从PK-PD看抗菌药物的合理应用.pptx

从pk/pd看抗菌药物的合理应用,李光辉 复旦大学附属华山医院,defenition,pk what the body does to the drug absorbtion cmax metabolism auc elimination half-life pd what the drug does to the body direct effects mic, mbc post-drug effects pae selection effects resistance,pharmacokinetics concentration vs time,from pk to pd,conc.,time,pharmacodynamics effet vs time,effect,conc.,pk/pd effect vs time,effect,time,peak/mic,auic,auc/mic,aucmic,pale,cmax/mic,tmic,pae,pa-sme,mpc,抗菌药药效学,细菌对抗菌药的敏感性 纸片扩散法（k-b法） 最低抑菌浓度( mic) 最低杀菌浓度(mbc),药物敏感试验,琼脂扩散法(纸片法，kirby-bauer)测抑菌圈大小画分s,i,r 稀释法琼脂稀释法，肉汤稀释法，微量稀释法 e测定法(epsilometer test)测mic值 判断标准：通常根据clsi判断结果 4. 自动化药敏测micatb系统，vitek系统，micro scan等,药敏试验的临床意义,敏感(s)常规剂量时的平均血浓度超过mic的5倍以上，用常规剂量通常有效 中介(i)常规剂量时的平均血浓度等于或略高于mic，需用高剂量或对药物浓缩部位的感染可能有效 耐药(r)药物的mic高于其常规剂量时的血浓度，通常治疗无效,chinet 2012年15家医院31277株肠杆菌科细菌耐药率（%）,chinet 2012年15家医院19613株非发酵菌耐药率（%）,各种酶抑制剂复方制剂的比较,头孢哌酮/舒巴坦与头孢菌素、亚胺培南特性比较,对于革兰阴性菌：+, r10%; +, r20%; +, r50%; +, r 80%,抗菌药药效学 mic and mbc参数的不足,mic和mbc反映体外活性，但不反映活性在体内的时间过程 mbc不能提供抗菌药的杀菌速度，不能预言增加药物浓度是否可以提高杀菌速度 mic也不能反映细菌在接触抗菌药后，被抑制的状态能持续多少时间,抗菌药药效学,杀菌曲线(time-kill curves) 杀菌曲线反映抗菌药杀灭细菌的动态过程与杀菌效率 当抗菌药浓度mic时，杀菌曲线有两种 菌量随时间延长逐渐减少，表明具有杀菌作用，为杀菌剂 菌量随时间变化不明显，曲线呈近水平状，表明仅具抑菌作用，为抑菌剂,effect of increasing concentrations of tobramycin(a), ciprofloxacin(b) and ticarcillin(c) on the bacterial activity against pseudomonas aeruginosa,log10cfu/ml,(a),(c),抗菌药药效学,抗生素后效应（pae） 是指细菌暴露于抗菌药后，在洗去抗菌药的情况下，数量增加十倍（1log10单位）所需的时间（与对照组的差） pae的大小反映抗生素作用后细菌再生长延迟相的长短，亦反映抗菌药作用于细菌后的持续抑制作用，故而又称持续效应（persistent effects）,抗菌药药效学,抗生素后效应（pae） pae在不同抗菌药、不同细菌持续时间有很大差异，且受抗菌药浓度、作用时间等影响 对于gpc，所有抗菌药均有pae； 对于gnb，抑制蛋白和核酸合成的抗菌药具有pae 内酰胺类对gnb几乎无pae或短，但亚胺培南对铜绿假单胞菌的pae为1-2h,post-antibiotic effect (pae),viable count (cfu/ml),pae = 3.1 - 1.6 = 1.5 hours due to antibiotic effect only,药效学/药动学（pk/pd）原则 根据杀菌活性对抗菌药物进行分类,第一大类：时间依赖型 在药物浓度超过mic 4-5倍以上时杀菌活力不再增加 代表药物：内酰胺类 、大环内酯类、克林霉素和万古霉素 第二大类：浓度依赖型 药物的杀菌活力在很大范围内随药物浓度的增高而增加 代表药物：氨基糖苷类、氟喹诺酮类和甲硝唑等,pk/pd parameters correlating with antibacterial efficacy,根据pk/pd原理制订的给药方案可以达到更高的疗效和清除病原菌的作用，并可能防止疗程中细菌产生耐药性 与时间依赖型药物杀菌活力有关的pk/pd参数是tmic，即血药浓度达到或超过mic持续的时间占2次给药间期的百分比 与浓度依赖型药物杀菌活力有关的主要参数是auc24/mic或cmax/mic,药效学/药动学（pk/pd）原则 pk/pd参数的意义,pharmacodynamics parameters & outcome,rybak mj. am j med 2006; 119:s37-s44.,time-dependent agents,time,antibacterial concentration (g/ml),2,drug a,drug b,drug a present at concentration of 2 g/ml for 50% of dosing interval drug b present at concentration of 2 g/ml for 30% of dosing interval,4,6,8,0,time above mic correlation of serum pharmacokinetics with mic (susceptibility) of an organism,mic,scand j infect dis suppl 96:11-16,1995,抗菌药发挥作用所必需的 time mic,给药间隔的多少%合适？