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1、抗菌药物在呼吸系统的药代动力学和药效学,主要内容,抗感染药物治疗的药代/药效要求 药物在肺内转运和穿透屏障的主要机制 药物在肺内转运的影响因素 代表性药物肺内的药代和药效,抗感染药物治疗的药代/药效要求,抗菌药物的临床效果除了取决于其抗菌谱、抗菌活性外，还受到它的血浆浓度、到达感染组织的浓度及维持时间的影响。抗菌药物进入体内后必须穿透血-支气管屏障和血-肺屏障才能到达感染部位。,抗感染药物治疗的药代/药效要求,PK 研究机体对药物的作用 PD 研究药物对机体的作用,剂量对药效的影响,药物对临床疾病的效果 PK/PD 将剂量时间浓度效应的关系联系在一起研究,抗感染药物治疗的药代/药效要求,con
2、c,effect,effect,time,time,conc,Pharmacokinetics DoseConc.vs.time,PK/PD DoseEffect.vs.time,Pharmacodynamics Conc. Effect,抗感染药物治疗的药代/药效要求,根据PK/PD参数的特点按杀菌活性分类 第一类：时间依赖杀菌剂 -内酰胺类 (青霉素类、头孢菌素、氨曲南、碳烯类)，克林和大环、四环、万古霉素 在 MIC4-5 倍时,杀菌率即处于饱和 杀菌范围主要依赖于接触时间 血药浓度超过MIC时间（TMIC)是与临床疗效相关的主要参数,抗感染药物治疗的药代/药效要求,第一类：时间依赖杀菌
3、剂 血药浓度高于 MIC 的时间是最主要参数 给药间期并不需要都超过MIC TMIC30-40% 起效 TMIC 40-50% 保证有效的细菌清除,抗感染药物治疗的药代/药效要求,有效的细菌清除： 青霉素： TMIC%40% 头孢菌素：TMIC%50%,肺炎链球菌感染动物的模型,头孢菌素,青霉素,Time above MIC (%),Bacteriologic Cure (%),抗感染药物治疗的药代/药效要求,抗感染药物治疗的药代/药效要求,第二类：浓度依赖杀菌药物 有持续的后效应 氨基糖苷类、喹诺酮类、甲硝唑 投药目标达到最大药物接触，药物浓度越高杀菌率及杀菌范围也越大 24小时AUC/MI
4、C(AUIC)、峰浓度(Cmax)/MIC是疗效相关的主要参数,Forrest研究发现，64例使用喹诺酮类治疗的肺炎患者中AUC0-24/MIC125时，疗效和细菌清除率为42%和26%,当AUC0-24/MIC125时，两者分别为80和82%，因此认为,AUC0-24/MIC为125时为抗肺炎链球菌的最低有效值,抗感染药物治疗的药代/药效要求,喹诺酮类属浓度依赖性抗菌药,评价疗效的主要参数为Cmax/MIC、AUC/MIC,研究表明左氧氟沙星对革兰阴性菌24小时AUC/MIC应在100以上,Cmax/MIC达8-10较合适,抗感染药物治疗的药代/药效要求,药物在肺内转运和穿透屏障的主要机制,
5、弥散 肺泡-毛细血管膜是双层的多孔生物膜。 抗菌药物依赖浓度梯度由血管腔经毛细血管孔进入肺间质和肺泡上皮村液（epithelial lining fluid,ELF） 渗透 药物穿透非多孔膜的一种方法，通过毛细血管膜细胞转运，亦属被动过程，但受药物脂溶性的影响，脂溶性高的药物易于渗透。 主动转运 是一种能量依赖的主动转运机制，在达到饱和状态即不再起作用。大环内酯类、克林霉素为巨噬细胞摄取是通过这一过程实现的，而喹诺酮药物摄取可能部分通过 氨基酸运输系统。,药物在肺内转运的影响因素,药物因素：脂溶性、蛋白结合率 解剖因素：肺循环和支气管循环提供巨大的血管床表面积 炎症因素：多数抗菌药物在炎症组织
6、的穿透力提高，但喹诺酮、氯霉素、土霉素、多西环素、米诺环素、阿奇霉素则属非炎症依耐性。 其他 ：呼吸道分泌物的H+、Ca2+、Mg2+等可使氨基糖苷类抗生素灭活。,代表性药物肺内的药代和药效,阿奇霉素在肺内的药代和药效 喹诺酮类药物在肺内的药代和药效 美罗培南在肺内的药代和药效 利奈唑胺在肺内的药代和药效,阿奇霉素在肺内的药代和药效,Azithromycin was widely distributed within the lower respiratory tract and sustained levels of the drug were detectable at the last
7、sampling time in lung tissue. Doubling the dose of the antibiotic resulted in a proportional increase in lung area under the curve (AUC, 1245.4 versus 2514.2 h x mg/kg) and peak tissue concentration (Cmax, 8.93 2.05 versus 18.6 2.20 mg/kg). The pharmacodynamic parameter AUC/MIC for susceptible and i
8、ntermediate strains of Streptococcus pneumoniae (MICs 0.5 and 2 mg/L, respectively) increased after administration of the 1000 mg schedule compared with 500 mg (AUC/MIC0.5 2414 versus 1144 and AUC/MIC2 2112 versus 814.1 h x mg/kg, respectively) in pulmonary tissue.,Pharmacokinetic parameters of azit
9、hromycin in plasma of 48 patients,Each value is the mean S.D. of 24 patients. aP 0.05 compared with azithromycin 500 mg once daily for 3 days.,Pharmacokinetic and pharmacodynamic parameters of azithromycin in lung and bronchial washing of 48 patients,Cmaxand Tmax are the mean S.D. of four patients.
