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1、Antifungal Treatment for Cryptococcal MeningitisLi-Ping Zhu, Xin-Hua WengHuashan Hospital, Fudan University Shanghai 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 AID
2、SnRemain 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 gluco
3、se was 1.5mmol/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 cell
4、s 15/28 ，monocytes 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
5、with fatigue, anorexia 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/m
6、LnSince 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 therapynHBV DNA was 6.19108 copies/mL in July 2005. Adefovir 10mg/d was added to lamivudineLiver CTHow can I i
7、nitially treat this patient?nAmBnL-AmBnFluconazolenItraconazolenPosaconazolenFlucytosine RoadmapnClinical studies in the pre-HIV EranClinical studies in the AIDS EranRecent studies for cryptococcal meningitisClinical studiesin the pre-HIV EraAmBnPrior to the availability of AmB, cryptococcal meningi
8、tis was considered to be 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 event
9、sLandmark therapy nTwo major 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 comparedThe first milestone clinical trialnAmB (0.4 mg/kg.d) vs. AmB
10、 (0.3 mg/kg.d) and 5-FCn27 treated with AmB alone for 10wks 24 with a combination of AmB and 5-FC for only 6wksnCombination more effectiveCure/improved (66% vs 41%)Relapses (5% vs 18%) Sterilization of CSF: rapidNephrotoxicity: decreased -Bennett et al. N Engl J Med. 1979. 301: 126 The second large
11、randomized trialnAmB (0.3mg/kg.d) + 5-FC for 4 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%)-Dismuke
12、s et al. N Engl J Med. 1987. 317:334Clinical studies in the AIDS EraThe first large randomized trialnAmB (0.4-0.5 mg/kg.d) vs. Fluconazole(400 mg/d) for 10 weeksnBetter efficacy for AmBSuccess (40% vs. 34%) and overall mortality rate same (14% vs. 18%)Higher mortality rate at 2 wks in Fluconazole pa
13、tients (15% vs. 8%)More rapid sterilization of CSF in the AmB recipients-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 wksfollowed by fluconazole (400mg/kg) or itraconazole (400mg/d) for 8 wks. n381 patients received AmB 0
14、.7 mg/kg/d for the first 2 weeks plus either 5-FC 100 mg/kg/d (202 patients) or placebo (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: 15Maintenance therapy in AIDS patie
15、ntnAmB (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 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.
16、 28: 297 The treatment of cryptococcal meningitis in patients with AIDSnInductionAmB + 5-FC for two wks.nConsolidationHigh dose fluconazole (400 mg/d for normal hepatic and renal function) can be initiatednMaintenanceAt 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 o
