隐球菌性脑膜炎抗真菌治疗课件.ppt
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- 球菌 脑膜炎 真菌 治疗 课件
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1、Antifungal Treatment for Cryptococcal MeningitisLi-Ping Zhu,Xin-Hua WengHuashan Hospital,Fudan UniversityShanghai ChinaChallenge for Cryptococcal MeningitisnCryptococcus neoformans is the most common cause of fungal meningitis in HIV and non-HIV-infected patientsnFound in 7%-10%patients with AIDSnRe
2、main high mortality rate(10%-44%),especially in immunocompromised patientsCase StudyPresent HistorynA 46-year-old man was admitted to our hospital because of fevers and headache for over 2 monthsnLumbar puncture showed a WBC count of 58106/L with 0.94 monocytes,protein was 176mg/dL,and glucose was 1
3、.5mmol/LnFailed for treating with broad spectrum antibiotics including ceftazidime,levofloxacin,etc.nHis temperature continued to climb up to 39C,and his headache developed into an intolerable one.He was then transferred to our hospitalLab ExaminationsnCSF:WBC28106/L,multinucleated cells 15/28,monoc
4、ytes 13/28,protein 1169mg/L,glucose1.3mmol/LnCSF smear for fungi was negativenCSF culture was positive for Cryptococcus neoformansnCSF cryptococcal antigen titres 1:160Cranial MRIPast History of Hepatitis BnIn 2002 he was diagnosed with decompensated hepatitis B cirrhosis,presenting with fatigue,ano
5、rexia and bloatingnHBVM:HBsAg(+),HBeAg(+),HBcAB(+)nHBV DNA was 2.2107 copies/mLPast History of Hepatitis BnHe took Lamivudine 100mg/d,and witnessed a reduction of viral load to 3.8103 copies/mL.15 months later he developed YMDD mutation and viral load rebounded to 1.0107copies/mLnSince then he had s
6、everal episodes of jaundice,liver enzyme elevation,ascites and spontaneous bacterial peritonitis.Symptoms were relieved each time after anti-infective and supportive therapynHBV DNA was 6.19108 copies/mL in July 2005.Adefovir 10mg/d was added to lamivudineLiver CTHow can I initially treat this patie
7、nt?nAmBnL-AmBnFluconazolenItraconazolenPosaconazolenFlucytosine RoadmapnClinical studies in the pre-HIV EranClinical studies in the AIDS EranRecent studies for cryptococcal meningitisClinical studies in the pre-HIV EraAmBnPrior to the availability of AmB,cryptococcal meningitis was considered to be
8、uniformly fatalnWhen AmB became available in the late 1950s,it became the drug of choice for crypotococcal meningitis with success rates of up to 60%nSuccessful therapy was often limited by severe nephrotoxicity,electrolyte abnormalities,and infusion-related adverse eventsLandmark therapy nTwo major
9、 randomized clinical trials addressing the treatment of cryptococcal meningitis were conducted in the late 1970s and mid-1980snEstablishing the“gold standard”to which every subsequent regimen has been compared The first milestone clinical trialnAmB(0.4 mg/kg.d)vs.AmB(0.3 mg/kg.d)and 5-FCn27 treated
10、with AmB alone for 10wks 24 with a combination of AmB and 5-FC for only 6wksnCombination more effective Cure/improved(66%vs 41%)Relapses(5%vs 18%)Sterilization of CSF:rapid Nephrotoxicity:decreased -Bennett et al.N Engl J Med.1979.301:126 The second large randomized trialnAmB(0.3mg/kg.d)+5-FC for 4
11、vs.6wks n91 patients met criteria for randomization to either discontinuing therapy at 4 wks.or continuing therapy for 2 additional wksnBetter 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.1987.317:334Clinical studies in the
12、AIDS Era The first large randomized trialnAmB(0.4-0.5 mg/kg.d)vs.Fluconazole(400 mg/d)for 10 weeksnBetter efficacy for AmB Success(40%vs.34%)and overall mortality rate same(14%vs.18%)Higher mortality rate at 2 wks in Fluconazole patients(15%vs.8%)More rapid sterilization of CSF in the AmB recipients
13、 -Saag et al.N Engl J Med.1992.326:83The second randomized,double-blinded studynAmB(0.7mg/kg.d)5-FC(100mg/kg.d)for 2 wks followed by fluconazole(400mg/kg)or itraconazole(400mg/d)for 8 wks.n381 patients received AmB 0.7 mg/kg/d for the first 2 weeks plus either 5-FC 100 mg/kg/d(202 patients)or placeb
14、o(179 patients)nAt 2 wks,mortality 5.5%nAt 10 wks,mortality 3.9%(no difference)and rapid sterilization of CSF with fluconazole -Van der Horst et al.N Engl J Med.1997.337:15 Maintenance therapy in AIDS patientnAmB(1.0mg/kg.wk)vs.fluconazole(200mg/d)for 12 mos.Relapse rate 19%vs.2%Serious drug-related
15、 events more frequent in AmB patients -Powderly et al.N Engl J Med.1992.326:793nFluconazole(200mg/d)vs.itraconazole(200mg/d)for 12 mos.Relapse rate 4%vs.23%-Saag et al.Clin Infect Dis.1999.28:297 The treatment of cryptococcal meningitis in patients with AIDSnInduction AmB+5-FC for two wks.nConsolida
16、tion High dose fluconazole(400 mg/d for normal hepatic and renal function)can be initiatednMaintenance At the completion of 8 weeks,fluconazole(200 mg/d)can be continued for long-term chronic suppressionThe treatment of cryptococcal meningitis in HIV-negative patientsRecent studiesUpdate on maintena
17、nce If the patient has an excellent response to HAART,then discontinuation of maintenance therapy can be considerednAsymptomaticnResponding 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)nThese patients s
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