pkpd与抗菌药物合理使用

,*,南京医科大学第一附属医院,*,南京医科大学第一附属医院,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,pkpd与抗菌药物合理使用,1,细菌耐药现状,2,PK/PD,概述,3,各类抗菌药物的,PK/PD,研究,4,主要内容,2,总结,感染变化,耐药菌感染增加,G,-,:,肠杆菌科,ESBLs,增加，葡萄糖非发酵菌耐药增加,(,铜绿,、不动、产碱,),G,:,MRSA / MRSE,，,PISP,，肠球菌,混合感染多,真菌感染增加,4,MRSA,在中国,-,临床分离率显著增高,全国,MRSA/MRCNS,监测结果,1-3,上海地区,MRSA/MRCNS,监测结果,4,1.,李家泰等。中华医学杂志，,2001;81(1):8-16,。,2.,李家泰等。中华医学杂志，,2003;83(5):365-374,。,3.,李家泰等。中华检验医学杂志，,2005;28(3):254-265,。,4.,朱德妹等。中华传染病杂志，,2004;22(3):154-159,。,5.,朱德妹等。中国感染与化疗杂志杂志，,2006;6(6):371-376,98-99,00-01,02-03,临床分离率,(%),80,年代前,85-86,年,2000,年,2002,年,90,年代,(,年,),MRSA,MRCNS,2005,年,HAP,CAP,临床分离率,(%),MSSA(1495,株,),与,MRSA(1916,株,),的耐药率（,%,）,中国,CHINET,（,2014,）,产,ESBLs,菌大问题,中国产,ESBLs,菌耐药问题形势严峻，尤以大肠埃希菌与肺炎克雷伯菌为重,对第,1,、,2,、,3,代头孢菌素均耐药,导致的是医院难治性感染，以肺部、泌尿系、腹盆腔感染多见,导致的原因是大量使用对,-,内酰胺酶不稳定的头孢类,铜绿假单胞菌,2006,2008,年耐药趋势,中国,CHINET,鲍曼不动杆菌,2006,2008,年耐药趋势,中国,CHINET,选择哪种抗菌药物,感染部位的常见病原学,选择能够覆盖病原体的抗感染药物,-,抗菌谱,/,组织穿透性,/,耐药性,/,安全性,/,费用,优化药代动力学/药效动力学,(PK/PD),考虑病人生理和病理生理状态,高龄/儿童/孕妇/哺乳,肾功能不全/肝功能不全/肝肾功能联合不全,其它因素,杀菌和抑菌/单药和联合/静脉和口服/疗程,经验性抗感染治疗合理使用药物,1,细菌耐药现状,2,PK/PD,概述,3,各类抗菌药物的,PK/PD,研究,4,主要内容,总结,16,9.5,8.5,7.5,7.5,6.5,Control,1/4MIC,MIC,4MIC,16MIC,64MIC,5.5,4.5,4.5,3.5,2.5,0 2 4 6,0 2 4 6,0 2 4 6 8,Tobramycin,Ciprofloxacin,Ticarcillin,Time (h),Log,10,cfu /ml,不同,MIC,妥布霉素、环丙沙星及替卡西林对铜绿假单胞菌的杀菌曲线,Zhanel GG, et al. A Critical review of the Fluoroquinolones focus on Respiratory tract infections J. Drugs, 2002, 62(1)13-59,PK/PD,体外研究,W.A. Craing. Diag Microbiol Infect 1995,18,抗菌药物的,P K/P D,分类,0,AUC:MIC,TMIC,C,max,:MIC,Concentration,Time (hours),MIC,AUC = Area under the concentrationtime curve,C,max,= Maximum plasma concentration,PK/PD参数,浓度依赖性抗菌药物的评价指标,时间依赖性抗菌药物的评价指标,1,细菌耐药现状,2,PK/PD,概述,3,各类抗菌药物的,PK/PD,研究,4,主要内容,总结,0,C,max,/MIC,Concentration,Time (hours),MIC,C,max,= Maximum plasma concentration,一、氨基糖苷类：,C,max,/MIC,Kashuba et al. Antimicrob Agents Chemother 1999;43:623629,Probability of resolution (%),First C,max,:MIC,10 gives,90% probability of WBC,and temperature resolution,Probability of temperature resolution by