抗真菌药物PKPDppt课件

1、1Solid 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; 24:206-2162Edmond et al. CID 1999; 29:239-44.30246810121416181950 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

2、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 074酵母菌酵母菌-培养时为菌丝，致病时为孢子也有菌丝，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菌在组织内菌丝为主，培养基上产生类似葡萄球菌的菌落落：的的酵母菌酵母菌单细胞真菌，呈圆形或卵圆形：单细胞真菌，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

3、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）：5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

4、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6最佳治疗方案最佳治疗方案最佳疗效最佳疗效减少耐药减少耐药最低毒性最低毒性PK微生物学微生物学PD7Cell membraneFungi use principally ergosterol instead of cholesterol Cell WallUnlike mammalian cells, fungi have a cell wall DNA Synthe

5、sisSome compounds may be selectively activated by fungi, arresting DNA synthesis. Atlas of fungal Infections, Richard Diamond Ed. 1999Introduction to Medical Mycology. Merck and Co. 2001 8Cell membrane Polyene antibiotics多烯类多烯类 - Amphotericin B, lipid formulations - Nystatin (topical) Azole antifung

6、als - Ketoconazole - Itraconazole - Fluconazole - Voriconazole - Miconazole, clotrimazole (and other topicals) 9Effect of azoles on C. albicansBefore exposureAfter exposure10Dodds-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11403020100浓度 (mg/L)Cmax

7、/MICTMIC0.5 8 16 24两性霉素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12PK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A

8、ndes D. Antimicrob Agents Chemother.2003;47:1179-1186.介于浓度依赖和时间依赖之间18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 treatme

9、nt of mucosal 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 treatment19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 flucona

10、zole disk on a 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.20念珠菌药敏试验FIG. 1. Fluconazole (FL) Etest reading patt

11、erns for C. albicans. (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 (F

12、L) Etest reading 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).21念珠菌药敏试验Etest results of a Candida albica

13、ns clinical isolate 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 s

14、hould be 0.008 mg/L, i.e. the first change in growth (black arrow). 22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)146423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=0.0924氟康唑氟康唑AUC或剂量或

15、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 2025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=0.00726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 Re