应用PK/PD模型和蒙特卡洛模拟优化ICU中铜绿假单胞菌感染的初始给药方案

目的:优化抗菌药物治疗重症监护病房(ICU)中铜绿假单胞菌感染患者的初始给药方案。方法:基于收集到的国内外抗菌药物药动学和药效学参数,结合卫生部全国细菌耐药监测网(Mohnarin)和中国CHINET与耐药监测网关于医院ICU铜绿假单胞菌耐药监测报告及美国临床实验室标准化协会(CLSI)2013版标准,对铜绿假单胞菌的最低抑菌浓度设置为离散均匀分布,拟订出6种抗菌药物的24种给药方案,运用药效/药动学(PK/PD)模型和蒙特卡洛模拟10 000例"真实患者"的达标概率和累积反应分数,优化出最佳初始给药方案。结果:对铜绿假单胞菌感染可选择的初始给药方案分别是哌拉西林/他唑巴坦4.5 g,q6 h;头孢吡肟2.0 g,q12 h;美罗培南1.0 g,q6 h;阿米卡星17.5 mg/(kg·d);环丙沙星0.4 g,q8 h;多黏菌素150 mg,q12 h。结论:作为优化的初始给药方案,ICU中的非多重耐药铜绿假单胞菌感染建议选用头孢吡肟;多重耐药铜绿假单胞菌感染建议选用头孢吡肟+环丙沙星;全耐药铜绿假单胞菌感染则建议选用头孢吡肟+环丙沙星+多黏菌素。     

次抑菌浓度的药物诱导细菌耐药与交叉耐药

铜绿假单胞菌接种于含次抑菌浓度的哌拉西林和阿米卡星的营养肉汤中，葡萄球菌接种于次抑菌浓度的氧氟沙星和环丙沙星的营养肉汤中，经传代培养可获得相对应的耐药菌株。哌拉西林诱导耐药的铜绿假单胞菌对头孢他啶亦耐药，但对阿米卡星、环丙沙星、亚胺培南／西司他丁不耐药；阿米卡星诱导耐药的铜绿假单胞菌对哌拉西林亦耐药，但对头孢他啶、环丙沙星、亚胺培南／西司他丁没有交叉耐药；氧氟沙星或环丙沙星诱导耐药的葡萄球菌对氟喹诺酮类药物都有交叉耐药，但对苯唑西林、阿米卡星、亚胺培南／西司他丁没有显著的交叉耐药性     

抗菌药物与奥美拉唑联合应用减少铜绿假单胞菌耐药突变的研究

目的 在体外探讨美罗培南、头孢他啶、阿米卡星和环丙沙星4种抗菌药物分别与铜绿假单胞菌主动外排泵抑制剂奥美拉唑联合应用,是否有利于减少其耐药突变体的出现.方法 分别应用微量稀释法测定4种抗菌药物对铜绿假单胞菌的最低抑菌浓度(MIC),棋盘格法测定药物联合后的MIC,琼脂平板二倍稀释法测定抗菌药物单药以及联合后防耐药突变浓度的MPC,并计算相应的选择指数(SI,MPC/MIC),根据SI下降的程度来判断减少耐药突变体的能力.同时用美罗培南、头孢他啶、环丙沙星分别联合阿米卡星,阿米卡星联合环丙沙星,分别测定联合前后的SI,比较联合抗菌药物与联合奥美拉唑在防铜绿假单胞菌耐药突变的能力.结果 美罗培南、头孢他啶、阿米卡星、环丙沙星单独应用对铜绿假单胞菌SI分别为＞32,＞32,16,16,与奥美拉唑联合后SI分别为16,32,16,8.美罗培南、头孢他啶、环丙沙星分别与阿米卡星联合后的SI分别为4,4,8.阿米卡星与环丙沙星联合后阿米卡星的SI为4.结论 美罗培南、头孢他啶、环丙沙星分别与奥美拉唑联用时,可以缩小单药应用时对铜绿假单胞菌突变选择窗,有利于减少耐药突变体的产生,但防耐药突变作用弱于联合阿米卡星.阿米卡星与奥美拉唑联合不能缩小单药的SI,与环丙沙星联合能降低阿米卡星的SI.     