10、aP 0.05 compared with azithromycin 500 mg once daily for 3 days. bPharmacodynamic parameters are calculated on the basis of the MIC for azithromycin-susceptible (0.5 mg/L) or -intermediate (2 mg/L) S. pneumoniae.,喹诺酮类药物在肺内的药动和药效,Oral administration of moxifloxacin （ MXF）, 400 mg, levofloxacin （ LEVO
11、）, 500 mg daily for five doses, BAL and venipuncture were completed at 4, 8, 12, or 24 h following the dministration of the last dose.,Steady-State MXF and LEVO Concentrations in the Plasma, pulmonary e pithelial lining fluid (ELF), and alveolar macrophage (AM)*,* Values given as mean SD, unless oth
12、erwise indicated. Three subjects. One subject was excluded due to insufficient data on the cell differential.,Pharmacodynamic Profile (AUC/MIC) of S pneumoniae for MFX and LEVO in Plasma and ELF*,* MIC90 values of S pneumoniae for each agent were obtained from US surveillance studies: MXF, 0.25 g/mL
13、; LEVO, 1 g/mL.,喹诺酮类药物在肺内的药动和药效,The intrapulmonary concentrations of MXF, LEV were superior to those obtained in the plasma. The AM concentrations of all agents studied were more than adequate relative to the minimum concentration required to inhibit 90% of the organism population (MIC90) of the com
14、mon intracellular pathogens ( 1 g/mL). based on the agents current minimum inhibitory concentration profile, whereas the mean concentrations of MXF and LEVO in the ELF exceed the MIC90 of the S pneumoniae population. Moreover, MXF concentrations exceeded the S pneumoniae susceptibility breakpoint (1
15、.0 g/mL) at all time points, while 2 of 15 concentrations (13%) failed to maintain LEVO concentrations above the breakpoint (2.0 g/mL) throughout the dosing interval.,美洛培南在肺内的药代和药效,Patients received 1 g of meropenem intravenously (i.v.) as a 20-min infusion every 8 h. In each patient, two microdialy
16、sis probes were placed percutaneously under direct vision 2 cm apart well into pneumonic tissue at the end of the operation, directly before the planned fifth dose of meropenem. By use of a microinfusion pump the in situ probes were constantly perfused with Ringers solution at a flow rate of 1.5 l/m
17、in. Microdialysis was started approximately 30 min after probe insertion, and the patients were monitored on the intensive care unit. For calibration, prior to the systemic administration of the study drug, the probes were perfused for 20 min with a solution of the drug, resulting in diffusion from
18、the lumen into the tissue.,美洛培南在肺内的药代和药效,After a sufficient washout period for the system, meropenem was administered i.v. at a dose of 1 g over 20 min. Sampling of dialysates and venous blood was performed at 20-min intervals for a period of 8 h. Blood samples were collected in plastic tubes and we
19、re immediately centrifuged at 1,600 g for 5 min. Serum and dialysate samples were shock frozen and stored over liquid nitrogen until analysis. Meropenem was assayed by using high-pressure liquid chromatography method with a limit of detection of 1mg/liter,Pharmacokinetic parameters for meropenem (no
20、ncompartmental analysis) in serum, lung interstitial fluid,a Parameters were measured after the i.v. administration of meropenem at 1 g to seven patients with sepsis and undergoing lateral thoracotomy for pneumonia ormetapneumonic pleural empyema. Except for Tmax, results are expressed as mean and s
