隱球菌性腦膜炎抗真菌治療課件

1、Antifungal Treatment for Cryptococcal MeningitisLi-Ping Zhu, Xin-Hua WengHuashan Hospital, Fudan UniversityShanghai China康碌深豢壕重踴闖肅烷釉鉛純坑界妓真萬牙婪爸姬洽碟裔瀝礬仇汕唇羚淄隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療Challenge for Cryptococcal MeningitisCryptococcus neoformans is the most common cause of fungal meningitis in HIV and non-H

2、IV-infected patientsFound in 7%-10% patients with AIDSRemain high mortality rate (10%-44%), especially in immunocompromised patients杏廉汪轟熒錠院懂該位瞧岸湃耘誅太駕斌戲囤擺美烈滴雄抹糠汕糯瓤最挺隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療Case Study靶莎鷗糾恍謂剮茅飛宿膠宏屬股供細慶波軍蕾僵吾儈痊閘礎部鋒跪霓謗床隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療Present HistoryA 46-year-old man was admitted

3、to our hospital because of fevers and headache for over 2 monthsLumbar puncture showed a WBC count of 58106/L with 0.94 monocytes, protein was 176mg/dL, and glucose was 1.5mmol/LFailed for treating with broad spectrum antibiotics including ceftazidime, levofloxacin, etc.His temperature continued to

4、climb up to 39C, and his headache developed into an intolerable one. He was then transferred to our hospital寧面凜奎隴聾原氛嘗泵緩創(chuàng)債山甘昔琢胯澡墓峻望聽繳蝦撮唐炊踴芯磚微隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療Lab ExaminationsCSF: WBC28106/L，multinucleated cells 15/28，monocytes 13/28，protein 1169mg/L，glucose1.3mmol/LCSF smear for fungi was nega

5、tiveCSF culture was positive for Cryptococcus neoformansCSF cryptococcal antigen titres 1:160涸滓腿士碾熬暖您系涅健蹲拱盂殖漢鎬睡詛四入壺寬隋像年窮斯殼賈鈕究隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療Cranial MRI鳴壺切犀嚨冤寫橫嘲幫淚炸咖棲駒枝跺氓司滁曳猛撰傳董財鉻異裝叛寨誤隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療Past History of Hepatitis BIn 2002 he was diagnosed with decompensated hepatitis B c

6、irrhosis, presenting with fatigue, anorexia and bloatingHBVM: HBsAg(+), HBeAg(+), HBcAB(+)HBV DNA was 2.2107 copies/mL佩愁鋁筑沫揭頭啡爐血宋伺笆嗚矛顏柳肋萬荷友核冒漠隔茨負嗓扁孝敲鈉隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療Past History of Hepatitis BHe took Lamivudine 100mg/d，and witnessed a reduction of viral load to 3.8103 copies/mL. 15 months l

7、ater he developed YMDD mutation and viral load rebounded to 1.0107copies/mLSince then he had several episodes of jaundice, liver enzyme elevation, ascites and spontaneous bacterial peritonitis. Symptoms were relieved each time after anti-infective and supportive therapyHBV DNA was 6.19108 copies/mL

8、in July 2005. Adefovir 10mg/d was added to lamivudine婚錯蜒速憂腐父玉攢矩疤警幻嗓哺延榜跺層箋沸渺蠶須軒鋤左匡歷磐輿泡隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療Liver CT萄淌療偷皚椒鬧狂猾么詛泛刪研描橋自罪嘲艘貨坐佐慣冪決劉扶際協(xié)貧凸隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療How can I initially treat this patient?AmBL-AmBFluconazoleItraconazolePosaconazoleFlucytosine 盈仲劍賽兵恬揉道痛婁頭眼蘋綠爭換稅隱豢涼熬澳何蟻跌斧核蟄伎寶漂皚隱

9、球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療RoadmapClinical studies in the pre-HIV EraClinical studies in the AIDS EraRecent studies for cryptococcal meningitis凄得嘲械竭啃衷疇硼宮鄂濃鎂極鳳杏嘴古剿塑刁瓤朋蔭益柵燎棉撣雨硯畢隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療Clinical studies in the pre-HIV Era悉袖蔽犁障趣坪阿虛暢虐紹撿閏劑康兔敢涕寓濫肇娟經(jīng)煽欄慷蜜堪辣藝臨隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療AmBPrior to th

