抗真菌药物PKPD

抗真菌药物PK/PD研究进展,刘学东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; 24:206-216,Candidemia Mortality rate,Edmond et al. CID 1999; 29:239-44.,Hospital acquired pathogens and their associated mortality,抗真菌药的研发、上市,0,2,4,6,8,10,12,14,16,18,1950,1955,1960,1965,1970,1975,1980,1985,1990,1995,2000,2005,Year,真菌的分类特点,类酵母菌-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落：念珠菌属的白念、热带、克柔等。酵母菌单细胞真菌，呈圆形或卵圆形：隐球菌属的新型隐球菌。霉 菌-产生分枝丝状菌丝：包括曲菌、毛霉菌。双相真菌：一定条件下呈酵母菌相，一定条件下呈霉菌相（长毛）：组织胞浆菌、球孢子菌、类球孢子菌、皮炎芽生菌等。,药物在人体中的吸收、分布、代谢和清除的过程，是药物作用与抗菌效果以及体外药代动力学参数与杀菌效果的关系,药物在体内发挥的作用，涉及药物的浓度与药理作用、毒副反应之间的关系,血浆浓度-时间曲线中的曲线下面积,血浆中药物的峰浓度,药物的半衰期,MIC,药效动力学,(AUC),Cmax,药代动力学和药效动力学(PK&PD)及其参数,TMIC,药物血浆浓度高于MIC的时间比例,杀菌效应作用的时间,病原菌的清除率,耐药菌的发生率,药代动力学,药代动力学和药效动力学(PK PD),最佳治疗方案,最佳疗效,减少耐药,最低毒性,PK,微生物学,PD,What 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 fungal Infections, Richard Diamond Ed. 1999Introduction to Medical Mycology. Merck and Co. 2001,Cell Membrane Active Antifungals,Cell membrane Polyene antibiotics多烯类 - Amphotericin B, lipid formulations - Nystatin (topical) Azole antifungals - Ketoconazole - Itraconazole - Fluconazole - Voriconazole - Miconazole, clotrimazole (and other topicals),Effect of azoles on C. albicans,Before exposure,After exposure,氟康唑作用靶点：真菌细胞膜上的14-固醇去甲基酶,Dodds-Ashley ES, et al. Clin Infect Dis. 2006;43:S28-39.,氟康唑特异性抑制,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,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,AmB，两性霉素B；LAB，脂质体两性霉素B；AUC，浓度曲线下面积；Cmax，药物峰浓度；ES，空腹；NA，无可用数据；ND，无数据；NE，无影响；Unk，未知；a，口服液；b，100 mg/d；c，人体；d，动物；e，活性药物或代谢物百分比。,Dodds-Ashley ES, et al. Clin Infect Dis. 2006;43(suppl 1):S28-39.,不同抗真菌药物在不同的部位组织浓度不同,1.汪复 实用抗感染治疗学第1版 2. 8年制药理学教材.第1版,对抗真菌药物PK/PD的影响因素,抗真菌药物的肾清除率增加：烧伤高的血液动力学使用了血液动力学活性的药物药物滥用,Marta Ulldemolins et al. CHEST 2011; 139: 1210 1220Tulien Textoris,et al.Eui J Anaesthesiol 2011;28:318-324,器官功能衰竭对抗菌药物PK参数的影响,多器官功能衰竭对抗菌药物PK的影响,胃肠道功能衰竭,组织灌注不足,肝功能衰竭,肾功能衰竭,药物吸收减少,药物组织浓度下降,减少高蛋白结合药物的结合率,减少亲脂性药物的新陈代谢,减少亲水性药物的清除率,给药剂量不足，需增加给药剂量,药物蓄积，需减少给药剂量,Ulldemolins M et al. Chest.2011;139;1210-1220,依据PK/PD的抗真菌药物分类,Andes D. Antimicrob Agents Chemother.2003;47:1179-1186.,介于浓度依赖和时间依赖之间,氟康唑按照PK/PD分类介于浓度依赖和时间依赖之间,Fluconazole exhibits time-dependent, concentration-independent fungistatic activity against Candida. Experimental studies in animals and clinical studies with fluconazole in the treatment of mucosal 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 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. 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 (FL) 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).,念珠菌药敏试验,Etest results of a Candida albicans 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 should be 0.008 mg/L, 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.,氟康唑AUC或剂量/MIC越高，患者死亡率越低,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AUC或剂量/MIC越高，患者死亡率越低,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 20,氟康唑AUC或剂量/MIC越高，患者死亡率越低,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 Reviews. 2006;19(2):435-47.,三项侵入性念珠菌病的研究及一项粘膜感染的研究的汇总结果,氟康唑日剂量/MIC对指导临床合理用药具有重要意义,Rex JH, et al. Clin Infect Dis. 2002 Oct 15;35(8):982-9.,针对白色念珠菌，药敏提示MIC为8mg/L时：敏感的念珠菌引起的菌血症需氟康唑50X8=400mg/天如针对光滑念珠菌，药敏提示MIC为16mg/L时：剂量依赖型敏感的念珠菌引起的菌血症需氟康唑50X16=800mg/天,念珠菌耐药机制,防突变浓度 (mutant prevention concentration, MPC)突变选择窗 (muant selection window, MSW)：以MPC为上界、MIC为下界的浓度范围,限制耐药发生的策略,Current Concepts in Antifungal Pharmacology,Adjusted CLSI CBPs for FLU and C. albicans, C. parapsilosis, C. tropicalis (S, 2 mcg/ml; SDD, 4 mcg/ml; R, 8 mcg/ml), and C. glabrata (SDD, 32 mcg/ml; R, 64 mcg/ml) should be more sensitive for detecting emerging resistance among common Candida species and provide consistency with EUCAST CBPs.CLSI: