抗真菌藥物pkpd

1、抗真菌藥物PK/PD研究進(jìn)展,劉學(xué)東青島市市立醫(yī)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; 24:20

2、6-216,Candidemia – Mortality rate,Edmond et al. CID 1999; 29:239-44.,Hospital acquired pathogens and their associated mortality,抗真菌藥的研發(fā)、上市,,,,,,,,,,,,,,,,,,,,,,,,,0,2,4,6,8,10,12,14,16,18,1950,1955,1960,1965,1970,1975,19

3、80,1985,1990,1995,2000,2005,Year,真菌的分類特點,類酵母菌--培養(yǎng)時為菌絲，致病時為孢子也有菌絲，在組織內(nèi)菌絲為主，培養(yǎng)基上產(chǎn)生類似葡萄球菌的菌落：念珠菌屬的白念、熱帶、克柔等。酵母菌—單細(xì)胞真菌，呈圓形或卵圓形：隱球菌屬的新型隱球菌。霉 菌--產(chǎn)生分枝絲狀菌絲：包括曲菌、毛霉菌。雙相真菌：一定條件下呈酵母菌相，一定條件下呈霉菌相（長毛）：組織胞漿菌、球孢子菌、類球孢子菌、皮炎芽生菌等。,,藥物在

4、人體中的吸收、分布、代謝和清除的過程，是藥物作用與抗菌效果以及體外藥代動力學(xué)參數(shù)與殺菌效果的關(guān)系,,藥物在體內(nèi)發(fā)揮的作用，涉及藥物的濃度與藥理作用、毒副反應(yīng)之間的關(guān)系,,,,血漿濃度-時間曲線中的曲線下面積,血漿中藥物的峰濃度,藥物的半衰期,,MIC,藥效動力學(xué),(AUC),Cmax,,藥代動力學(xué)和藥效動力學(xué)(PK&PD)及其參數(shù),T>MIC,藥物血漿濃度高于MIC的時間比例,,,,殺菌效應(yīng)作用的時間,病原菌的清除率,耐

5、藥菌的發(fā)生率,,藥代動力學(xué),藥代動力學(xué)和藥效動力學(xué)(PK ? PD),,最佳治療方案,最佳療效,減少耐藥,最低毒性,,,,,,PK,微生物學(xué),PD,What are the targets for antifungal therapy?,Cell membraneFungi use principally ergosterol instead of cholesterol,,Cell WallUnlike mammalian ce

6、lls, 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 C

7、o. 2001,,Cell Membrane Active Antifungals,Cell membrane ? Polyene antibiotics多烯類 - Amphotericin B, lipid formulations - Nystatin (topical) ? Azole antifungals - Ketoconazole - Itraconazole

8、 - Fluconazole - Voriconazole - Miconazole, clotrimazole (and other topicals),,Effect of azoles on C. albicans,Before exposure,After exposure,氟康唑作用靶點：真菌細(xì)胞膜上的14-α-固醇去甲基酶,Dodds-Ashley ES, et al. Clin Infect D

9、is. 2006;43:S28-39.,氟康唑特異性抑制,氟康唑通過特異性抑制真菌細(xì)胞膜上的14-α-固醇去甲基酶的活性來減少 真菌細(xì)胞膜麥角固醇的合成,注：PAE，抗生素后效應(yīng)； T1/2 ，半衰期；AUC，藥時曲線下面積；MIC，最低抑菌濃度；Cmax，峰濃度,各類抗真菌藥物藥代動力學(xué)比較,AmB，兩性霉素B；LAB，脂質(zhì)體兩性霉素B；AUC，濃度曲線下面積；Cmax，藥物峰濃度；ES，空腹；NA，無可用數(shù)據(jù)；ND，無數(shù)據(jù)；N

10、E，無影響；Unk，未知；a，口服液；b，100 mg/d；c，人體；d，動物；e，活性藥物或代謝物百分比。,Dodds-Ashley ES, et al. Clin Infect Dis. 2006;43(suppl 1):S28-39.,不同抗真菌藥物在不同的部位組織濃度不同,1.汪復(fù) 《實用抗感染治療學(xué)》第1版 2. 8年制《藥理學(xué)》教材.第1版,對抗真菌藥物PK/PD的影響因素,抗真菌藥物的腎清除率增加：燒傷高的

11、血液動力學(xué)使用了血液動力學(xué)活性的藥物藥物濫用,Marta Ulldemolins et al. CHEST 2011; 139: 1210 – 1220Tulien Textoris,et al.Eui J Anaesthesiol 2011;28:318-324,器官功能衰竭對抗菌藥物PK參數(shù)的影響,多器官功能衰竭對抗菌藥物PK的影響,胃腸道功能衰竭,組織灌注不足,肝功能衰竭,腎功能衰竭,藥物吸收減少,藥物組織濃度下降,減少高

