8.00±0.00)h和(2.0±0.8)～(1 031.3 ±401.4)、(0.29 ±0.10) ～ (1.83 ±0.26)h.甲硝唑对厌氧菌的杀菌指数和T＞MIC分别为7.4 ～294.9和1.88 ～5.00 h.结论 6种抗菌药物均可在胆汁中达到有效杀菌浓度,哌拉西林、头孢哌酮、美罗培南、甲硝唑在家兔胆汁中呈一房室模型,头孢曲松、左氧氟沙星为二房室模型分布.哌拉西林/他唑巴坦和头孢哌酮/舒巴坦杀菌效力最强,甲硝唑对厌氧菌有较强的杀菌力,肝胆系统感染应结合临床选用杀菌效力强的抗菌药物.     

常用抗生素在动物及人胆汁中的浓度分布和药效学研究

目的研究常用抗生素在胆汁中的浓度和对致病菌的抗菌活性。方法分别静脉注射常用6种抗生素后于不同时间收集家兔胆汁标本，采用高效液相色谱法测定各抗生素的浓度，计算出药动学参数；测定胆道手术患者胆汁常用5种抗生素浓度，对临床分离的157株胆道细菌进行抗菌活性分析。结果家兔胆汁平均药峰浓度较高的为：哌拉西林7950．16μg／ml，头孢哌酮5274．52μg／ml，头孢曲松1107．01μg/ml。在患者胆总管和胆囊胆汁中的平均浓度较高的为：头孢哌酮／舒巴坦563．75／14．76和169．90／8．83μg／ml，哌拉西林／他唑巴坦350．38／16．69和139．81／15．92μg／ml，头孢曲松249．78和82．06μg／ml。美罗培南和莫西沙星的体外抗菌活性最强，增加β-内酰胺酶抑制剂后的哌拉西林和头孢哌酮复合制剂较单一制剂的抗菌活性显著增强。头孢哌酮／舒巴坦、哌拉西林／他唑巴坦、莫西沙星对胆道致病菌的杀菌指数最大。结论家兔胆汁中6种测定的抗生素均超过有效杀菌浓度，哌拉西林、头孢哌酮、头孢曲松胆汁药物浓度很高。头孢哌酮／舒巴坦和哌拉西林／他唑巴坦、莫西沙星在人胆汁中杀菌效力最强，可作为肝胆系统感染经验治疗的首选用药。     

美罗培南在家兔胆汁中的药物浓度-时间分布的实验研究

目的研究美罗培南在家兔胆汁中的浓度及其分布规律,为预防和治疗胆道感染用药提供参考和依据。方法家兔行胆总管造瘘术,先留取空白胆汁,静脉注射美罗培南后分别于不同时间点采集胆汁标本。行专属性试验后,取空白胆汁加美罗培南对照品和流动相,配成0.5~500μg/ml不同浓度的系列胆汁样品,经高效液相色谱仪分析,采用外标法行药物色谱峰面积定量,以胆汁样品药物浓度对色谱峰面积进行线性回归,得回归方程。注射美罗培南后的家兔胆汁样品经预处理后用高效液相色谱仪测定峰面积,按标准曲线回归方程计算得出胆汁药物浓度,从而了解美罗培南的胆汁药物浓度-时间分布情况。结果专属性试验显示,在本研究的流动相色谱条件下测定药物,胆汁杂质峰、美罗培南药物色谱峰分离效果良好。标准曲线回归方程为S=2209.10C-1251.34,r=0.9999,美罗培南的最低定量限为0.5μg/ml。家兔静脉注射美罗培南(75mg/kg)后即时在胆汁中达(38.36±14.17)μg/ml,远远超过其对革兰阴性杆菌的最小抑菌浓度(MIC90)0.031~2μg/ml,之后美罗培南的胆汁药物浓度随时间而迅速降低。用药后180min,胆汁中的药物均被完全消除。结论美罗培南在胆汁中能达到较高的有效杀菌浓度,可作为预防和治疗胆道感染的较佳的药物。由于消除速度较快,临床用药应缩短间隔时间。     