, ba （%）,pharmacodynamic goals (tmic as percent of interval) with beta-lactams,maximum class organism stasis killing cephalosporins gnr, pneumo 40-50 70-80 staph 20-30 40-50 penicillins gnr, pneumo 30-40 60-70 staph 20-30 40-50 carbapenems gnr, staph 20-30 40-50 pneumo 10-20 25-40,craig 1999,0,20,40,60,80,100,0,20,40,60,80,100,time above mic (%),penicillins,cephalosporins,mortality after 4 days of therapy (%),craig. diagn microbiol infect dis 1996; 25:213217,relationship between time above mic and efficacy in animal infection models infected with s. pneumoniae,细菌学疗效： 青霉素：tmic%40% 头孢菌素：tmic%50%,relationship between tmic and efficacy for cephalosporins (yellow), penicillins (aqua) and carbapenems (red),mic：64mg/l,mic：16mg/l,8. okamura k, et al. acta urol jpn. 1989;35:727-734. 9. suzuyama y, et al. chemotherapy. 1984;32(s-4):355-367. 10. aoyama h, et al. jpn j antibiot. 1988;41:1279-1284. 11. tsuyuki k, et al. chemotherapy. 1984;32(s-4):404-412 12. cho n, et al. world gynecol. 1984;36(8):649-675.,13. nakagawa k, et al. surg care. 1990;32(6):875-879. 14. hayasaki m, et al. chemotherapy. 1984;32(s-4):649-665. 15 cetobid product monograph. physicians desk reference(53th ed.) 16 warnke ip, et al. int j clin pharmacol ther 1998;36(5):253-257 17 foulds g, et al. antimicrob agents chemother 1997;31(11):1703-1705 18 stahl jp, et al. rev infect dis 1986;8(5):s612-s616,药效学/药动学（pk/pd）原则 头孢哌酮-舒巴坦复合制剂中头孢哌酮pk/pd参数比较,不动杆菌属,大肠埃希菌,铜绿假单胞菌,产气肠杆菌,tmic90(%),头孢哌酮-舒巴坦2克q8h和3克q12h在难治的革兰阴性耐药菌中tmic90%均达到50以上,嗜麦芽窄食单胞菌,阴沟肠杆菌,普深在肺组织内的平均浓度超过常见致病菌的mic90值,舒,0.1,0.5,致病菌 mic90(mg/ml) 金黄色葡萄球菌 16 (产b-内酰胺酶) 铜绿假单胞菌 8 金黄色葡萄球菌 2 肺炎克雷伯菌 2 阴沟肠杆菌 1 大肠埃希菌 0.5 鲍曼不动杆菌 0.12,0,1,2,10,20,舒巴坦,头孢哌酮,7.84mg/ml,24.60mg/ml,肺组织内平均药物浓度(mg/ml),舒普深在静注2g后在肺组织内的平均浓度 与对常见致病菌的mic90值比较*,deguchi k, yokota n, koguchi m,et al,. b-lactamase activty in sputum of patients with community-agguired lower respiratory tract infections. jon j antibiot 1994; 47:161-169.,34,舒普深(2:1) 3g q6h的pk/pd,*基于舒普深药代动力学参数计算。,2. 舒普深1.5g说明书；3. reitberg dp, marble da, schultz rw, et al. antimicrobial agents and chemotherapy, 1988, p. 503-509；5. reitberg dp, whall tj, chung m, et al. antimicrobial agents and chemotherapy, jan. 1988, p. 42-46,头孢哌酮/舒巴坦(2:1)3种给药方案对非发酵菌不同mic值时%tmic（头孢哌酮）,mic16mg/l:3g,q8h、 3g,q12h ；mic 32mg/l:3g,q6h 鲍曼：疗程11.24.6天，临床治愈率为79.3%（23/29） ；微生物学治愈率为69.0%（20/29） 铜绿：疗程11.74.5天，临床治愈率为68.2%（15/22）；微生物学治愈率为19.0%（4/21）， 混合感染：临床治愈率：2/3；微生物学治愈率：其中2例铜绿未清除,舒普深3g,q8h,疗程14天治疗鲍曼不动杆菌hap患者pk/pd参数与临床疗效关系的研究（n=12),kuti et al. am j health syst pharm 2002;59:22092215,concentration (g/ml),0,0.1,1,10,100,4,8,6,2,time (hours),mic = 2 g/ml; 60% tmic,mic = 4 g/ml; 46% tmic,meropenem 1 g three-times daily: 5000 patient monte carlo simulation,替加环素pk/pd特性,抗生素后效应（pae） 体外pae 金葡菌： 3.44.0 h 大肠埃希菌：1.82.9 h 体内pae 大肠杆菌：4.9 h 肺炎链球菌：8.9 h 中一长时效的pae pk/pd参数：auc24/mic,cap患者: f auc0-24:mic) of 12.8 were associated with a faster time to fever resolution patients with lower drug exposures had a slower time to fever resolution (p0.05),替加环素pta 结果,.,50 and 100 mg q12h of tigecycline provided pta (auc24/mic18) values of 100% for mics0.25 mg/l going down to 65% and 0 for an mic of 0.5 mg/l, with 100 and 50 mg q12h respectively,a. canut .eur j clin microbiol infect dis (2012) 31:2227,多粘菌素pk/pd特性,phillip j. pharmacokinetic/pharmacodynamic investigation of colistin against pseudomonas aeruginosa using an in vitro model aac sept. 2010, p. 3783,多粘菌素e硫酸盐：口服给药、局部给药 多粘菌素e甲磺酸盐（cms）：静脉注射、肌内注射，雾化吸入或鞘内注射 多粘菌素b硫酸盐：静脉注射，肌内注射，雾化吸入 浓度依赖性：auc/mic pk/pd靶值：肺部感染中细菌数减少1个 lgcfuauc/mic 铜绿假单胞菌： 15.6-22.8；鲍曼不动杆菌：8.18-42.1,大环内酯类pk/pd研究,4种大环内酯类药物对肺炎链球菌的杀菌曲线 结果表明2种酮内酯类药物telithromycin和abt-773呈浓度依赖性,大环内酯类为时间依赖性，但其中的酮内酯类属浓度依赖性。,糖肽类抗生素 pk/pd研究,(a)在万古霉素2, 4, 8, 16, 和64倍mic对 s. aureusatcc29213 的kcs. (b)在万古霉素2, 4, 8, 16和64倍mic对 s. epidermidisatcc29886 的kcs 结果提示万古霉素属于时间依赖性抗菌药物 。,non-concentration dependent killing of teicoplanin against s. aureus,1,2,3,4,5,6,7,8,9,10,0,3,6,9,12,15,18,21,24,h,log10 cfu/ml,2xmic,4xmic,8xmic,16xmic,64xmic,control,2,1,0,-1,-2,-3,-4,30,100,300,1000,10,30,100,300,1000,20,40,60,80,100, log10 cfu/g over 24 h,24-h auc/mic,peak/mic,t mic,ebert s. et al. 27th icaac 1987. craig wa & andes dr. 46th icaac 2006.,relationship of pk/pd for vancomycin bacteriologic efficacy vs. mssa in thighs of neutropenic mice,linezolid治疗大鼠股部肺炎链球菌感染,pk/pd参数与细菌学疗效关系 可见linezolid tmic与细菌学疗效相关系数最高为84，当tmic为40即可达到良好的细菌学疗效。,andes d, et al. antimicrob agents chemother 2002;46:3484-9.,斯沃auc24/mic 100临床疗效卓越,whitehouse t,et al. j antimicrob chemother. 2005 r;55:333-40,斯沃 auc24/mic 100时，细菌清除率高达75以上,一项随机、双盲、安慰剂对照性研究，比较利奈唑胺与替考拉宁治疗icu患者的药代动力学，用法用量：斯沃600mg iv q12h；替考拉宁安慰剂400mg iv q12h ，给药3次后400mg q24h；替考拉宁400mg iv q12h ，给药3次后400mg q24h,*cons：凝固酶阴性葡萄球菌,利奈唑胺pta结果,pta (auc24/mic100) higher than 90% for mics2 mg/l for an mic of 4 mg/l, the pta reached a value of about 40%,a. canut .eur j clin microbiol infect dis (2012) 31:2227,concentration-dependent agents,antibiotic concentration,mic,time,24-hr auc/mic is correlated with outcome of infection, the magnitude required for success and mic at which this occurs becomes the pd breakpoint,24-hr auc/mic and peak/mic ratios correlation of serum pharmacokinetics with mic of an organism,levofloxacin pk/pd parameters against s. pneumoniae in neutropenic mouse thigh infection model,%t mic,peak/mic,24-hr auc/mic,handbook of experimental pharmacology. vol 127: quinolone antibacterials. 