抗真菌药物PKPD

1、抗真菌药物抗真菌药物PK/PD研究进展研究进展刘学东刘学东青岛市市立医院呼吸科青岛市市立医院呼吸科Invasive fungal infections - Incidence Solid organ transplant: 5-42% Bone marrow transplant: 15-25% ICU: 17%Singh N. Clin Infect Dis 2000;31:545-53Vincent JL. Intens Care Med 1998; 24:206-216Candidemia Mortality rateEdmond et al. CID 1999; 29:239-44.抗

2、真菌药的研发、上市抗真菌药的研发、上市0246810121416181950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005ABCD 96L-AmB 97ABLC 95特比奈芬特比奈芬制霉菌素制霉菌素两性霉素两性霉素 B 58灰黄霉素灰黄霉素氟胞嘧啶氟胞嘧啶 72咪康唑咪康唑酮康唑酮康唑Year氟康唑氟康唑 9090伊曲康唑伊曲康唑 9292卡泊芬净卡泊芬净0101伏立康唑伏立康唑0202阿尼芬净阿尼芬净 06米卡芬净米卡芬净02J 05US泊沙康唑泊沙康唑 07真菌的分类特点真菌的分类特点酵母菌酵母菌-培养时为菌丝，致病时为孢子也

3、有菌丝培养时为菌丝，致病时为孢子也有菌丝，在组织内菌丝为主，培养基上产生类似葡萄球菌的，在组织内菌丝为主，培养基上产生类似葡萄球菌的菌落菌落：的的 酵母菌酵母菌单细胞真菌单细胞真菌，呈圆形或卵圆形：呈圆形或卵圆形：的的 霉霉 菌菌-菌丝菌丝 双相真菌双相真菌：一定条件下呈酵母菌相，一定条件下呈一定条件下呈酵母菌相，一定条件下呈霉菌相（长毛）：霉菌相（长毛）：药物在人体中药物在人体中的吸收、分布、的吸收、分布、代谢和清除的代谢和清除的过程，是药物过程，是药物作用与抗菌效作用与抗菌效果以及体外药果以及体外药代动力学参数代动力学参数与杀菌效果的与杀菌效果的关系关系药物在体内药物在体内发挥的作用，发挥

4、的作用，涉及药物的涉及药物的浓度与药理浓度与药理作用、毒副作用、毒副反应之间的反应之间的关系关系血浆浓度血浆浓度-时时间曲线中的间曲线中的曲线下面积曲线下面积血浆中药物血浆中药物的峰浓度的峰浓度药物的半药物的半衰期衰期MIC药效动力学药效动力学(AUC)Cmax药代动力学药代动力学和药效动力学和药效动力学(PK&PD)及其参数及其参数TMIC药物血浆浓度药物血浆浓度高于高于MIC的时的时间比例间比例杀菌效应作用杀菌效应作用的时间的时间病原菌的病原菌的清除率清除率耐药菌的发耐药菌的发生率生率药代动力学药代动力学药代动力学和药效动力学(PK PD)最佳治疗方案最佳治疗方案最佳疗效最佳疗效减

5、少耐药减少耐药最低毒性最低毒性PK微生物学微生物学PDWhat are the targets for antifungal therapy?Cell membraneFungi use principally ergosterol instead of cholesterol Cell WallUnlike mammalian cells, fungi have a cell wall DNA SynthesisSome compounds may be selectively activated by fungi, arresting DNA synthesis. Atlas of fun

6、gal Infections, Richard Diamond Ed. 1999Introduction to Medical Mycology. Merck and Co. 2001 Cell Membrane Active AntifungalsCell membrane Polyene antibiotics多烯类多烯类 - Amphotericin B, lipid formulations - Nystatin (topical) Azole antifungals - Ketoconazole - Itraconazole - Fluconazole - Voriconazole

7、- Miconazole, clotrimazole (and other topicals) Effect of azoles on C. albicansBefore exposureAfter exposure氟康唑作用靶点：真菌细胞膜上的氟康唑作用靶点：真菌细胞膜上的14-固醇去甲基酶固醇去甲基酶Dodds-Ashley ES, et al. Clin Infect Dis. 2006;43:S28-39. 氟康唑通过特异性抑制真菌细胞膜上的14-固醇去甲基酶的活性来减少 真菌细胞膜麦角固醇的合成403020100浓度 (mg/L)Cmax/MICTMIC0.5 8 16 24两性霉素

