抗真菌药临床应用进展.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,真菌可感染人体各部位,深部真菌感染呈持续增多趋势,真菌病,每年每百万人发病率,1970年,1976年,1980-1982年,1992-1993年,组织胞浆菌病,19.7,23.0,13.9,7.1,球孢子菌病,10.3,17.9,11.2,15.3,曲霉病,1.9,4.8,8.4,12.4,隐球菌病,1.3,2.3,4.0,65.5,念珠菌病,1.8,1.8,2.6,72.8,孢子丝菌病,0.9,0.2,2.4,70%80%,念珠菌血流感染的菌种分布 US(1998-2000),Hajjeh et al.(2004)J.Clin.Microbiol.42(4):1519-1527,.,Other,1.12%,lusitaneae,1.02%,krusei,2.04%,tropicalis,12.23%,parapsilosis,13.25%,glabrata,24.46%,albicans,45.87%,定义侵袭性真菌感染,EORTC-IFICG&NIAID-MSG,确诊,Proven invasive fungal infections,Tissue,Blood culture,histology,culture,Mycology,拟诊,Probable invasive fungal infetions,Host factor,Clinical features,Mycology,+,+,Invasive Fungal Infections Cooperative Group,疑似,Possible invasive fungal infections,Host factor,Clinical features,Mycology,+,OR,Invasive Fungal Infections Cooperative Group,GOAL OF ADAPTING DEFINITIONS,proven,probable,possible,present,proven,probable,possible,future,Treatment,Disease Likelihood,0,36,37,38,39,40,41,Temperature(,C),Culture,+,Tissue,+,-7,0,7,14,21,28,35,42,49,56,63,-14,0.1,1,10,Days of Neutropenia,Granulocytes,Empirical,Possible,Prophylaxis,Remote,Specific,Proven,Pre-emptive,Probable Disease,Therapeutic Strategies,Courtesy of Ben DePauw,MD,EORTC.,治疗策略-1,预防性治疗,对尚无真菌感染的高危病人给予抗真菌药，可减少侵袭性真菌感染并减少抗真菌药的全身应用，降低与真菌感染相关的病死率和某些粒缺和器官移植患者的总病死率,药物：氟康唑、伊曲康唑、两性霉素B及含脂制剂、米卡芬净、泊沙康唑,适用于,急性白血病诱导期采用细胞毒药物者,同种异体造血干细胞移植受者及自身骨髓移植患者,采用增强免疫抑制剂者,AIDS患者,肝移植受者术后早期,治疗策略-2,经验治疗,临床研究已证实，对粒缺发热患者经广谱抗菌药治疗无效者采用AmB可减少真菌感染的发生率和病死率,在经验性治疗中药物的选择不仅要考虑药物的确切疗效，更应考虑药物的安全性,经验治疗可选用两性霉素B、两性霉素B脂质体（AmBisome）、氟康唑、伊曲康唑、伏立康唑、卡泊芬净,治疗策略-1,先发治疗（pre-emptive therapy）,对高危病人有深部真菌感染迹象时，在出现临床症状前采取先发制抗真菌治疗，可能有益,问题是尚缺少合适的替代指标提示真菌感染迹象如GM试验、G试验、PCR检测等，在病程中需多次检测实验指标或CT检查等,尚须更多临床研究资料以确定先发制抗真菌治疗的适应证及有效性,治疗策略-4,目标治疗,对已获病原真菌的侵袭性真菌病患者，采用针对性抗真菌治疗,Medical Mycology:The Last 50 Years,Nystatin,Amphotericin B(1958),Griseofulvin,5-FC,Miconazole,Ketoconazole,Fluconazole,Itraconazole,L-AmB,ABCD,ABLC,Terbinafine,Voricon,Posacon,Sordarins,Caspofungin,Micafun,Ravucon,Anidulafungin,#of drugs,抗真菌药物,多烯类,两性霉素,B,及含脂制剂,制霉菌素脂质体（,Liposomal,nystatin,）,吡咯类（,azole,）,(,三唑类,triazole,）,氟康唑,伊曲康唑,伏立康唑,泊沙康唑,(,Posaconazole,),雷夫康唑,(,Ravuconazole,),棘白菌素类（,Echinocandins,）,卡泊芬净,米卡芬净,(,Micafungin,),阿尼芬净,(,Anidulafungin,),氟胞嘧啶,Amphotericin B,Polyene group affects fungal cytoplasmic membrane,Broad spectrum,Covers almost all candida,aspergillus,Cryptococcosis,Mucormycosis,Endemic mycoses,IV,Amphotericin B,Not absorbed from gut,skin or mm,IV-highly protein bound 91%95,Good penetration into serous cavities,Poor CSF penetration,Low blood level,Crosses placenta,Half life 24 hours,Slow renal excretion 2%5/d,40%/w,Amphotericin B,IV infusion chills,fever,vomiting,Flushing,muscle,joint pains,Avoid other nephrotoxic drugs,Steroids worsen hypokalemia,Potentiates activity of Flucytosine,Amphotericin B,FDA Approved Indications,Empiric anti-fungal therapy,Candida spp.,Aspergillus spp.,Cryptococcosis,Mucormycosis,Endemic mycoses,Blastomycosis,Histoplasmosis,Coccidioidomycosis,Paracoccidioidomycosis,Penicilliosis,Sporotrichosis,Leishmaniasis,1.Ostrosky-Zeichner et al.,Clin Infect Dis,.2003;37:415-425.,2.Bates et al.,Clin Infect Dis,.2001;32:686-693.,Conventional AmB Is No Longer the“Gold