哌拉西林与环丙沙星对铜绿假单胞菌的联合药敏研究

目的评价哌拉西林与环丙沙星联合应用对铜绿假单胞菌的体外联合杀菌作用.方法采用棋盘法设计,微量肉汤稀释法测定其MIC值,计算抑菌指数(FIC).结果哌拉西林与环丙沙星联合应用后,哌拉西林对铜绿假单胞菌的MIC50值由8mg/L降至0.25mg/L,环丙沙星对铜绿假单胞菌的MIC50由1mg/L降至0.25mg/L,FIC指数范围主要在0～l.结论哌拉西林与环丙沙星药物联合应用,对铜绿假单胞菌的体外抗菌作用以协同和相加为主.     

马鞍山地区铜绿假单胞菌感染与耐药分析

目的了解马鞍山地区铜绿假单胞菌感染情况及耐药性，为临床合理应用抗茵药物提供依据。方法对我院2005年1月～2006年12月从临床标本中分离出的396株铜绿假单胞菌，利用美国Microscan walk away40型全自动细菌鉴定分析系统进行鉴定，并采用MIC法对分离出的铜绿假单菌选用15种抗菌药物进行敏感性测定。结果铜绿假单胞菌保持抗菌活性较强而耐药低于30％的抗菌药物有阿米卡星、头孢吡肟、头孢哌酮等，对哌拉西林／他唑巴坦、环丙沙星、头孢他啶、亚胺培南等主要抗菌药物的耐药率有普遍上升的趋势。感染部位依次为呼吸道、伤口、血液、胆汁等。结论铜绿假单胞菌存在较严重的交叉耐药及多重耐药现象。应加强对铜绿假单胞菌的耐药性监测，规范抗菌药物的应用，及早进行菌株培养和药敏，是控制铜绿假单胞菌感染和耐药上升的有效措施。     

利用MIC法筛选不同厂家生产的同一种抗菌药物

目的了解不同厂家生产的左氧氟沙星注射液和环丙沙星注射液的最低抑菌浓度（MIC），为临床医生合理选药提供依据。方法用琼脂稀释法和肉汤稀释法检测来自7个厂家的左氧氟沙星注射液和4种环丙沙星注射液对金黄色葡萄球菌、大肠埃希菌、铜绿假单胞菌的MIC。结果同一种抗菌药物的MIC从0．06-4．0μg／mL不等，高低相差60倍以上（相差6个质控浓度）；7个厂家左氧氟沙星对铜绿假单胞菌的MIC从0．25～4．0μg／mL不等，高低相差16倍（相差4个质控浓度）。结论当一个医院同时存在多个厂家的同一种抗菌药物时，应该选用敏感性较高（MIC较低）的药物。     

铜绿假单胞菌药物敏感性分析及防治对策

目的 :了解铜绿假单胞菌药物敏感性情况。方法 :对 1999年 11月至 2 0 0 1年 11月间我院分离出铜绿假单胞菌药敏进行分析。结果 :铜绿假单胞菌对亚胺培南、阿米卡星、奈替米星、环丙沙星、哌拉西林 三唑巴坦耐药率相对较低 ,对氨曲南、头孢他啶、庆大霉素耐药率相对较高。结论 :治疗铜绿假单胞菌感染 ,应建立在体外药敏的基础上 ,有针对性地选用抗菌药物     

联用抗菌药物对铜绿假单胞菌的抗生素后效应

铜绿假单胞菌是最常见的病原菌之一,其对多种用于治疗危及生命的感染性疾病的药物耐药已成为临床医生经常面临的难题。联合用药一般用于提供更好的疗效和防止耐药性的出现。严重性铜绿假单胞菌感染常常需要多药治疗,一般采用氨基糖苷类抗生素、β－内酷胺类抗生素和／或喹诺酮类药物联合。Ｓｏｏｄ等通过对３种抗菌药物（阿米卡星·头孢他啶,环丙沙星）单用和联用对铜绿假单胞菌的最低抑菌浓度（ＭＩＣ）和抗生素后效应（ＰＡＥ）的测定,为最佳剂量方案的设计提供理论基础。实验采用５株铜绿假单胞菌临床分离菌株和１株标准菌株（ＡＴＣ…     

