抗真菌藥臨床應(yīng)用進(jìn)展課件

1、抗真菌藥臨床應(yīng)用進(jìn)展真菌可感染人體各部位深部真菌感染呈持續(xù)增多趨勢(shì)真菌病每年每百萬人發(fā)病率1970年1976年1980-1982年1992-1993年組織胞漿菌病19.723.013.97.1球孢子菌病10.317.911.215.3曲霉病1.94.88.412.4隱球菌病1.32.34.065.5念珠菌病1.81.82.672.8孢子絲菌病0.90.22.470%80%念珠菌血流感染的菌種分布 US (1998-2000)Hajjeh et al. (2004) J. Clin. Microbiol. 42(4):1519-1527.Other1.12%lusitaneae1.02%krus

2、ei2.04%tropicalis12.23%parapsilosis13.25%glabrata24.46%albicans45.87%確診Proven invasive fungal infectionsTissueBlood culturehistologycultureMycology擬診Probable invasive fungal infetionsHost factorClinical featuresMycology+Invasive Fungal Infections Cooperative Group疑似Possible invasive fungal infection

3、sHost factorClinical featuresMycology+ORInvasive Fungal Infections Cooperative GroupTreatmentDisease Likelihood0363738394041Temperature (C)Culture+Tissue+-7071421283542495663-140.1110Days of NeutropeniaGranulocytesEmpiricalPossibleProphylaxisRemoteSpecificProvenPre-emptiveProbable DiseaseTherapeutic

4、 StrategiesCourtesy of Ben DePauw, MD, EORTC.治療策略-1預(yù)防性治療對(duì)尚無真菌感染的高危病人給予抗真菌藥，可減少侵襲性真菌感染并減少抗真菌藥的全身應(yīng)用，降低與真菌感染相關(guān)的病死率和某些粒缺和器官移植患者的總病死率藥物：氟康唑、伊曲康唑、兩性霉素B及含脂制劑、米卡芬凈、泊沙康唑適用于急性白血病誘導(dǎo)期采用細(xì)胞毒藥物者同種異體造血干細(xì)胞移植受者及自身骨髓移植患者采用增強(qiáng)免疫抑制劑者AIDS患者肝移植受者術(shù)后早期 治療策略-1先發(fā)治療（pre-emptive therapy）對(duì)高危病人有深部真菌感染跡象時(shí)，在出現(xiàn)臨床癥狀前采取先發(fā)制抗真菌治療，可能有益問題是

5、尚缺少合適的替代指標(biāo)提示真菌感染跡象如GM試驗(yàn)、G試驗(yàn)、PCR檢測(cè)等，在病程中需多次檢測(cè)實(shí)驗(yàn)指標(biāo)或CT檢查等尚須更多臨床研究資料以確定先發(fā)制抗真菌治療的適應(yīng)證及有效性治療策略-4目標(biāo)治療對(duì)已獲病原真菌的侵襲性真菌病患者，采用針對(duì)性抗真菌治療 Medical Mycology:The Last 50 YearsNystatinAmphotericin B (1958)Griseofulvin5-FCMiconazoleKetoconazoleFluconazoleItraconazole L-AmB ABCD ABLCTerbinafineVoriconPosaconSordarinsCaspo

6、funginMicafunRavuconAnidulafungin# of drugs抗真菌藥物多烯類兩性霉素B及含脂制劑制霉菌素脂質(zhì)體（Liposomal nystatin）吡咯類（azole）(三唑類, triazole）氟康唑伊曲康唑伏立康唑泊沙康唑(Posaconazole)雷夫康唑(Ravuconazole) 棘白菌素類（Echinocandins）卡泊芬凈米卡芬凈(Micafungin,)阿尼芬凈(Anidulafungin)氟胞嘧啶Amphotericin BPolyene group affects fungal cytoplasmic membraneBroad spectr