Day 7,Probability of white blood cell (WBC) count resolutionby Day 7,0,0,20,40,60,80,100,5,10,25,30,15,20,First C,max,:MIC,氨基糖苷,: C,max,/MIC,与,CAP,治疗反应,Once-daily regimen,Conventional (three-times daily regimen),Nicolau et al. Antimicrob Agents Chemother 1995;39:650655,Concentration (mg/L),0,8,14,4,6,10,12,Time (hours),0,12,24,20,4,8,16,2,氨基糖苷,: QD,与,TID,给药,MIC,0,AUC/MIC,Concentration,Time (hours),MIC,AUC = Area under the concentrationtime curve,二、,喹诺酮类：,AUC/MIC,Forrest et al. Antimicrob Agents Chemother 1993;37:10731081,Patients cured (%),0,20,40,60,80,100,62.5125,125250,250500,500,AUC/MIC,Clinical,Microbiological,氟喹诺酮,: AUC/MIC,与,CAP,治疗反应,氟喹诺酮最佳,AUIC,（,AUC/MIC,）,30,125,G,+,G,-,0,5,10,15,20,0,20,40,60,80,100,提高,AUIC,可以减少耐药,敏感率（,%,）,AUIC100,AUIC100-125,G,+,:,AUIC 30-40,防止耐药,C,max,MPC,争取较高的,AUIC,三、,-,内酰胺类：,TMIC,0,TMIC,Concentration,Time (hours),MIC,Walker et al. ICAAC 1994 Abstr. A-91,Change in log,10,CFU/thigh over 24 h,-3,-2,2,-1,0,1,Escherichia coli,Pseudomonas aeruginosa,0,80,TMIC (% of 24-h period),60,40,20,0,80,60,40,20,Carbapenem pharmacodynamics:relationship between TMIC and efficacy,Required %TMIC for cidal:, 40% for carbapenems, 50% for penicillins,70% for cephalosporins,Drusano GL.,Clin Infect Dis.,2003;36(suppl 1):S42-S50.,R,equired %TMIC for static,20%,for carbapenems,30%,for penicillins,40%,for cephalosporins,-,lactam,:,optimal TMIC?,Kuti et al. Am J Health Syst Pharm 2002;59:22092215,Concentration (,g/mL),0,1,10,100,4,8,6,2,Time (hours),MIC = 2,g/mL; 60% TMIC,MIC = 4,g/mL; 46% TMIC,1 g tid,给药的蒙特卡罗模拟,MIC = 8,g/mL; MIC,-,内酰胺类,属于时间依赖性抗菌药物，其杀菌能力与,TMIC,密切相关，要求,TMIC,至少达到,40-50%,多数半衰期仅,1h,左右的,-,内酰胺类,，对重症患者或耐药菌感染，,Q12h/Q8h,的给药方式不能获得,40-50%,的,TMIC,优化,-,内酰胺类,的给药方式,加大剂量：受肾功能限制可能需要调整剂量,增加给药次数：,Q8h,转为,Q6h,采用持续静脉滴注,/,延长滴注时间,替加环素,PK/PD,研究结果的局限性,仅有体外研究和动物实验,动物实验：粒缺小鼠大腿感染模型,半衰期不同：人类为,40h,，小鼠仅,1-2h,人类为线性药代动力学，小鼠为非线性药代动力学,体外实验：组织浓度较高，血药浓度不能代替组织浓度,小 结,合理使用抗菌药物，应根据,PK/PD,优化给药,浓度依赖性抗菌药物推荐,QD,给药,时间依赖性抗菌药物推荐一日多次给药，尤其是半衰期短的,-,内酰胺类，如大多数青霉素类、头孢菌素类,重症感染,/,多重耐药菌感染，推荐,持续静脉滴注,延长滴注时间,增加给药次数,病人,药物,病原,Thank You !,40,谢谢,