优化抗生素联合应用的研究

目的 了解环丙沙星、阿米卡星与抗铜绿假单胞菌的β内酰胺类药物体外联用的抗菌活性,优化抗生素治疗方案. 方法采用棋盘法设计,微量肉汤稀释法测定上述抗生素不同组合对33株临床分离的铜绿假单胞菌的最低抑菌浓度(MIC),判定联合效应,计算其药代动力学/药效学(PK/PD)参数. 结果阿米卡星与头孢他啶联用主要表现为协同作用,协同比率为57.6%;环丙沙星与头孢他啶、头孢毗肟、亚胺培南/西司他丁、美罗培南联用以协同和相加作用为主.氨基糖苷类和氟喹诺酮类抗生素,在PK/PD研究中,以血药浓度峰值(Cmax)/MIC为主要参数;β内酰胺类抗生素以血药浓度超过MIC的时间(T>MIC)为主要参数. 结论抗菌药物联用后,MIC显著降低,抗菌作用明显增强.所有抗生素的联用均以协同和相加作用为主,无拮抗作用.PK/PD研究,对制定合理给药方案、提高临床疗效具有晕要作用.     

哌拉西林/他唑巴坦体外诱导铜绿假单胞菌释放DNA的初步研究

目的　观察不同浓度哌拉西林/他唑巴坦在体外诱导铜绿假单胞菌释放DNA的情况。方法　选择体外对铜绿假单胞菌菌株敏感的哌拉西林/他唑巴坦为本研究所用抗生素。制备铜绿假单胞菌菌液后,测定其浓度并检测哌拉西林/他唑巴坦最低抑菌浓度(MIC)和最低杀菌浓度(MBC).将不同稀释度的哌拉西林/他唑巴坦加入铜绿假单胞菌菌液中,于37℃下培养4、24h,取其上清液,采用加入SYBRGold染料的DNA电泳法检测其DNA释放情况。　结果　无论有无哌拉西林/他唑巴坦的作用,体外培养4h的铜绿假单胞菌均未测得DNA释放。无哌拉西林/他唑巴坦时,铜绿假单胞菌在体外培养24h可自发释放一定量的DNA分子,其碱基对数目分布在>2 000bp和<100bp两个区域;以第3次测定的MIC(0. 008g/L)为例,哌拉西林/他唑巴坦浓度在亚MIC(0. 002、0. 004g/L)时,诱导铜绿假单胞菌释放的DNA分子碱基对数目仍分布在上述两个区域, 但<100bp的DNA分子明显增多。哌拉西林/他唑巴坦在大于MIC时,仅诱导铜绿假单胞菌释放少量<400bp的DNA.结论　自然生长情况下铜绿假单胞菌可释放一定量的DNA分子。不同浓度的哌拉西林/他唑巴坦诱导铜绿假单胞菌释放的DNA分子,在碱基对数目和分子数量方面均有明显差别。     

头孢曲松(罗氏芬)在T-管胆汁中药动学研究

目的　研究经T型管收集的胆汁中头孢曲松的药动学。方法　采用高压液相色谱法(HPLC)测定胆汁中头孢曲松浓度。结果　静脉滴注头孢曲松后 ,0 5h胆汁浓度达峰值 :(12 11±938 0 ) μg/ml,2 4h后胆汁平均药物浓度仍达 (10 2 77± 6 7 0 4 ) μg/ml。 结论　头孢曲松在胆汁中具有较高的药物浓度 ,可以作为胆道感染的预防和治疗的选择药物。     