Standard”for Treatment,Approved in 1958 with no randomized studies,Became treatment of choice due to broad-spectrum efficacy and low rate of resistance,1,Nephrotoxicity was initially underestimated,Currently,AmB treatment results in 30%incidence of acute renal failure,resulting in,2,:,Increased mortality,Increased hospital stay,Lipid Amphotericin B Formulations,Ribbon-like particles,Carrier lipids:DMPC,DMPG,Particle size,(m),:1.6-11,Abelcet,ABLC,Amphotec,ABCD,Ambisome,L-AMB,Disk-like particles,Carrier lipids:Cholesteryl sulfate,Particle size,(m),:0.12-0.14,Unilaminar liposome,Carrier lipids:HSPC,DSPG,cholesterol,Particle size,(m),:0.08,DMPC-Dimyristoyl phospitidylcholine,DMPG-Dimyristoyl phospitidylcglycerol,HSPC-Hydrogenated soy phosphatidylcholine,DSPG-Distearoyl phosphitidylcholine,Key Biopharmaceutical Differences of the Amphotericin B Formulations,AmB-d,Fungizone,L-AmB,AmBisome,ABLC,Abelcet,ABCD,Amphotec,Mol%AmB,34%,10%,35%,50%,Lipid Config.,Micelles,SUVs,Ribbon-like,Disk like,Diameter(m),AMB-deoxy,Nephrotoxicity,L-AMB,ABLC,ABCD AMB-deoxy,Infusion related toxicity,L-AMB ABLC ABCD,ABLC ABCD AMB-deoxy,Lipid AMB Formulations,Indications,not indicate as initial therapy for most patients with the various candida syndromes,cryptococcosis and the endemic mycoses,indications,Preexisting renal dysfunction(serum Cr 2.5-3 mg/dL),Refractory to or intolerate of amphotericin B or azole therapy,L-AmB,Febrile neutropenic patients with suspected fungal infections,Flucytosine,Pyrimidine,IV or oral,Narrow spectrum mainly candida and cryptococcus,Not used as sole drug used along with ampho B,Oral absorption good 80%,low protein binding,Indications,serious infections caused by susceptible strains of candida and/or cryptococcus,Candida,septicemia,endocaarditis,urinary tract infections and pulmanary infections,Cryptococcus,meningitis,pulmanary infections,septicemia,urinary tract infections,Flucytosine,The Azoles,Triazoles,Fluconazole,Itraconazole,Voriconazole,Posaconazole,Ravuconazole,Fluconazole,Azole,IV,oral suspension,capsule,Spectrum,Useful against cryptococcus and,C.albicans,Ineffective against some Candida species such as,C.krusei,and,C.glabrata,Ineffective against,Aspergillus,species,Fluconazole,Indications,Cryptococcal meningitis,Systemic infections caused by,Candida sp.,Vaginal candidiasis-single 150 mg dose.,Oralpharyngeal/esophageal candidiasis,Prophylaxis-BMT and chemotherapy patients to decrease the incidence of candidiasis.,Itraconazole,Azole,IV,oral solution,capsules,Very broad spectrum covers aspergillus,candida,cryptococcus,blastomyces,histoplasma and others,Itraconazole,Pharmacokinetics not ideal,Oral absorption not good33 and 55%,Liquid tastes bad,Very highly protein bound,Needs repeated dosing before optimal concentrations are achieved,Poor CSF concentrations,reasonable tissue concentrations,Itraconazole,Indications for capsules,Blastomycoses-pulmonary and extrapulmonary,Histoplasmosis-pulmonary and disseminated,Aspergillosis-pulmonary and extrapulmonary,Onychomycosis due to dermatophytes of the toenails and fingernails.,Itraconazole,Indications for oral solution,Febrile neutropenic patients with suspected fungal infections,Oralpharyngeal/esophageal