医院内科系统铜绿假单胞菌耐药与抗菌药物的使用的相关性研究

目的分析我院内科系统9年间铜绿假单胞菌耐药率与抗菌药物使用量之间的关系,进一步指导临床合理使用抗菌药物。方法使用Whonet5.4软件回顾性分析我院2002-2010年铜绿假单胞菌的耐药率和调查具有抗铜绿假单胞菌活性的抗菌药物的使用消耗量,采用SPSS16.0软件做统计学分析。结果铜绿假单胞菌在内科患者中主要以呼吸道感染为主,占55.2%,且呼吸道感染的铜绿假单胞菌与其它部位感染的该菌,在耐药率上有显著差异,p≤0.05。9年间所监测抗菌药物的耐药率除氨基糖苷类外,均呈上升趋势;阿米卡星、头孢他啶和环丙沙星耐药率低于30%,可作为我院内科治疗铜绿假单胞菌的经验用药。抗菌药物的使用频度2005-2006年间使用达高峰,之后均有不同程度的下降。相关性分析发现发现三代头孢菌素的使用对头孢哌酮和头孢他啶对铜绿假单胞菌的耐药率呈现负相关,其余抗菌药物使用对其耐药率的增加均呈正相关。左氧氟沙星、环丙沙星、美罗培南和亚胺培南用量与铜绿假单胞菌对其的耐药率呈正相关,且有统计学意义,p≤0.05。结论我院分离的铜绿假单胞菌的耐药率呈逐年上升趋势,与抗菌药物使用量之间存在相关性。定期监测本地区内科系统抗菌药物使用和铜绿假单胞菌耐药率变化,对于临床治疗铜绿假单胞菌引起的感染具有现实意义。     

神经外科患者铜绿假单胞菌感染的耐药性分析

目的探讨神经外科患者铜绿假单胞菌感染的耐药性,给临床防治铜绿假单胞菌感染提供科学依据。方法用梅里埃VITEK-2全自动细菌鉴定药敏系统及纸片扩散法（K-B法）测定铜绿假单胞菌对15种抗菌药物的敏感性。结果近两年从神经外科共分离出285株铜绿假单胞菌,主要来源于下呼吸道标本,占88.8%（253株）,药敏结果显示,除对多粘菌素B、阿米卡星、舒普深（头孢哌酮/舒巴坦）、环丙沙星保持较好的敏感性外,其余都显示高度耐药。结论神经外科患者铜绿假单胞菌感染的耐药性较严重,临床应加强铜绿假单胞菌的耐药性监测,根据药敏结果合理选用抗菌药物,防止多耐药菌株的流行。     

基于Excel函数设计抗菌药物间歇静脉滴注给药方案

目的:设计抗菌药物间歇静脉滴注给药方案。方法:以头孢唑啉钠、头孢曲松钠、阿米卡星为例,采用多剂量函数法处理相关药动学数据,将药动学与药效学(PK/PD)参数相结合,应用Excel软件编写计算程序,设计合理给药方案。结果:时间依赖性抗菌药物的杀菌效应主要取决于血药浓度高于细菌最低抑菌浓度(MIC)的时间;对于血浆消除半衰期短的抗菌药物宜采取小剂量均匀分次给药,甚至持续给药;半衰期较长者12～24h给药1次即可。浓度依赖性抗菌药物优化临床抗菌疗效的最佳PK/PD参数为Cmax/MIC,适宜日剂量单次给予。结论:基于PK/PD,应用Excel函数设计抗菌药物间歇静脉滴注给药方案,方法简便、可靠、直观。     

Pharmacokinetics of pefloxacin and amikacin administered simultaneously to intensive care patients