美罗培南用于耐药革兰阴性杆菌感染最佳输注速度的研究

目的探讨美罗培南应用于耐药革兰阴性杆菌感染的最佳输注速度,以提高抗菌作用和临床效果。方法选取60例耐药革兰阴性杆菌感染患者,随机分为A、B、C三组各20例。美罗培南0.5 g溶于0.9%氯化钠注射液,滴速为A组200 ml/h(30 min输完),B组100 ml/h(1 h输完),C组33 ml/h(约3 h输完)。比较三组的药效学指标(TMIC)、细菌学指标和临床疗效。结果三组临床疗效比较,差异无统计学意义(P0.05);三组TMIC比较及两两比较,差异有统计学意义(均P0.01);A组筛选出耐美罗培南细菌6株,B组和C组均未筛选出耐美罗培南细菌。结论对于耐药革兰阴性杆菌感染患者,延长美罗培南滴注时间能达到良好的抗菌作用和临床疗效,建议33 ml/h输注最佳。     

鼻胆管胆汁细菌培养及抗生素敏感性分析

目的:分析ERCP鼻胆管胆汁的微生物检测及细菌对抗生素的敏感性。方法:对2012年1月至2013年8月的112例病人ERCP后临床无感染征象时行鼻胆管胆汁细菌培养和抗生素敏感试验。结果:在123次鼻胆管胆汁微生物培养中52次检测结果阳性,阳性率为42.3%,其中细菌10种,真菌3种。所有胆汁培养共检出细菌58株,其中革兰阴性菌6种42株,革兰阳性菌4种11株,真菌3种5株。胆汁革兰阴性菌对碳青霉烯类抗生素(亚胺培南、厄他培南)和氨基糖苷类抗生素(阿米卡星、庆大霉素)的敏感性最高,对头孢曲松、头孢他啶等第三代头孢菌素和左氧氟沙星、哌拉西林/三唑巴坦中度敏感,对环丙沙星、氨苄西林/舒巴坦等抗生素较不敏感,对头孢唑林均不敏感。革兰阳性菌对万古霉素仍较敏感,对喹努普汀/达福普汀、利奈唑胺、替加环素高度敏感,但对苯唑西林等青霉素和克林霉素、红霉素等敏感性不高。结论:临床无感染症状病人的鼻胆管胆汁具有较高的细菌感染率。本研究对于ERCP后胆道感染复发病人早期使用抗生素,控制病情进展提供了参考。     

烧伤病房铜绿假单胞菌β内酰胺类抗生素耐药基因分析

目的 了解烧伤病房铜绿假单胞菌B内酰胺类抗生素耐药基因携带情况及耐药性。方法 采用K-B法检测来自烧伤创面和病房的铜绿假单胞菌对9种β内酰胺类抗生素的耐药谱。用PCR扩增法检出β内酰胺类抗生素耐药基因的阳性菌株，用他唑巴坦对哌拉西林阻断实验判断上述阳性菌株是否产超广谱β内酰胺酶（ESBL）。结果 12株检出β内酰胺类耐药基因的铜绿假单胞菌对所试的头孢菌素类抗生素和哌拉西林均耐药，其中7株对包括亚胺培南和氨曲南在内的9种抗生素耐药。他唑巴坦对哌拉西林耐药阻断实验提示，这7株耐药基因阳性菌株均产ESBL。本实验扩增出6种β内酰胺耐药基因，分别为VEB、IMP、PSE、FOX、OXA、VIM。结论 烧伤病房铜绿假单胞菌β内酰胺类抗生素耐药基因携带率较高，与细菌多重耐药有密切关系。     