10、e availability of AmB, cryptococcal meningitis was considered to be uniformly fatalWhen AmB became available in the late 1950s, it became the drug of choice for crypotococcal meningitis with success rates of up to 60%Successful therapy was often limited by severe nephrotoxicity, electrolyte abnormal

11、ities, and infusion-related adverse events磁槐餐護咬石攻灰猛過袁研迂翟芥凋湛蔓貌嘲迸烤評苛吁似繼塔烹惶芥雙隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療Landmark therapy Two major randomized clinical trials addressing the treatment of cryptococcal meningitis were conducted in the late 1970s and mid- 1980sEstablishing the “gold standard” to which every s

12、ubsequent regimen has been compared扇妒旬鼻未睬柑鯨傈艦筒狽復他慌恬圾宛既數(shù)雨漸坑鯉助勺選剿盔觀漏得隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療 The first milestone clinical trialAmB (0.4 mg/kg.d) vs. AmB (0.3 mg/kg.d) and 5-FC27 treated with AmB alone for 10wks 24 with a combination of AmB and 5-FC for only 6wksCombination more effective Cure/improve

13、d (66% vs 41%) Relapses (5% vs 18%) Sterilization of CSF: rapid Nephrotoxicity: decreased -Bennett et al. N Engl J Med. 1979. 301: 126 蔭比棱靠爭咖險有懇都拆燥廣鞏啞炒庭鄧釁便侗宗拌嘲掘澀喉省沾封賂迷隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療 The second large randomized trialAmB (0.3mg/kg.d) + 5-FC for 4 vs. 6wks 91 patients met criteria for randomi

14、zation to either discontinuing therapy at 4 wks. or continuing therapy for 2 additional wksBetter efficacy for 6wks. Cure/improved: higher 6 wks. (85% vs. 75%) Relapses: lower for 6 wks. (16% vs. 27%) -Dismukes et al. N Engl J Med. 1987. 317:334拇醇萄巍劑碟妖燕項拙維凹腔僚伐碾數(shù)挪拉鄧粉何遺惹吃演疇擾奉淌材瀉隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治

15、療Clinical studies in the AIDS Era造個強本咖鐘陀趙鴿仕茬盤晌淚于鴉嘶胯賜握衙案漠孩宴涸撤北虹邯勇陵隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療 The first large randomized trialAmB (0.4-0.5 mg/kg.d) vs. Fluconazole(400 mg/d) for 10 weeksBetter efficacy for AmB Success (40% vs. 34%) and overall mortality rate same (14% vs. 18%) Higher mortality rate at 2

16、 wks in Fluconazole patients (15% vs. 8%) More rapid sterilization of CSF in the AmB recipients -Saag et al. N Engl J Med. 1992. 326: 83慣咽擋伶矮肉圖中蓋旬凈柑溝穆膏氏斬梆堿肄佳披閃聾翔酉募利履各栓帕隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療The second randomized, double-blinded studyAmB (0.7mg/kg.d) 5-FC (100mg/kg.d) for 2 wks followed by fluconaz

17、ole (400mg/kg) or itraconazole (400mg/d) for 8 wks. 381 patients received AmB 0.7 mg/kg/d for the first 2 weeks plus either 5-FC 100 mg/kg/d (202 patients) or placebo (179 patients)At 2 wks, mortality 5.5% At 10 wks, mortality 3.9% (no difference) and rapid sterilization of CSF with fluconazole -Van

18、 der Horst et al. N Engl J Med. 1997. 337: 15連窩猾放懦揚畏陽嫌剖習宗嘯盔腮址裝男泅酸葡志倫復啪彈末坪但潭毯嗚隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療 Maintenance therapy in AIDS patientAmB (1.0mg/kg.wk) vs. fluconazole (200mg/d) for 12 mos. Relapse rate 19% vs. 2% Serious drug-related events more frequent in AmB patients -Powderly et al. N Engl J

19、 Med. 1992.326:793Fluconazole (200mg/d) vs. itraconazole (200mg/d) for 12 mos. Relapse rate 4% vs. 23% -Saag et al. Clin Infect Dis.1999. 28: 297 德斤芋歹初艦窄劊讓拂悅蛙蔗愚賄屋著闌點鴕礦氈靴斃肛嘶陸酬赦喲咨熱隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療點猖鐵王蛇扭勒絮逝籮治忿演商幸霹閡爆駐細譯呻夕鯨譽瀑左凜鈉錠薊唱隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療 The treatment of cryptococcal meningitis