Summary Ten adult patients with severe infections in an intensive care unit were treated simultaneously with 6 mg/kg pefloxacin and 7.5 mg/kg amikacin, infused i.v. over 1 h every 12 h for 5 days. Twelve h after the last infusion, pefloxacin alone was administered orally (400 mg tablet) every 12 h for 10 days. The pharmacokinetics of pefloxacin and its main metabolites, norfloxacin and pefloxacin N-oxide, were determined after the first (Day 1) and last (Day 5) infusions and after the last oral dose (Day 15). The kinetics of amikacin was determined after the first and the last infusion.The maximal and minimal steady-state plasma concentrations of amikacin were 27.3 and 3.3 mg/l. The total plasma clearance was 83.1 and 67.0 ml/min after the first and the last infusions, respectively, and the half-life was 3.9 and 5.0 h.The maximal and minimal steady-state plasma concentrations of pefloxacin were 13.1 and 7.9 mg/l after i.v. infusion and 13.4 and 9.0 mg/l after oral administration. Pefloxacin elimination (t_1/2) increased from 11.3 h after the first infusion to 19.4 h after the last infusion and 21.1 h after the last oral dose. Total body clearance decreased from 90.8 (Day 1) to 51.9 (Day 5) and 56.4 ml/min (Day 15). The volume of distribution did not change significantly over the course of pefloxacin. Mean steady-state plasma concentrations of norfloxacin and pefloxacin N-oxide were respectively 0.5–0.6 mg/l and 0.9–1.3 mg/l after intravenous and oral administration of pefloxacin.There were no pharmacokinetic interaction between the drugs. The dosage regimen led to plasma concentrations of pefloxacin and amikacin within their therapeutic range.     

蒙特卡洛模拟评价和优化产超广谱β-内酰胺酶大肠埃希菌血流感染抗菌药物给药方案

目的： 评价和优化某院产超广谱β-内酰胺酶大肠埃希菌（ESBLs-EC）血流感染抗菌药物给药方案。方法： 收集该院2019年产ESBLs-EC血流感染对亚胺培南西司他丁、哌拉西林钠他唑巴坦、头孢吡肟、头孢他啶和阿米卡星耐药监测报告,确定亚胺培南西司他丁、哌拉西林钠他唑巴坦、头孢吡肟、头孢他啶和阿米卡星治疗方案,根据各抗菌药物的药动学/药效学（PK/PD）模型,运用蒙特卡洛模拟（MCS）计算5种抗菌药物不同给药方案的达标概率（PTA）和累积反应分数（CFR）,评价疗效和优化出最佳初始给药方案。结果： 亚胺培南西司他丁1 g q12h、1 g q8h和1 g q6h,哌拉西林钠他唑巴坦4.5 g q8h和4.5 g q6h共5种给药方案的CFR ≥ 90%,而头孢吡肟、头孢他啶和阿米卡星所有给药方案CFR均小于90%。结论： 该院产ESBLs-EC血流感染时,经验选择可用亚胺培南西司他丁1 g q12h,哌拉西林钠他唑巴坦4.5 g q8h,不推荐头孢吡肟、头孢他啶和阿米卡星经验性治疗,临床经验性治疗与模拟结果基本一致,个体化治疗则应根据MIC值调整给药方案。     

Ceftriaxone/Amikacin vs Ceftazidime/Amikacin as Empirical Therapy for Fever in Patients with Haematological Malignancy and Severe Granulocytopenia: Clinical and Economic Outcomes

To assess the economic outcomes produced when a conventional antibiotic treatment regimen requiring three administrations per day was replaced with a treatment regimen requiring only one daily administration, the efficacy, tolerability and cost of ceftazidime was compared with that of ceftriaxone (both drugs in combination with amikacin) for the empirical treatment of febrile granulocytopenic patients with haematological malignancy. 102 febrile patient-episodes were randomly assigned to receive ceftazidime (6g in three divided doses) or ceftriaxone (2g as a single daily dose), both in combination with amikacin. The response was evaluable in 94 patients (47 in each group). 75 (80%) patients had an absolute granulocyte count lower than 100/mm(3) at the onset of fever or during the first week of antibiotic therapy. 61 (64.9%) were affected by acute leukaemia. Multiple daily ceftazidime plus amikacin was effective in 33 of 47 (70.2%) patients, and single daily ceftriaxone plus amikacin in 31 of 47 (66%) patients (p > 0.2). Among patients successfully treated, median time to defervescence was 3.3 days (range 1 to 11) for ceftazidime plus amikacin and 4.5 days for ceftriaxone plus amikacin (range 1 to 15) [p = 0.14]; study drugs were continued for 12 (range 7 to 26) and 12.3 days (range 7 to 28), respectively. Our study demonstrated that single daily administration of ceftriaxone was as effective and well tolerated as multiple daily administration of ceftazidime when both were administered in combination with amikacin. Cost analysis showed that compared with the thrice daily regimen, administration of single daily doses of ceftriaxone for a 12-day treatment period would result in a net cost saving of $US392 (626 940 Italian lire).     