β-内酰胺类抗生素在胆汁中的浓度和药动学的实验研究

Objective To study the concentrations and pharmacokinetics of beta-lactams antibi-otics in rabbit bile and evaluate their microbicidal potential to present theoretical evidence and reference for choosing effective antibiotics for the prevention and therapy of hepatobiliary infection. Methods After anesthesia, the common bile duct of rabbits was isolated and cannulated with a silicone tube. The rabbits were administered intravenously with the equal-effect dose of beta-lactams antibiotics. Bile (1.5 ml) was collected at the time of 0. 25,0.5,0. 75,1,1.5,2,3,4,6,8 h after administration and as-sayed by HPLC. The bile drug concentration-time data were processed by software to figure out the pharmacokinetic parameters such as maximum concentration (Cmax), peak time (Tmax), half-life time (T1/2), clearance (CL) and apparent volume of distribution (VD). The bile antibiotics concen-tration contrasted to the minimum inhibitory concentration (MIC), and attained the bactericidal index (Cmax/MIC) and the time the drug concentration exceeded the MIC (TMIC) to evaluate microbicidal potential of the antibiotics in bile. Results The Cmax and T1/2 of each antibiotic were as follow: pip-eracillin (7950.16±3023.00)μg/ml and (1.97±1.23) h, ceftriaxone (1107.01±247.61)μg/ml and (3.14±0. 57)h,meropenem (31.97±12.44)μg/ml and (0. 36±0. 11)h. Piperacillin/tazobactam had the largest bactericidal index and the longest TMIC, and it can form 100 times of concentration than the MIC90 of the common pathogens in bile. Also its TMIC maintained 5～8 h. The bactericidal index and TMIC of ceftriaxone and meropenem were smaller as contrasted to the former. Conclusions The bile concentrations of three antibiotics all exceed their effective bactericidal concentrations. Piperacil-lin/tazobactam has the largest bactericidal index and the longest TMIC, so it can be of the first choice for the therapy in hepatobiliary infection.     

Pharmacodynamic modeling of beta-lactam antibiotics for the empiric treatment of secondary peritonitis: a report from the OPTAMA program

BACKGROUND: In this report of the OPTAMA (Optimizing Pharmacodynamic Target Attainment using the MYSTIC Antibiogram) program, we utilized Monte Carlo simulation to compare the probabilities of achieving bactericidal time above the minimum inhibitory concentration (MIC) (%T > MIC) exposures for imipenem-cilastatin 500 mg q6h and 1000 mg q8h, meropenem 500 mg q6h and 1000 mg q8h and piperacillin/tazobactam 3.375 g q6h and 4.5 g q8h in the empiric treatment of secondary peritonitis. METHODS: The prevalence of pathogens causing secondary peritonitis was identified from the primary surgical and infectious diseases literature. Data for these pathogens with respect to MIC were obtained from the 2003 MYSTIC surveillance study and weighted by the prevalence of each pathogen. A sensitivity analysis varying the prevalence of P. aeruginosa was performed with two additional models to determine the robustness of the data. Pharmacokinetic parameters, obtained from previously published studies in healthy volunteers were used to simulate the %T > MIC for 10,000 patients receiving imipenem-cilastatin, meropenem, and piperacillin/tazobactam. The likelihood of obtaining bactericidal exposure is reported. RESULTS: Empiric utilization of imipenem-cilastatin and meropenem 500 mg q6h and 1000 mg q8h regimens achieved 99.6%-99.7% likelihood of bactericidal exposure. Piperacillin/ tazobactam 3.375 g q6h and 4.5 g q8h produced bactericidal target attainments of 92.9% and 85.2%, respectively. Models simulating higher prevalence of P. aeruginosa reduced the likelihood of bactericidal exposure for piperacillin/tazobactam regimens significantly and had little effect on the carbapenems. CONCLUSION: All of the beta-lactams used in the current analysis were predicted to achieve high target attainment consistently for the empiric treatment of secondary peritonitis. However, imipenem-cilastatin 500 mg q6h and 1000 mg q8h, meropenem 1000 mg q8h and 500 mg q6h, and piperacillin/tazobactam 3.375 g q6h achieved the highest likelihood. These, in particular, would be effective choices for the empiric treatment of secondary peritonitis.     