7、umCovers almost all candida,aspergillus, Cryptococcosis, Mucormycosis, Endemic mycosesIVAmphotericin BNot absorbed from gut, skin or mmIV- highly protein bound 91%95Good penetration into serous cavitiesPoor CSF penetrationLow blood levelCrosses placentaHalf life 24 hoursSlow renal excretion 2%5/d, 4

8、0%/wAmphotericin BFDA Approved IndicationsEmpiric anti-fungal therapyCandida spp.Aspergillus spp.Cryptococcosis Mucormycosis Endemic mycosesBlastomycosis, Histoplasmosis Coccidioidomycosis, Paracoccidioidomycosis Penicilliosis, SporotrichosisLeishmaniasis 1. Ostrosky-Zeichner et al. Clin Infect Dis.

9、 2003;37:415-425.2. Bates et al. Clin Infect Dis. 2001;32:686-693.Conventional AmB Is No Longer the “Gold Standard” for TreatmentApproved in 1958 with no randomized studiesBecame treatment of choice due to broad-spectrum efficacy and low rate of resistance1Nephrotoxicity was initially underestimated

10、Currently, AmB treatment results in 30% incidence of acute renal failure, resulting in2:Increased mortalityIncreased hospital stayKey Biopharmaceutical Differences of the Amphotericin B FormulationsAmB-dFungizone L-AmBAmBisomeABLCAbelcetABCDAmphotecMol% AmB34%10%35%50%Lipid Config.MicellesSUVsRibbon

11、-likeDisk likeDiameter (m) AMB-deoxyNephrotoxicityL-AMB ABLC ABCD AMB-deoxyInfusion related toxicityL-AMB ABLC ABCD ABLC ABCD AMB-deoxyLipid AMB FormulationsIndications not indicate as initial therapy for most patients with the various candida syndromes, cryptococcosis and the endemic mycosesindicat

12、ions Preexisting renal dysfunction (serum Cr 2.5-3 mg/dL)Refractory to or intolerate of amphotericin B or azole therapyL-AmBFebrile neutropenic patients with suspected fungal infectionsFlucytosinePyrimidine IV or oralNarrow spectrum mainly candida and cryptococcusNot used as sole drug used along wit

13、h ampho B Oral absorption good 80%, low protein bindingIndicationsserious infections caused by susceptible strains of candida and/or cryptococcusCandida septicemia, endocaarditis, urinary tract infections and pulmanary infectionsCryptococcusmeningitis, pulmanary infections, septicemia, urinary tract

14、 infections FlucytosineThe AzolesTriazolesFluconazoleItraconazoleVoriconazolePosaconazoleRavuconazoleFluconazoleAzole IV, oral suspension, capsuleSpectrumUseful against cryptococcus and C.albicansIneffective against some Candida species such as C.krusei and C.glabrataIneffective against Aspergillus

15、speciesFluconazole IndicationsCryptococcal meningitisSystemic infections caused by Candida sp. Vaginal candidiasis - single 150 mg dose. Oralpharyngeal/esophageal candidiasisProphylaxis - BMT and chemotherapy patients to decrease the incidence of candidiasis. ItraconazoleAzole IV, oral solution, cap

16、sulesVery broad spectrum covers aspergillus, candida, cryptococcus, blastomyces, histoplasma and othersItraconazolePharmacokinetics not idealOral absorption not good33 and 55% Liquid tastes badVery highly protein boundNeeds repeated dosing before optimal concentrations are achievedPoor CSF concentra

17、tions, reasonable tissue concentrationsItraconazoleIndications for capsulesBlastomycoses - pulmonary and extrapulmonaryHistoplasmosis- pulmonary and disseminatedAspergillosis - pulmonary and extrapulmonaryOnychomycosis due to dermatophytes of the toenails and fingernails. ItraconazoleIndications for

18、 oral solutionFebrile neutropenic patients with suspected fungal infectionsOralpharyngeal/esophageal candidiasisIndications for intravenousFebrile neutropenic patients with suspected fungal infectionsBlastomycoses - pulmonary and extrapulmonaryHistoplasmosis- pulmonary and disseminatedAspergillosis