21、tandard deviation. b At the end of the infusion.,美洛培南在肺内的药代和药效,In the present study, meropenem was administered at a dose of 1 g every 8 h, as recommended by the manufacturer. At this dosage, sufficient concentrations of unbound meropenem were found in the interstitial space fluid of infected lung t
22、issue in patients with metapneumonic empyema. The concentrations of meropenem in tissue were maintained above the MIC90 threshold for many clinically relevant pathogens, including S. aureus, S. pneumoniae, P. aeruginosa, E. aerogenes, and K. pneumoniae, for up to 6 h (i.e., 80% of the dosing interva
23、l).,利奈唑胺多剂口服后的药代动力学和组织穿透性,利奈唑胺多剂口服后的药代动力学和组织穿透性,利奈唑胺属于一类新的抗菌药噁唑烷酮类 通过抑制蛋白质合成的起始阶段起抗菌作用 在体外和体内对革兰阳性菌具有良好的抗菌作用，包括耐药菌株 目的：评价在600mg多剂口服后，利奈唑胺的药代动力学和组织穿透性 采用水泡液模拟炎症渗出液,THEKLI GEE，et al, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2001,45(6),1843-1846,材料与方法,受试者：8名，平均年龄29.68.7岁，平均体重78.67.1 kg，平均身高180.414.1 cm，1名
24、受试者因发热推出研究，实际参加者7名,受试者7名,利奈唑胺 600/12h, 共5剂,给药前及 末次给药 后取血标本,取标本：给药前及末次给药后0.5，1，1.5，2，3，4，6，8，10，和12 h 取血标本，同时取水泡液,THEKLI GEE，et al, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2001,45(6),1843-1846,水泡液中药物浓度检测,血中药物浓度检测,药代动力学分析,采用HPLC，联合三重四极杆质谱,采用高效液相色谱（HPLC）， 每份标本检测2次，取平均值,标准的无房室，非稳态分析,材料与方法,THEKLI GEE，et al
25、, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2001,45(6),1843-1846,结果,1例试验后数天出 现口腔念珠菌病， 口服制霉菌素治疗,1例在服用首剂利 奈唑胺2h后出现心 率增快，自88次/分 升至120次/分，血 压自150/88mmHg 上升至163/90 mmHg。该受试者入 院观察不良事件考虑 与焦虑有关，但不能 除外与研究药物的关 系，因此退出研究,THEKLI GEE，et al, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2001,45(6),1843-1846,图：末次给药后血浆和炎症渗出液中利奈
26、唑胺的浓度,水泡液,血浆,利奈唑胺浓度,THEKLI GEE，et al, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2001,45(6),1843-1846,末次给药后，利奈唑胺在血浆和炎症渗出液中的药代动力学参数,THEKLI GEE，et al, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2001,45(6),1843-1846,利奈唑胺在水泡液中具有较好的药动学数据,6名受试者都产生了水泡，但1名受试者的水泡液的总量不够用做完整的药代动力学分析（即至少在清除期要有3个点）,Tmax,Cmax,T1/2,平均比例,利奈
27、唑胺,3h (2h4h),16.4 mg/ml （ 6.836.8 mg/ml）,5.7h,104% （ 80%130%）,THEKLI GEE，et al, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2001,45(6),1843-1846,讨论,炎症渗出液中的平均比例为104%，取决于2个因素,12h内，利奈唑胺在炎症渗出液中的平均浓度为4.9 mg/L,多数金葡菌（甲氧西林敏感及耐药株）、链球菌和肠球菌的MIC 4 g/ml,提示可用于治疗这些细菌所致感染,蛋白结合力：利奈唑胺相对较低，为31%,分布容积：利奈唑胺约为50L,THEKLI GEE，et
28、al, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2001,45(6),1843-1846,利奈唑胺与常用PK/PD数据,氟喹诺酮类和氨基糖苷类的研究表明, AUC24/MIC 反映临床疗效,AUC24/MIC,临床效果,100,125,可能具有较好疗效,理想的抗菌作用,利奈唑胺对金葡菌,利奈唑胺对肺炎链球菌,215,107.5,研究表明,THEKLI GEE，et al, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2001,45(6),1843-1846,利奈唑胺与常用PK/PD数据,Cmax/MIC的比值，与防止细菌突变发
29、生耐药（目前的研究主要来源于氟喹诺酮类和氨基糖苷类的研究，内酰胺类药物少）有关,Cmax/MIC,出现耐药的几率,810,低,研究表明,利奈唑胺,9.1,THEKLI GEE，et al, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2001,45(6),1843-1846,利奈唑胺与常用PK/PD数据,TMIC 小鼠大腿模型的研究显示，药物浓度在血浆中的浓度高于细菌MIC的时间与疗效有关，其目标值是给药间隔的40% 本研究显示，利奈唑胺的TMIC至少为12h 超过了每日2次给药的时间间隔,THEKLI GEE，et al, ANTIMICROBIAL AGEN
30、TS AND CHEMOTHERAPY,2001,45(6),1843-1846,利奈唑胺与常用PK/PD数据,本研究显示，血浆和ELF利奈唑胺的TMIC至少为24h 超过了每日2次给药的时间间隔,THEKLI GEE，et al, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2001,45(6),1843-1846,利奈唑胺在肺组织内的药代动力学,背景,材料与方法,前瞻性、非盲研究,志愿者：25例,利奈唑胺 600/12h,给药5剂后4h,给药5剂后8h,给药5剂后12h,给药5剂后24h,给药5剂后48h,血浆和 肺组织 的稳态 浓度,分组,John E.