Evaluating empiric treatment options for secondary peritonitis using pharmacodynamic profiling

BACKGROUND: Selecting an appropriate agent for empiric antibiotic therapy for secondary peritonitis is challenging. The pathogens responsible, aerobic gram-negative bacilli in particular, are becoming more resistant to antibiotics. The purpose of this study was to predict the ability of common antimicrobial regimens to achieve optimal pharmacodynamic exposure against aerobic bacteria implicated in secondary peritonitis, while considering current national resistance trends. METHODS: Monte Carlo simulation was used to model pharmacodynamic endpoints and compare the cumulative fraction of response (CFR) for imipenem-cilastatin, meropenem, ertapenem, piperacillin/tazobactam, ceftazidime, ceftriaxone, ciprofloxacin, and levofloxacin against isolates of species associated with secondary peritonitis. Minimum inhibitory concentration (MIC) distributions for isolates collected in North America were obtained from the 2004 MYSTIC database. Pharmacokinetic parameters were derived from the literature; the endpoints evaluated included free drug time above the MIC (fT(>MIC)) and the area under the concentration-time curve to MIC ratio (AUC:MIC). RESULTS: The simulation predicted that several compounds would have a superior probability of providing appropriate coverage of aerobic bacteria: Imipenem-cilastatin (98.6% CFR at 1 g q8h), meropenem (98.2% CFR at 1 g q8h), ertapenem (91.7% CFR at 1 g q24h), piperacillin/ tazobactam (93.7% CFR at 3.375 g q6h), ceftazidime (91.1% CFR at 2 g q8h), and cefepime (92.9% CFR at 1 g q12h and 95.8% CFR at 2 g q12h). Ceftriaxone, ciprofloxacin, and levofloxacin exhibited CFRs < 82%. CONCLUSIONS: Considering contemporary susceptibility data for aerobic bacteria, monotherapy with any of the three carbapenems or piperacillin/tazobactam 3.375 g q6h would provide optimal exposure for the pathogens commonly encountered in secondary peritonitis. Cefepime (in combination with metronidazole to provide anti-anaerobic coverage) also would be an acceptable choice, as would ceftazidime given at 2 g q8h (again in combination with metronidazole). Despite the popularity of combination therapy based on ciprofloxacin, levofloxacin, or ceftriaxone with metronidazole, these choices appear to be inferior to the other options because of emerging antibiotic resistance, particularly in E. coli.     

抗菌药物用药频度与铜绿假单胞菌和鲍曼不动杆菌耐药率的相关性

目的分析抗菌药物用药频度与铜绿假单胞菌和鲍曼不动杆菌耐药率的相关性,为临床合理使用抗菌药物,降低细菌耐药率提供依据。 方法对云南省第三人民医院2013年1月至2017年12月年常用抗菌药物用药频度以及同期分离的铜绿假单胞菌和鲍曼不动杆菌耐药情况进行回顾性调查分析。 结果本院抗菌药物2014年用药频度（28 809）较2013年（16 259）显著上升,铜绿假单胞菌对头孢曲松、头孢吡肟、氨曲南、庆大霉素、左氧氟沙星、亚胺培南、美罗培南、头孢哌酮/舒巴坦和哌拉西林/他唑巴坦的耐药率,鲍曼不动杆菌对头孢曲松、头孢吡肟、庆大霉素、亚胺培南、美罗培南、头孢哌酮/舒巴坦和哌拉西林/他唑巴坦抗菌药物的耐药率亦有所上升。鲍曼不动杆菌对头孢哌酮/舒巴坦较敏感,但对其他常用抗菌药物的耐药率,特别是对头孢类（平均耐药率为78.23%）和碳青霉烯类药物（平均耐药率为72.69%）的耐药率仍居高不下。抗菌药物年用药频度分析结果显示,2013年至2017年铜绿假单胞菌耐药率与左氧氟沙星用药频度呈高度正相关（r = 0.70、P = 0.20）;鲍曼不动杆菌耐药率与美洛培南用药频度呈显著正相关（r = 0.94、P = 0.02）。 结论本院所分离铜绿假单胞菌耐药率与左氧氟沙星用药频度,鲍曼不动杆菌耐药率与美洛培南用药频度均呈显著正相关,为避免常见的感染菌和定植菌耐药的发生,应加强抗菌药物的监管。     

Determination of cephazolin, ceftazidime, and ceftriaxone distribution in nucleus pulposus

Background

The intervertebral disc is the largest avascular structure in the adult body and minimal blood flow through capillary beds only supplying the outer regions of the disc, which relies on the passive diffusion as a major factor for nutrition and uptake of molecules, including antibiotics. This study is to detect the serum and nucleus pulposus (NP) levels of cephazolin, ceftazidime, and ceftriaxone and to assess this antibiotic permeability into the intervertebral disc.