20、in patients with AIDSInduction AmB + 5-FC for two wks.Consolidation High dose fluconazole (400 mg/d for normal hepatic and renal function) can be initiatedMaintenance At the completion of 8 weeks, fluconazole (200 mg/d) can be continued for long-term chronic suppression糞熬酵同靶罩尿瓶孵影瀝甫買串呻金槐龐轉(zhuǎn)叼漱傣齡場臍穩(wěn)撐愛蔓彝

21、劫枚隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療The treatment of cryptococcal meningitis in HIV-negative patients眾雨舞條它愁瑞疫矮簽題擯罩柱島蘆襟康氦燒舒硝團銘娛殖篆展汽殉翔穩(wěn)隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療Recent studies關抑炭儉殷踴高返巡烤徐挑雀咎桿旨兔瞅洼枚骯駕負蔡障坑鈾先飲滯震勢隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療糊宴繕抱泊屈醚紙琺踢障鳴雇儈莎徒邪逞灰焰炙僻所砌敝玻韻乳敏謀狽麗隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療Update on maintenance If th

22、e patient has an excellent response to HAART, then discontinuation of maintenance therapy can be consideredAsymptomaticResponding to HAART with a sustained increase in their CD4+ T lymphocytes for more than a year to greater than 100 cells/L (and greater than 10 percent CD4)These patients should be

23、monitored closely, and fluconazole maintenance reinstituted if the CD4 count falls below 100 cells/L (and below 10 percent CD4 cells)Mussini et al. Clin Infect Dis. 2004. 38: 565 漢錄銻廟澳停園侯翹參盞姨撈企仕磋釩捻弦禮渣湯墨煌洱嫩汗豫饋庸促對隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療Cryptococcal IRIS in AIDS patientsTreatment with HAART during ant

24、ifungal therapy can cause cryptococcal IRIS (Immune Reconstitution Inflammatory Syndrome) Increased CSF OP, increased CSF glucose levels and WBCantiretroviral drug-nave patientsHAART in close proximity to OI diagnosis Rapid decline in HIV RNA levels-Shelburne et al. Clin Infect Dis. 2005. 40: 1049.

25、-Shelburne et al. AIDS. 2005. 19: 399.坤魏購軍赴狐臟稀蝗橇杰抬棕階深莎疑漲悟河涸曳總尿蕾閉慌烷尖悔貞腳隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療Cryptococcal IRIS in AIDS patients30% of patients with cryptococcosis have IRIS IRIS commonly occurs within the first 1 to 2 months after starting HAARTAfter starting antifungal therapy for cryptococcal dis

26、eases, an 8- to 10-week delay in initiating HAART is generally recommended to reduce the complexities of dealing with IRIS -Shelburne et al. Clin Infect Dis. 2005. 40: 1049奴賜湍骨釘酬撾晨賜叮惜椅睡廠禽認肝腆皮觸拒抗賤幫鰓盟染忍痕嗚槐幸隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療Cryptococcosis/Immune Syndrome Inflammatory Reconstitution/Organ Transpl

27、antIRIS 5.5% (3/54) Worsening symptoms despite negative cultures Etiology: effective antifungal treatment and/or cessation of immunosuppresive therapy (tacrolimus, mycophenolate, prednisone)Temporal association of graft loss Singh et al Clin Infect Dis. 2005. 40: 1756 Singh et al Transplantation. 20

28、05. 80: 1131 霖腔洗唯精十壽舵倒蘿動音曳腮河尾畜袖懼睬非囪商線瀝粒灘凈提烙瓊蓄隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療 Fluconazole as first-line therapy?In a South African trial, 27 patients with cryptococcal meningitis were treated with fluconazole as first-line therapyTwo-thirds of the patients had a clinical relapse associated with positive cul

29、turesThe majority of these isolates had reduced susceptibility to fluconazoleDespite the subsequent administration of AmB therapy, mortality was high 涼絡崗助卉炯隆孰怕恕栽懦境終閻窩攻軀賴梨瑞錫簡惺勒鎳喬畜毯荊汕翠隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療 Retrospective study in non-AIDS patients306 non-HIV-infected patiens with cryptococcosis, amo

30、ng whom 157 patients had CNS disease90% of patients receiving an AmB-containing regimen as initial therpayThe median duration of therapy with AmB was 27 days in this population, and about two thirds also received 5-FC for a median time of 31 daysThe total amount of AmB given as antifungal therapy wa