31、Conte, et al, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2002, 46(5)14751480,材料与方法,支气管镜和BAL,采用标准方法，标本离心后，细胞与上清液分别冷冻保存,血标本,给药前后及完成支气管镜、BAL后,标本处理,分离血清，冷冻保存,利奈唑胺分析a.血浆中，利奈唑胺浓度分析：HPLC；b. BAL和细胞悬液中利奈唑胺浓度分析：HPLC联合三重四极杆质谱；c. ELF体积定量与ELF和AC中利奈唑胺浓度测定：采用尿素法定量后换算浓度,统计,John E. Conte, et al, ANTIMICROBIAL AGENTS AND
32、 CHEMOTHERAPY, 2002, 46(5)14751480,表2. 血浆、ELF和AC中利奈唑胺的浓度,John E. Conte, et al, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2002, 46(5)14751480,血浆浓度(ug/ml),48小时,24小时,12小时,8小时,4小时,给药后 采样时间,3.50,4.22,2.38,3.53,4.15,ELF/血浆浓度,0.70.8,7.66.0,24.313.3,31.433.0,64.333.1,ELF(ug/ml),0.20.2,1.80.6,10.22.3,8.93.2,15.
33、54.9,平均浓度,*口服斯沃600mg，每12小时一次， 共给药5剂,Linezolid concentrations in plasma， pulmonary epithelial lining fluid (ELF), and pulmonary alveolar cells (AC) a,a Data are means SD; ranges are given in parentheses. b There were no significant differences among the plasma linezolid concentrations at 12 h after t
34、he fourth dose (P 0.05). c ELF drug concentrations at 4, 8, 12, and 24 h were significantly greater than AC drug concentrations at the same times (P 0.05). d Concentrations in ELF at 4 h were significantly greater than those at 8, 12, 24, and 48 h (P 0.05). e n4. f BLQ, below level of quantitation.,
35、图1.行气管镜时，血浆内的利奈唑胺浓度,金葡菌的MIC90,肠球菌属的MIC90,肺炎链球菌的MIC90,实测浓度,计算浓度,给药间隔,利奈唑胺浓度,图2. ELF内利奈唑胺浓度,金葡菌的MIC90,肠球菌属的MIC90,肺炎链球菌的MIC90,实测浓度,计算浓度,利奈唑胺浓度,给药间隔,斯沃在肺上皮细胞衬液中具有较高浓度,Conte JE Jr et al. Antimicrob Agents Chemother.2002 ;46 :1475-1480.,斯沃在肺上皮衬液浓度远高于金黄色葡萄球菌MIC90,一项由25名健康志愿者参加的前瞻性、开放性研究，给予斯沃600mg，po，q12h,
36、给药5次后测定受试者血浆及肺上皮衬液中药物浓度,肺上皮细胞衬液中平均浓度对比（ug/mL）,给药后时间(小时),肺上皮衬液浓度,血浆浓度,金葡菌MIC90,4ug/mL,斯沃,万古霉素,利奈唑胺组织浓度与血浆浓度的比例,1. Graziani 1988; 2. Matzke 1986; 3. Albanese 2000; 4. Georges 1997; 5. Lamer 1993; 6. Daschner 1987; 7. Blevins 1984; 8. Wilson 2000; 9. Stahl 1987; 10. Wise 1986; 11. Frank 1997; 12. Lover
37、ing 2002; 13. SmPC; 14. Gee 2001; 15. Gendjar 2001.,讨论,ELF中利奈唑胺的浓度与血浆浓度之比分别,AC中利奈唑胺的浓度与血浆浓度之比分别,4h,8h,16h,24h,48h,4.21.4,0.150.05,3.12.2,2.41.2,3.92.3,2.31.6,0.150.14,0.130.10,0.110.07,未检出,药物浓度MIC90的时间为100%； ELF和AC药物浓度与血浆之比的差异均无统计学意义,John E. Conte, et al, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2002, 46(5)14751480,谢谢！,