Influence of the route of administration on the pharmacokinetics of amikacin

Summary The pharmacokinetics of amikacin was studied in 17 hospitalized patients with normal renal function (creatinine clearance greater than 90 ml/min), after the administration of a single dose of 7.5 mg/kg body weight. In 10 patients the antibiotic was administered intravenously and in the other 7 it was injected intramuscularly. After i. v. administration, the antibiotic followed an open two-compartment kinetic model, and after i. m. administration it followed a single compartment kinetic model. The route of administration did not significantly modify the pharmacokinetic parameters of amikacin. On the basis of the pharmacokinetic parameters thus established, an intravenous infusion for therapeutic use should have an administration rate of 2.5 [mg/kg/h] and a duration of 6 h.     

Clinical studies of intravenous drip infusion of micronomicin. 1. Absorption and excretion

Pharmacokinetics of MCR administered by 1 hour intravenous drip infusion were studied in healthy volunteers by two-compartment model. In 120 mg-dosage group (n = 3) studies were made by single administration, and in 60 mg-dosage group (n = 4) were administered twice daily and continued until a total of 9 doses. Results: When MCR was administered in a 60 mg dosage, its Cmax was 4.3 +/- 0.3 micrograms/ml (mean +/- S.D.) after the 1st dose and 3.7 +/- 0.4 micrograms/ml after the 9th dose, while it was 8.8 +/- 1.0 micrograms/ml when the dosage was 120 mg. It should be noted that in the case of repeated dosing with 60 mg, serum levels just before administration were always below the analytical limit. The mean of T 1/2 was 1.69 +/- 0.14 hours, remaining stable at all determination. The kinetic parameters that showed different values between determinations performed after the 1st and 9th 60 mg doses were V1 (0.107 vs 0.164 L/kg) and Kel (1.02 vs 0.68 hr-1). This was also the case with comparison of 2 different dosage groups (60 mg 1st vs 120 mg; V1: 0.107 vs 0.135 L/kg, Kel: 1.02 vs 0.72 hr-1). There was no evidence indicative of side effect of MCR. Discussion: The above results demonstrated that Cmax and other kinetic parameters were little influenced by whether MCR was administered by intravenous drip infusion or by intramuscular injection. There was a little larger difference in AUC between those 2 routes of administration but the differences seemed negligible when the same dosage was used. Pharmacokinetic studies are to be continued in subjects whose renal function is impaired in different ways to establish the optimum dosage regimen for MCR.     

Which fluoroquinolones are suitable for the treatment of urinary tract infections?

A number of fluoroquinolone agents are now available for clinical use and even more under development. Whether these compounds are equally effective and thus interchangeable in the treatment of urinary tract infection (UTI) has to be answered by comparing their antimicrobial activity against uropathogens, the pharmacokinetic and pharmacodynamic parameters and outcome of statistically meaningful clinical studies. Whereas almost all fluoroquinolones give equivalent results with short term therapy of acute uncomplicated cystitis in women, for patients with complicated UTI, only those compounds at the appropriate dosage regimen should be chosen for empiric therapy, which would exhibit sufficiently high urinary bactericidal activity against Gram-negative as well as Gram-positive uropathogens. When considering antibacterial activity, pharmacokinetic and pharmacodynamic properties as well as the results of the published clinical studies, a dosage of 500 mg ciprofloxacin twice daily, 500 mg levofloxacin once daily, or 400 mg gatifloxacin once daily may be comparable dosage regimens in the treatment of severe complicated UTI. In the case of ciprofloxacin (750 mg twice daily) and levofloxacin (500 mg twice daily), the dose could even be increased in UTI caused by less susceptible uropathogens, such as Pseudomonas aeruginosa.     