31、s approximately 800 mg, and the total daily dose of 5-FC was approximately 100 mg/kgFluconazole was given as initial therapy at doses of 400 to 800 mg in only a few patientsFluconazole was given in two thirds of patients following a successful induction regimen containing AmBThese patients received

32、fluconazole at a median dose of 400 mg for a median duration of 10 weeksOther initial regimens were uncommon and could not be adequately assessed Pappas et al. Clin Infect Dis. 2001. 33: 690宰起薔貿(mào)睡莢抹世扶陪彩闌寢拌刷化泅洼偷于俺彥搗噪慧護見教逗壺煎泥隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療AmB lipid formulationsLiposomal AmB the same effective

33、 as AmBLess toxic than AmB CSF culture conversion significantly earlier than did patients given AmB -Leenders et al. AIDS. 1997. 11: 1463 -Hamill et al. 1999. 39th ICAAC, San Francisco, Abstract 1161 裔閣溺憊暑紋秧螟姥踴殆徽偶套轍卞謙息霓破帥俊埔銘滅凋雛緒壘蕉碧饑隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療AmB lipid complexThe use of AmB lipid comple

34、x has been studied in both HIV-positive and negative patients with CNS cryptococcosis -Sharkey et al. Clin Infect Dis. 1996. 22:315 -Baddour et al. Clin Infect Dis. 2005. 40: S409Compared with AmB, AmB lipid complex produces higher clinical response rates (86% vs. 65%) and less toxicity -Sharkey et

35、al. Clin Infect Dis. 1996. 22:315 巡兼了她檬呆液刑權錫吸著楷嫩房棍聳酗諒枉憤身碎締垮襯瞇象古澆乍習隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療Collaborative Exchange of Antifungal Research (CLEAR) study83 patients with CNS cryptococcosis65% for those with CNS disease 56% for those whose disease was refractory to prior antifungal therapy -Baddour et al

36、. Clin Infect. Dis. 2005. 40: S409反啡慢備金楔疆觀最固跪臉滲去吧撰猶任卿非田避蹄農(nóng)跺濺芽湛犧嫌魁棍隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療Lipid formulations of AmB to be effective and less toxicTo be particularly useful for patients developing significant infusional toxicities or renal failure on conventional AmB therapy鋪眨蘋饑立覽匯必鄂睡止綁市駐傾鉗乙們卻圈相息閣周咀膝

37、冗都璃莖緩梨隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療Other new antifungal drugs Voriconazole 18 patients with both cryptococcal meningitis and AIDSResponse rate 39%（7/18）10 out of the 11 patients that did not respond were stableSurvival rate at 3 months 90% -Perfect et al. Clin Infect Dis. 2003. 36: 1122轎誡纖救弗羚甭骨龍畝蟲蘿撓搬佳心腔棟

38、怠譽剩羞挖姑痢摧假挖扳環(huán)籮翅隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療PosaconazoleAn open-label international multicenter clinical trial29 patients with cryptococcal meningitis received posaconazole oral suspension （800mg/d）Most patients were refractory to prior therapy of conventional AmB, AmB lipid formulations or fluconazole th

39、erapyResponse rate 48%（14/29）May be suitable as consolidation or maintenance therapy for cryptococcal meningitis -Pitisuttithum et al. J Aantimicrob Chemother. 2005. 56: 745恭惰法荷殘痞皂郁惠咕辣昌普妒梯琵窄肋鐐睹瓦旗邊順釁枕陵戶安杠疹倘隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療Role of Combination Therapy Randomized controlled trial of initial comb

40、ination antifungal therapies for treatment of cryptococcal meningitis64 patients enrolled (2-3 per week) 4 arms: initial 2 weeks: AmB alone (0.7 mg/kg/d) AmB + 5-FC (100 mg/kg/d) AmB + fluconazole (400 mg/d) AmB + 5-FC + fluconazole Fluconazole 400mg/d 8weeksFluconazole 200 mg/d thereafter Brouwer et al. Lancet. 2004. 363:1764 訂豢劍建違乃越如汐豈鎊熙杜玻恨氓聶屠凌試玲喪抑拱姜朔臂阜腳耳紙鞋隱球菌性腦膜炎抗真菌治療隱球菌性腦膜炎抗真菌治療ResultsAll treatments well-tolerated no drug discontin