1998,relationship between 24 hr auc/mic and mortality for fluoroquinolones against s. pneumoniae in immunocompetent animals,relationship between 24 hr auc/mic and mortality for fluoroquinolones against gram-negative bacilli in immunocompromised animals,clinical failure rate 43% 11.5% 1%,levofloxacin pk/pd correlations 134 hospitalized patients with rti, ssti or uti treated with 500 mg qd for 514 days,jacobs. clin microbiol infect 2001;7:58996 adapted from preston et al. jama 1998;279:1259,relationship between 24-hr auc/mic and efficacy of ciprofloxacin in 64 patients with serious bacterial infections,24-hr auc/mic,relationship between max. peak/mic ratio and the rate of clinical response for aminoglycosides moore et.al. j infect dis, 1987, 155: 93,maximum peak/mic ratio,response rate, %,kashuba et al. antimicrob agents chemother 1999;43:623629,probability of resolution (%),first cmax:mic 10 gives 90% probability of wbc and temperature resolution,probability of temperature resolution by day 7,probability of white blood cell (wbc) count resolution by day 7,0,0,20,40,60,80,100,5,10,25,30,15,20,first cmax:mic,optimising aminoglycoside therapy for nosocomial pneumonia,氨基糖苷类日剂量单次给药,1、提高抗菌活性 氨基糖苷类属于浓度依赖型抗生素，氨基糖苷类cmax/mic与临床疗效呈正相关。 在日剂量不变的情况下，单次给药可以获得较多次给药更高的cmax，使cmax/mic比值增大，从而明显提高抗菌活性和临床疗效。但应注意cmax不得超过最低毒性剂量。 2、降低耐药性发生 gould im,milne k and jason c. drug exp clin res.1990;16:6218. 3、降低肾毒性 verpooten ga,giuliano ra,verbist l,et al. clin pharmacol ther 1989;45:22-27 4、降低耳毒性 fishman d n ,kaye k m. infect dis clin nirth am ,2000，14(2):475,daptomycin pharmacodynamics,bactericidal in vitroa rapid concentration-dependent killing key predictors of efficacy based on animal models peak exposure: cmax/mic total exposure: auc/mic 5 -10 h postantibiotic effect,cmax=maximum plasma concentration; mic=minimum inhibitory concentration; auc=area under the concentration-time curve. athe clinical significance of in vitro data has not been established. cubicin (daptomycin for injection) current prescribing information; louie a, kaw p, liu w, jumbe n, miller mh, drusano gl. pharmacodynamics of daptomycin in a murine thigh model of staphylococcus aureus infection. antimicrob agents chemother. 2001;45(3):845-851; safdar n, andes d, craig wa. in vivo pharmacodynamic activity of daptomycin. antimicrob agents