Methods

Forty-five consecutive patients undergoing lumbar interbody fusion surgery were divided into three groups to participate in the study. Approximately 30?min before the procedures, a bolus dose 2?g antibiotic of cephazolin, ceftazidime, and ceftriaxone was administered intravenously. The NP tissue and serum sample levels of antibiotic were assayed by high performance liquid chromatography.

Results

Three cases failed in the ceftriaxone group because the NP tissue contaminates the blood. Average time between antibiotic injection and tissue/blood collection was 41?min (range 27–57?min). The antibiotic concentration level of cephazolin, ceftazidime, and ceftriaxone was 144.26?±?29.15, 127.19?±?30.22, and 227.81?±?51.48?μg/ml in serum and 2.33?±?0.45, 3.74?±?1.91, and 2.23?±?1.86?μg/g in NP, respectively. The antibiotic penetration in to NP of cephazolin was 1.67?±?0.44, 2.99?±?1.99 of ceftazidime, and 1.08?±?1.44 of ceftriaxone.

Conclusions

The antibiotics of cephazolin, ceftazidime, and ceftriaxone had concentration in the NP tissue, which was higher than the stated MIC. Ceftazidime had highest penetration in to NP tissue, and ceftriaxone had the lowest penetration in to NP tissue.     

Meropenem pharmacokinetics in children and adolescents receiving hemodialysis

The emergence of multi-drug-resistant bacteria is of great concern to the care of pediatric end-stage renal disease (ESRD) patients who receive either hemodialysis or peritoneal dialysis via a catheter. Infections with gram-negative organisms, especially Pseudomonas aeruginosa, are difficult to eradicate and often necessitate catheter removal. Meropenem, a broad-spectrum antibiotic of the carbapenem class of beta-lactams, is effective against most gram-positive and gram-negative bacteria and has enhanced activity against P. aeruginosa. We studied the pharmacokinetics of meropenem during and between hemodialysis treatments in seven pediatric patients. Meropenem was given as a single dose of 20 mg/kg (maximum 500 mg) before and after two separate hemodialysis treatments. Meropenem administration was tolerated without any adverse effects. Hemodialysis effectively cleared meropenem in a manner that correlated with percent urea reduction. Median drug half-life was 7.3 h off dialysis (range 4.9-11.7 h). The dose of 20 mg/kg was not sufficient to produce an acceptable interdialytic pharmacodynamic profile of 70% duration with a meropenem concentration >4 microg/ml, the MIC90 of meropenem for P. aeruginosa. Dosing simulations revealed that a daily dose of 25 mg/kg or an alternate day dose of 40 mg/kg would result in an acceptable pharmacodynamic profile. Both simulated doses achieved acceptable peak concentrations.     