candidiasis,Indications for intravenous,Febrile neutropenic patients with suspected fungal infections,Blastomycoses-pulmonary and extrapulmonary,Histoplasmosis-pulmonary and disseminated,Aspergillosis-pulmonary and extrapulmonary,Triazole Antifungals:Voriconazole,Posaconazole,Ravuconazole,Spectrum of Activity,Candida,spp.,Aspergillus,spp.,Blastomyces spp.,Histoplasma,spp.,Cryptococcus,spp.,Cocciodiodes spp.,Fusarium spp.,Scedosporium,VoriconazoleSummary of Pharmacokinetics,Rapid and consistent absorption with high oral bioavailability(96%),Large volume of distribution(4.6 L/kg),Non-linear elimination,Hepatic metabolism by CYP2C19,2C9 and 3A4 isoenzymes,Adverse Events,Hepatic,Overall rate of 13%.2-fold more than Flu,Visual,Noted by 30%.A sense of altered light perception,blurring,or photophobia,EXHAUSTIVELY studied.No apparent consequences.,Miscellaneous,Photosensitivity(1%)?Avoid strong sunlight.,Sabo Ann Pharmacother 34:1032,00;Voriconazole package insert,May 2002;Voriconazole FDA Advisory Cmte,01,伏立康唑适应症,侵袭性曲霉病,念珠菌病,非粒缺患者念珠菌血症,念珠菌所致播散性皮肤感染、腹部、肾脏、膀胱壁及伤口感染,食道念珠菌病,不能耐受其他药物或其他药物无效的赛多孢菌和镰孢菌，包括腐皮镰孢菌所致的严重真菌感染,泊沙康唑(Posaconazole),第二代三唑类抗真菌药,广谱抗真菌药，对念珠菌属、新型隐球菌、曲霉、根霉、皮炎芽生菌、球孢子菌属、组织胞浆菌、皮肤真菌、暗色孢科菌均有良好作用,对光滑念珠菌，克柔念珠菌及对,Flu,Itr,耐药的念珠菌作用差,对念珠菌属为抑菌剂，但对新型隐球菌和曲霉具杀菌作用，作用优于棘白菌素类,组织分布广，终末期半衰期为,25,31h,不良反应,胃肠道反应、皮疹、视力障碍、肝功能异常、低血钾、白细胞、血小板减少、,QT,延长等,2006.9,美国,FDA,批准上市，适应症,预防侵袭性曲霉病和念珠菌病感染,预防对象为,13,岁及以上高危的严重免疫缺陷患者，如造血干细胞移植受者发生,GVHD,或血液系统恶性肿瘤化疗后长期粒细胞缺乏,成人剂量,200 mg(5,mL,),tid,口咽部念珠菌病，包括伊曲康唑和,/,或氟康唑治疗无效者,首日,100 mg(2.5,mL,)bid,，继以,100 mg(2.5,mL,)qd13,日,用于伊曲康唑和,/,或氟康唑治疗无效者剂量为,400 mg(10,mL,)bid,泊沙康唑(Posaconazole),Kartsonis NA.Presented at the 12,th,European Congress of Clinical Microbiology and Infectious Diseases.April 24-27,2002.Milan,Italy.,Echinocandins,:New Class of Drug,Nucleoside Analogs,-(1,3)-D-glucan,Ergosterol,Polyenes,Azoles,Phospholipid bilayerof the fungal cell,membrane,Fungal cell wall,-(1,6)-glucan,-(1,3)-D-glucan synthase,Glucan Synthesis,Inhibitor,nucleus,Breakthrough Mechanism of Action:Targets the Pathogen,Not the Patient,Echinocandins:Caspofungin and Micafungin,Spectrum of Activity:,Candida spp.,Aspergillus spp.,Histoplasma spp.,Blastomyces spp.,Pneumocystis spp.,Echinocandins:Caspofungin and Micafungin,Pros:,fungicidal(Candida spp.),minimal drug-drug interactions,minimal adverse effects,Cons:,No activity against,Cryptococcus spp.,Fusarium,spp,.,or,Scedosporium,spp,.,only IV formulations,卡泊芬净的适应症,粒缺发热经验治疗,念珠菌血症和下列念珠菌感染：腹腔脓肿、腹膜炎和胸腔感染,食道念珠菌病,难治性或不能耐受其他治疗（即AmB、AmB LF和/或伊曲康唑）的侵袭性曲霉病,米卡芬净 Micafungin,棘白菌素类，抗菌谱与卡泊芬净相仿,蛋白结合率高（,99,），,t,1/2,10-15 h,主要经肝脏代谢，少部分由肾脏排出,2002,年日本上市，,2005,年美国上市,FDA,批准适应证及给药方案,食道念珠菌病的治疗，,150mg/d,静滴,造血干细胞移植患者预防念珠菌感染，,50mg/d,静滴,主要不良反应：恶心、呕吐、血胆红素升高及肝功能异常,阿尼芬净 Anidulafungin,抗菌活性,对念珠菌属作用强，对近平滑和季列蒙念珠菌的作用稍差,对曲霉及卡氏肺孢菌有作用,对新型隐球菌、皮炎芽生菌，申克孢子丝菌、毛孢子菌、镰刀菌属等作用差,t,1/2,25.6 h,2006.2,美国批准上市，适应证及用法,念珠菌血症、其他念珠菌感染（腹腔脓肿、腹膜炎）：首剂,200mg,，继,100mg qd,静滴,食管念珠菌病：首剂,100mg,，继以,50mg qd,静滴,不良反应：静脉炎、头痛、恶心、呕吐,Clinical Infectious Diseases 2006;43:S2839,Clinical Infectious Diseases 2006;43:S2839,Clinical Infectious Diseases 2006;43:S2839,Is the AMB-deoxycholate Era Over?,Imidazoles Fluconazole Lipid-AMB Echinocandins/,Itraconazole New Triazoles,AMB-D,AMB-D,AMB-D,AMB-D,