Application of Bayesian estimation for the prediction of an appropriate dosage regimen of amikacin

A Bayesian approach was developed to determine an amikacin dosage regimen to achieve the desired plasma concentrations for each patient. Statistical characteristics of pharmacokinetic parameters were first evaluated in a group of patients (reference population), which when combined with three individual plasma concentrations of drug led to a Bayesian estimation of individual pharmacokinetic parameters. By using these parameters, an individual dosage regimen was then established to avoid residual and peak amikacin concentrations of up to 3 and 25 micrograms/mL, respectively. In a test group of 33 patients, adapted amikacin dosage regimens ranged from 4 to 43 mg/kg/d, with schedules requiring up to four infusions per day. Infusion time varied from 40 min to 4 h. These differences in drug administration protocol result from the wide interindividual variability of amikacin pharmacokinetic parameters. Performance of the developed methodology was evaluated by computing bias and precision of the estimated total body clearance and of the trough and peak amikacin concentrations that were reached after dosage regimen determinations.     

Analysis on the effective dosage regimens for meropenem, biapenem and doripenem against P. aeruginosa infection based on pharmacokinetics and pharmacodynamics theory

Recently, PK/PD (pharmacokinetics/pharmacodynamics) analysis for the antimicrobial dosage method became one of the popular categories in chemotherapy and infectious disease societies world wide. Carbapenems are often used for empiric therapy because of its broad-spectrum and activities against microorganisms. PK/PD analysis is well studied in some antibiotics including carbapenems and it is necessary also from the point of view of prevention for emergence of resistant strains. We report the result of the analysis for the effective dosage regimens of meropenem, biapenem and doripenem against Pseudomonas aeruginosa infection based on PK/PD theory with the MIC distributions against the strains isolated from the patients blood at Keio University in 2004 and 2006. The highest target attainment rate for the free drug 40% time above the MIC (40%T > or = MIC) in traditional infusion with the MIC distribution against P. aeruginosa isolated from the patients blood at Keio University Hospital in 2004 was as follows: 90.89% in 500 mg every 6 hours regimen for meropenem, 83.25% in 300 mg every 6 hours regimen for biapenem, 81.73% in 250 mg every 6 hours regimen for doripenem in the approved maximum daily dose for each agent. The highest target attainment rate for the free drug 40%T > or = MIC in prolonged infusion with the MIC distribution against P. aeruginosa isolated from the patients blood at Keio University Hospital in 2004 was as follows: 100% in 500 mg every 6 hours regimen for meropenem, 83.97% in 300 mg every 8 hours regimen for biapenem, 99.98% in 500 mg every 8 hours regimen for doripenem in the maximum daily dose for each agents. The highest target attainment rate for the free drug 40%T > or = MIC in traditional infusion with the MIC distribution against P. aeruginosa isolated from the patients blood at Keio University Hospital in 2006 was as follows: 80.57% in 500 mg dose in every 6 hours regimen for meropenem, 56.70% in 300 mg every 6 hours regimen for biapenem, 69.44% in 250 mg every 6 hours regimen for doripenem in the maximum daily dose for each agent. The highest target attainment rate for the free drug 40%T > or = MIC in prolonged infusion with the MIC distribution against P. aeruginosa isolated from the patients blood at Keio University Hospital in 2006 was as follows: 89.35% in 500 mg every 6 hours regimen for meropenem, 60.84% in 300 mg every 6 hours regimen for biapenem, 82.78% in 500 mg every 8 hours regimen for doripenem in the maximum daily dose for each agent. The target attainment rates for the free drug Css/MIC > or = 1 with continuous infusion were lower than the target attainment rates for the free drug 40%T > or = MIC in the regimens of prolonged infusion intermittent dose regimens in all three agents using both of the MIC distributions against P. aeruginosa in 2004 and 2006. The result of the PK/PD analysis for meropenem, biapenem and doripenem indicated that intermittent dose with prolonged infusion was the best method to obtain higher target attainment rate.