三种碳青霉烯类抗菌药物联用头孢哌酮舒巴坦对耐碳青霉烯鲍曼不动杆菌的抗菌活性分析

目的：探讨亚胺培南、美罗培南、厄他培南3种碳青霉烯类抗菌药物与头孢哌酮舒巴坦联用,对耐碳青霉烯鲍曼不动杆菌的抗菌活性。方法分别检测亚胺培南、美罗培南、厄他培南对36株耐碳青霉烯鲍曼不动杆菌的最小抑菌浓度（MIC）值,及3种抗菌药物与头孢哌酮舒巴坦联用的部分抑菌浓度（FIC）指数,计算3种碳青霉烯抗菌药物与头孢哌酮舒巴坦联用累计抑菌率曲线。结果36株泛耐药鲍曼不动杆菌,亚胺培南、美罗培南MIC50为16 mg/L,亚胺培南MIC90为64 mg/L;美罗培南MIC90为128 mg/L。厄他培南MIC50为32 mg/L,MIC90为256 mg/L。亚胺培南、美罗培南、厄他培南与头孢哌酮舒巴坦联用,FIC指数≤0.5、0.5～1、1～2和＞2者分别为1株、16株、14株、5株;1株、17株、13株和5株;0株、1株、30株和5株。三种药物与头孢哌酮舒巴坦联用后,亚胺培南累计抑菌率曲线左移,美罗培南累计抑菌率曲线改变不明显;厄他培南联用后,累计抑菌率曲线轻度右移。结论亚胺培南、美罗培南与头孢哌酮舒巴坦联用对耐碳青霉烯鲍曼不动杆菌多数呈相加或无关作用,厄他培南与头孢哌酮舒巴坦联用呈无关作用;3种碳青霉烯抗菌药物与头孢哌酮舒巴坦对部分耐碳青霉烯鲍曼不动杆菌具有拮抗作用。     

肝动脉灌注和外周静脉输注5-FU在大鼠肝脏和血液中的浓度分布的实验研究

目的探讨经肝动脉区域灌注和外周静脉注射5-FU在大鼠血液和肝脏组织中的浓度分布规律及差异。方法本研究将24只Wistar大鼠随机分为两组：A组为肝动脉灌注组;B组为外周静脉（颈静脉）输注组,分别经肝动脉插管区域灌注与经颈静脉注射5-FU,剂量为20mg/kg体重,每组均有6只大鼠取血,6只取肝组织样本。采用高效液相色谱法测定血浆及肝脏组织中5-FU的含量,并计算5-FU在肝脏和血浆中的药动学参数、穿透比率、穿透指数和相对治疗优势度。结果经外周静脉注射后肝脏组织的药物峰浓度（Cmax）和药物时量曲线下面积（AUC）分别为13.79±4.56μg/g,342.20±108.20μg·h/g;血浆Cmax和AUC分别为36.85±5.96μg/ml,842.00±158.00μg·h/ml。肝动脉灌注5-FU后肝脏组织药物Cmax和AUC分别为29.58±4.30μg/g,794.60±115.40μg·h/g;血浆Cmax和AUC分别为24.39±4.63μg/ml,639.70±133.80μg·h/ml。结论与外周静脉注射全身化疗比较,区域性肝动脉灌注5-FU可显著提高肝脏组织中的药物浓度,同时减少化疗药物在外周血中的分布。     

Pharmacodynamic performance of tigecycline versus common intravenous antibiotics for the empiric treatment of complicated skin and skin structure infections

BACKGROUND: In clinical trials tigecycline was similar to vancomycin/aztreonam for complicated skin and skin structure infections, but data comparing it with other widely used antibiotics are lacking. We predicted the pharmacodynamic cumulative fraction of response (CFR) of tigecycline against bacteria implicated in complicated skin and skin structure infections and compared it with the CFRs for piperacillin/tazobactam, ceftriaxone, levofloxacin, and imipenem/cilastatin. METHODS: A 5,000-patient Monte Carlo simulation using a two-compartment intravenous infusion model was used to simulate steady-state concentrations for common dosages of these antibiotics. Population pharmacokinetics data from infected patients were employed. The CFR was calculated against Staphylococcus aureus (42% methicillin-resistant S. aureus [MRSA]), streptococci, coagulase-negative staphylococci, Escherichia coli, Enterobacter, enterococci, Proteus mirabilis, Klebsiella, and Pseudomonas aeruginosa collected from worldwide surveillance (TEST and SENTRY) and weighted by prevalence of involvement in complicated skin and skin structure infections. RESULTS: Excluding MRSA, the weighted CFR was greatest for imipenem/cilastatin and piperacillin/tazobactam regimens (93.9%-95.9%). With 42% MRSA added to the model, only tigecycline monotherapy achieved a high CFR (88.2%). The addition of vancomycin raised the CFR to 91.0%, 89.5%, 88.3%, 82.9%, and 78% for imipenem/cilastatin 500 mg q6h, imipenem/cilastatin 500 mg q8h, piperacillin/tazobactam, levofloxacin, and ceftriaxone regimens, respectively. CONCLUSION: Tigecycline monotherapy had a likelihood of achieving its requisite pharmacodynamic exposure similar to that of combinations of piperacillin/tazobactam or imipenem/cilastatin plus vancomycin for the empiric treatment of complicated skin and skin structure infections.     