19、- pulmonary and extrapulmonaryTriazole Antifungals: Voriconazole, Posaconazole, RavuconazoleSpectrum of ActivityCandida spp.Aspergillus spp. Blastomyces spp.Histoplasma spp. Cryptococcus spp. Cocciodiodes spp.Fusarium spp.ScedosporiumVoriconazoleSummary of PharmacokineticsRapid and consistent absorp

20、tion with high oral bioavailability (96%)Large volume of distribution (4.6 L/kg)Non-linear eliminationHepatic metabolism by CYP2C19, 2C9 and 3A4 isoenzymesAdverse EventsHepaticOverall rate of 13%. 2-fold more than FluVisualNoted by 30%. A sense of altered light perception, blurring, or photophobiaEX

21、HAUSTIVELY studied. No apparent consequences. MiscellaneousPhotosensitivity (1%)? Avoid strong sunlight.Sabo Ann Pharmacother 34:1032, 00; Voriconazole package insert, May 2002; Voriconazole FDA Advisory Cmte, 01伏立康唑適應(yīng)癥侵襲性曲霉病念珠菌病非粒缺患者念珠菌血癥念珠菌所致播散性皮膚感染、腹部、腎臟、膀胱壁及傷口感染食道念珠菌病不能耐受其他藥物或其他藥物無效的賽多孢菌和鐮孢菌，包括腐

22、皮鐮孢菌所致的嚴(yán)重真菌感染泊沙康唑 (Posaconazole) 第二代三唑類抗真菌藥廣譜抗真菌藥，對(duì)念珠菌屬、新型隱球菌、曲霉、根霉、皮炎芽生菌、球孢子菌屬、組織胞漿菌、皮膚真菌、暗色孢科菌均有良好作用對(duì)光滑念珠菌，克柔念珠菌及對(duì)Flu,Itr耐藥的念珠菌作用差對(duì)念珠菌屬為抑菌劑，但對(duì)新型隱球菌和曲霉具殺菌作用，作用優(yōu)于棘白菌素類組織分布廣，終末期半衰期為2531h不良反應(yīng)胃腸道反應(yīng)、皮疹、視力障礙、肝功能異常、低血鉀、白細(xì)胞、血小板減少、QT延長等 2006.9 美國FDA批準(zhǔn)上市，適應(yīng)癥預(yù)防侵襲性曲霉病和念珠菌病感染預(yù)防對(duì)象為13歲及以上高危的嚴(yán)重免疫缺陷患者，如造血干細(xì)胞移植受者發(fā)生G

23、VHD或血液系統(tǒng)惡性腫瘤化療后長期粒細(xì)胞缺乏成人劑量200 mg (5 mL) tid口咽部念珠菌病，包括伊曲康唑和/或氟康唑治療無效者首日100 mg (2.5 mL) bid，繼以100 mg (2.5 mL) qd13 日用于伊曲康唑和/或氟康唑治療無效者劑量為400 mg (10 mL) bid 泊沙康唑 (Posaconazole) Kartsonis NA. Presented at the 12th European Congress of Clinical Microbiology and Infectious Diseases. April 24-27, 2002. Mila

24、n, Italy. Echinocandins : New Class of Drug Nucleoside Analogs-(1,3)-D-glucanErgosterolPolyenesAzolesPhospholipid bilayerof the fungal cellmembraneFungal cell wall-(1,6)-glucan-(1,3)-D-glucan synthaseGlucan SynthesisInhibitornucleusBreakthrough Mechanism of Action: Targets the Pathogen, Not the Patient Echinocandins: Caspofungin and MicafunginSpectrum of Activity:Candida spp. Aspergillus spp. Histoplasma spp. Blastomyces spp. Pneumocystis spp.Echinocandins: Caspofungin and MicafunginPros:fungicidal (Candida spp.)minimal drug-drug interactionsminimal adverse effectsCon