8、B棘白菌素类AUC/MIC唑类PAEMIC小时注：PAE，抗生素后效应； T1/2 ，半衰期；AUC，药时曲线下面积；MIC，最低抑菌浓度；Cmax，峰浓度各类抗真菌药物药代动力学比较PK参数参数AmBLAB氟康唑氟康唑伊曲康唑伊曲康唑a伏立康唑伏立康唑卡泊芬净卡泊芬净口服生物利用度口服生物利用度 %5595509695951099.85897脑脊液穿透率脑脊液穿透率 %0-46010605眼组织穿透率眼组织穿透率 %0-38cd0-38cd28-75cd10c38c0c尿液浓度尿液浓度 %e3-204.5901-102MIC主要参数AUC/MIC时间依赖性唑类抗真菌药Andes D. Ant

9、imicrob Agents Chemother.2003;47:1179-1186.介于浓度依赖和时间依赖之间氟康唑按照氟康唑按照PK/PD分类介于浓度依赖分类介于浓度依赖和时间依赖之间和时间依赖之间 Fluconazole exhibits time-dependent, concentration-independent fungistatic activity against Candida. Experimental studies in animals and clinical studies with fluconazole in the treatment of mucosal

10、 and invasive candidiasis suggest that achieving a serum free-drug AUC:MIC ratio of greater than 25 is the parameter most closely linked to successful treatment念珠菌药敏试验FIG. 1. (A) A 25-mg fluconazole disk on a lawn of 104 CFU of C. albicans after 24 h of incubation. (B) A 50-mg fluconazole disk on a

11、lawn of 104 CFU of C. albicans after 48 h of incubation. Inhibitory zone diameters were measured at the transitional point where growth abruptly decreased (interior edges of bars), as determined by a marked reduction in colony sizes.念珠菌药敏试验FIG. 1. Fluconazole (FL) Etest reading patterns for C. albic

12、ans. (A) Growth of microcolonies inside the entire inhibition zone (ellipse); MIC, 0.38 mg/ml. (B) Clear ellipse on Casitone agar; MIC, 0.5 mg/ml. The numbers on the scale correspond to the fluconazole concentrations on the strip (in micrograms per milliliter).FIG. 2. Fluconazole (FL) Etest reading

13、patterns for C. glabrata. A resistant subpopulation appears as macrocolonies within the ellipse on Casitone agar. MIC, .256 mg/ml. The numbers on the scale correspond to fluconazole concentrations on the strip (in micrograms per milliliter).念珠菌药敏试验Etest results of a Candida albicans clinical isolate

14、 tested against amphotericin B, fluconazole, itraconazole, posaconazole, and voriconazole. Note the lawn of microcolonies inside the ellipses of triazole strips; according to the endpoint rule recommended by the manufacturer, the minimum inhibitory concentration for voriconazole should be 0.008 mg/L

15、, i.e. the first change in growth (black arrow). 念珠菌药敏结果Rex JH, et al. Clin Infect Dis. 2002 Oct 15;35(8):982-9.抑菌环直径(mm)MIC(ug/ml)敏感(S)198剂量依赖敏感(SDD)15-1816-32耐药(R)1464氟康唑氟康唑AUC或剂量或剂量/MIC越高，患越高，患者死亡率越低者死亡率越低 62例生存者中氟康唑AUC24h/MIC生存者也较死亡者高775739 vs. 589715，p=0.09氟康唑氟康唑AUC或剂量或剂量/MIC越高，患越高，患者死亡率越低者死亡率越

16、低 62例生存者中氟康唑剂量/MIC显著高于15例死亡患者(13.310.5 vs.7.0 8.0，p=0.03) 30% for dosewn/MIC ratios between 0 and 5, 23% to 25% for ratios between 5 and 15, 10% for ratios between 15 and 20, and 5% for ratios above 20氟康唑氟康唑AUC或剂量或剂量/MIC越高，患越高，患者死亡率越低者死亡率越低 2002-2005年，氟康唑对77例患者分离念珠菌的体外敏感性研究，并评估AUC/MIC及剂量/MIC与患者死亡率的关系。 氟康唑AUC24h/MIC越高，患者死亡率越低，折点为55.2，p=0.008 氟康唑剂量24h/MIC越高，患者死亡率越低，折点为12.0，p=0.007氟康唑剂量/MIC50时临床有效率可达86%以上氟康唑不同给药剂量/MIC比值治疗粘膜/侵袭性念珠菌病总体临床治愈率Pfaller MA. Clinical Microbiology