手术去势对前列腺癌患者胰岛素抵抗及释放节律的影响

目的：探讨前列腺癌患者手术去势后,雄激素水平降低对机体胰岛素抵抗及胰岛素释放节律的影响.方法：36例患者经前列腺穿刺,病理诊断为前列腺癌,Gleason评分7～9分,临床分期Ⅲ～Ⅳ期,行双侧睾丸切除,术前无Ⅱ型糖尿病史.术前、术后1个月、3个月、6个月及1年分别测定血清睾酮（T）,血清游离睾酮（FT）,空腹及餐后0.5 h、1 h、2 h、3 h胰岛素.空腹及餐后0.5 h、1 h、2 h、3 h血糖.计算胰岛素抵抗指数及绘制胰岛素释放曲线.结果：本组患者去势术后1个月血清T、FT较术前显著下降[（0.45±0.05）ng/ml vs.（4.88±0.23）ng/ml,P〈0.001;（2.07±0.19）pmol/L vs.（35.10±4.37）pmol/L,P〈0.001].此后继续下降,术后6个月左右达到最低,并维持低水平.空腹血糖、空腹胰岛素、餐后2 h血糖及胰岛素于术后1个月显著升高[（5.63±0.78）mmol/L vs.（5.11±0.21）mmol/L,P〈0.05;（10.48±3.68）μU/ml vs.（7.56±2.58）μIU/ml,P〈0.05;（6.66±0.72）mmol/L vs.（5.78±0.33）mmol/L,P〈0.01;（16.31±0.45）μIU/ml vs.（13.21±0.35）μIU/ml,P〈0.01）],此后仍呈上升趋势,胰岛素释放曲线示餐后0.5 h峰值低于空腹时5倍或峰值后移.胰岛素抵抗指数（空腹胰岛素×空腹血糖÷22.5）术后1个月开始显著升高（2.62±0.13 vs.1.72±0.02,P〈0.05）（HOMA法,稳定模型法）,此后呈上升趋势.结论：双侧睾丸切除后,雄激素水平下降而导致胰岛素抵抗增加,且胰岛素释放曲线峰值下降或后移.Ⅱ型糖尿病发生风险显著增加.     

Investigation of pharmacokinetics of crushed imidafenacin 0.1-mg tablet after single oral administration in healthy men

The crushing of tablets and opening of capsules should not be performed without proper care, as these actions may adversely affect the pharmaceutical release mechanisms. However, various clinical circumstances occasionally necessitate these actions. The long-term stability of the commercial formulation of imidafenacin was confirmed after crushing of tablets. For the safe administration of crushed imidafenacin tablets, we examined the pharmacokinetics of crushed imidafenacin 0. 1-mg tablet after single oral administration in healthy men. Plasma concentrations were measured in 6 male volunteers (age, 33.3 ± 10.6 years) orally administered crushed imidafenacin under fasting conditions. Imidafenacin was rapidly absorbed and plasma concentrations peaked (Cmax) at 414 ± 108 pg/ml after 1.5 h (Tmax ; median), after which the drug was rapidly eliminated with a half-life (t1/2) of 2.8 ± 0. 3 h. Area under the plasma concentration-time curve (AUC0-10) was 1,680 ± 334 pg?h/ml. There were no significant differences in Cmax, Tmax and t1/2 between the crushed and tablet medications. Thus, crushing has almost no influence on the pharmacokinetics of imidafenacin. Consequently, this study was made available as information for patients requiring crushed anticholinergic agents.