抗真菌藥物PKPD

1、抗真菌藥物抗真菌藥物PK/PD研究進(jìn)展研究進(jìn)展劉學(xué)東劉學(xué)東青島市市立醫(yī)院呼吸科青島市市立醫(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; 24:206-216Candidemia Mortality rateEdmond et al. CID 1999; 29:239-44.抗

2、真菌藥的研發(fā)、上市抗真菌藥的研發(fā)、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兩性霉素兩性霉素 B 58灰黃霉素灰黃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卡泊芬凈卡泊芬凈0101伏立康唑伏立康唑0202阿尼芬凈阿尼芬凈 06米卡芬凈米卡芬凈02J 05US泊沙康唑泊沙康唑 07真菌的分類特點(diǎn)真菌的分類特點(diǎn)酵母菌酵母菌-培養(yǎng)時(shí)為菌絲，致病時(shí)為孢子也

3、有菌絲培養(yǎng)時(shí)為菌絲，致病時(shí)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，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菌落：的的 酵母菌酵母菌單細(xì)胞真菌單細(xì)胞真菌，呈圓形或卵圓形：呈圓形或卵圓形：的的 霉霉 菌菌-菌絲菌絲 雙相真菌雙相真菌：一定條件下呈酵母菌相，一定條件下呈一定條件下呈酵母菌相，一定條件下呈霉菌相（長(zhǎng)毛）：霉菌相（長(zhǎng)毛）：藥物在人體中藥物在人體中的吸收、分布、的吸收、分布、代謝和清除的代謝和清除的過(guò)程，是藥物過(guò)程，是藥物作用與抗菌效作用與抗菌效果以及體外藥果以及體外藥代動(dòng)力學(xué)參數(shù)代動(dòng)力學(xué)參數(shù)與殺菌效果的與殺菌效果的關(guān)系關(guān)系藥物在體內(nèi)藥物在體內(nèi)發(fā)揮的作用，發(fā)揮

4、的作用，涉及藥物的涉及藥物的濃度與藥理濃度與藥理作用、毒副作用、毒副反應(yīng)之間的反應(yīng)之間的關(guān)系關(guān)系血漿濃度血漿濃度-時(shí)時(shí)間曲線中的間曲線中的曲線下面積曲線下面積血漿中藥物血漿中藥物的峰濃度的峰濃度藥物的半藥物的半衰期衰期MIC藥效動(dòng)力學(xué)藥效動(dòng)力學(xué)(AUC)Cmax藥代動(dòng)力學(xué)藥代動(dòng)力學(xué)和藥效動(dòng)力學(xué)和藥效動(dòng)力學(xué)(PK&PD)及其參數(shù)及其參數(shù)TMIC藥物血漿濃度藥物血漿濃度高于高于MIC的時(shí)的時(shí)間比例間比例殺菌效應(yīng)作用殺菌效應(yīng)作用的時(shí)間的時(shí)間病原菌的病原菌的清除率清除率耐藥菌的發(fā)耐藥菌的發(fā)生率生率藥代動(dòng)力學(xué)藥代動(dòng)力學(xué)藥代動(dòng)力學(xué)和藥效動(dòng)力學(xué)(PK PD)最佳治療方案最佳治療方案最佳療效最佳療效減

5、少耐藥減少耐藥最低毒性最低毒性PK微生物學(xué)微生物學(xué)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多烯類多烯類 - 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氟康唑作用靶點(diǎn)：真菌細(xì)胞膜上的氟康唑作用靶點(diǎn)：真菌細(xì)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. 氟康唑通過(guò)特異性抑制真菌細(xì)胞膜上的14-固醇去甲基酶的活性來(lái)減少 真菌細(xì)胞膜麥角固醇的合成403020100濃度 (mg/L)Cmax/MICTMIC0.5 8 16 24兩性霉素

8、B棘白菌素類AUC/MIC唑類PAEMIC小時(shí)注：PAE，抗生素后效應(yīng)； T1/2 ，半衰期；AUC，藥時(shí)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(dòng)力學(xué)比較PK參數(shù)參數(shù)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凈卡泊芬凈口服生物利用度口服生物利用度 %5595509695951099.85897腦脊液穿透率腦脊液穿透率 %0-46010605眼組織穿透率眼組織穿透率 %0-38cd0-38cd28-75cd10c38c0c尿液濃度尿液濃度 %e3-204.5901-102MIC主要參數(shù)AUC/MIC時(shí)間依賴性唑類抗真菌藥Andes D. Ant

9、imicrob Agents Chemother.2003;47:1179-1186.介于濃度依賴和時(shí)間依賴之間氟康唑按照氟康唑按照PK/PD分類介于濃度依賴分類介于濃度依賴和時(shí)間依賴之間和時(shí)間依賴之間 Fluconazole exhibits time-dependent, concentration-independent fungistatic activity against Candida. Experimental studies in animals and clinical studies with fluconazole in the treatment of mucosal

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念珠菌藥敏試驗(yàn)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.念珠菌藥敏試驗(yàn)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).念珠菌藥敏試驗(yàn)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). 念珠菌藥敏結(jié)果Rex JH, et al. Clin Infect Dis. 2002 Oct 15;35(8):982-9.抑菌環(huán)直徑(mm)MIC(ug/ml)敏感(S)198劑量依賴敏感(SDD)15-1816-32耐藥(R)1464氟康唑氟康唑AUC或劑量或劑量/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生存者也較死亡者高775739 vs. 589715，p=0.09氟康唑氟康唑AUC或劑量或劑量/MIC越高，患越高，患者死亡率越低者死亡率越

16、低 62例生存者中氟康唑劑量/MIC顯著高于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或劑量或劑量/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?qū)?7例患者分離念珠菌的體外敏感性研究，并評(píng)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(diǎn)為55.2，p=0.008 氟康唑劑量24h/MIC越高，患者死亡率越低，折點(diǎn)為12.0，p=0.007氟康唑劑量/MIC50時(shí)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