12、蛋白結(jié)合藥物的結(jié)合率,減少親脂性藥物的新陳代謝,減少親水性藥物的清除率,給藥劑量不足，需增加給藥劑量,藥物蓄積，需減少給藥劑量,Ulldemolins M et al. Chest.2011;139;1210-1220,依據(jù)PK/PD的抗真菌藥物分類,Andes D. Antimicrob Agents Chemother.2003;47:1179-1186.,介于濃度依賴和時間依賴之間,氟康唑按照PK/PD分類介于濃度依賴和時間依賴之

13、間,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 candi

14、diasis suggest that achieving a serum free-drug AUC:MIC ratio of greater than 25 is the parameter most closely linked to successful treatment,念珠菌藥敏試驗,FIG. 1. (A) A 25-mg fluconazole disk on a lawn of 104 CFU of C. albica

15、ns 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 (i

16、nterior edges of bars), as determined by a marked reduction in colony sizes.,念珠菌藥敏試驗,FIG. 1. Fluconazole (FL) Etest reading patterns for C. albicans. (A) Growth of microcolonies inside the entire inhibition zone (ellipse

17、); 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 re

18、ading 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

19、micrograms per milliliter).,念珠菌藥敏試驗,Etest results of a Candida albicans clinical isolate tested against amphotericin B, fluconazole, itraconazole, posaconazole, and voriconazole. Note the lawn of microcolonies inside the

20、 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

21、藥敏結(jié)果,Rex JH, et al. Clin Infect Dis. 2002 Oct 15;35(8):982-9.,氟康唑AUC或劑量/MIC越高，患者死亡率越低,62例生存者中氟康唑AUC24h/MIC生存者也較死亡者高775±739 vs. 589±715，p=0.09,氟康唑AUC或劑量/MIC越高，患者死亡率越低,62例生存者中氟康唑劑量/MIC顯著高于15例死亡患者(13.3±10.5 v

22、s.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或劑量/MIC越高，患者死亡率越低,2002-2005年，氟康唑?qū)?7例患者分離念珠菌的體外

23、敏感性研究，并評估AUC/MIC及劑量/MIC與患者死亡率的關(guān)系。氟康唑AUC24h/MIC越高，患者死亡率越低，折點為55.2，p=0.008氟康唑劑量24h/MIC越高，患者死亡率越低，折點為12.0，p=0.007,氟康唑劑量/MIC≥50時臨床有效率可達(dá)86%以上,氟康唑不同給藥劑量/MIC比值治療粘膜/侵襲性念珠菌病總體臨床治愈率,Pfaller MA. Clinical Microbiology Reviews. 200

24、6;19(2):435-47.,三項侵入性念珠菌病的研究及一項粘膜感染的研究的匯總結(jié)果,氟康唑日劑量/MIC對指導(dǎo)臨床合理用藥具有重要意義,Rex JH, et al. Clin Infect Dis. 2002 Oct 15;35(8):982-9.,針對白色念珠菌，藥敏提示MIC為8mg/L時：敏感的念珠菌引起的菌血癥需氟康唑50X8=400mg/天如針對光滑念珠菌，藥敏提示MIC為16mg/L時：劑量依賴型敏感的念珠菌引起的菌血

25、癥需氟康唑50X16=800mg/天,,念珠菌耐藥機(jī)制,防突變濃度 (mutant prevention concentration, MPC)突變選擇窗 (muant selection window, MSW)：以MPC為上界、MIC為下界的濃度范圍,限制耐藥發(fā)生的策略,Current Concepts in Antifungal Pharmacology,Adjusted CLSI CBPs for FLU and C. alb

26、icans, 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 spec

27、ies and provide consistency with EUCAST CBPs.CLSI: Clinical and Laboratory Standards InstituteEUCAST: European Committee on Antimicrobial Susceptibility TestingCBPs: clinical breakpoints,IDSA 2009年念珠菌指南中氟康唑給藥劑量,治療性應(yīng)用

28、：800mg首劑，400mg qd: 念珠菌血癥、疑似念珠菌病的經(jīng)驗治療、慢性播散性念珠菌病、骨髓炎、化膿性關(guān)節(jié)炎400~800 mg qd: 中樞神經(jīng)系統(tǒng)感染、心包炎或心肌炎、 植入起搏器等感染、化膿性血栓性靜脈炎、眼內(nèi)炎200～400 mg qd: 食道念珠菌病、膀胱炎、腎盂腎炎100～200 mg qd：口咽部念珠菌病150 mg SD：外陰陰道念珠菌病,Pappas PG, Clin Infect Dis. 2009

29、; 48: 503,腎功能不全的病人氟康唑使用方法★單一劑量的治療無調(diào)整之需要★多劑量治療者，在第一天及第二天應(yīng)給予正常劑量， 隨後視CCr來調(diào)整每日劑量或給藥間隔，調(diào)整方式為：★三小時的血液透析可降低血漿濃度50%，定期進(jìn)行血 液透析的病人，每次透析後給與一次建議劑量,總結(jié),根據(jù)PK/PD原理給藥可增加療效根據(jù)PK/PD原理給藥可減少耐藥根據(jù)PK/PD原理給藥可增加安全性,藥代動力學(xué)和藥效動力學(xué)