隐球菌性脑膜炎抗真菌治疗.ppt

Antifungal Treatment for Cryptococcal MeningitisLi-Ping Zhu, Xin-Hua WengHuashan Hospital, Fudan UniversityShanghai ChinaChallenge for Cryptococcal MeningitisnCryptococcus neoformans is the most common cause of fungal meningitis in HIV and non-HIV-infected patientsnFound in 7%-10% patients with AIDSnRemain high mortality rate (10%-44%), especially in immunocompromised patientsCase StudyPresent 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 58×106/L with 0.94 monocytes, protein was 176mg/dL, and glucose was 1.5mmol/LnFailed for treating with broad spectrum antibiotics including ceftazidime, levofloxacin, etc.nHis temperature continued to climb up to 39˚C, and his headache developed into an intolerable one. He was then transferred to our hospitalLab ExaminationsnCSF: WBC28×106/L，，multinucleated cells 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 1:160Cranial MRIPast History of Hepatitis BnIn 2002 he was diagnosed with decompensated hepatitis B cirrhosis, presenting with fatigue, anorexia and bloatingnHBVM: HBsAg(+), HBeAg(+), HBcAB(+)nHBV DNA was 2.2×107 copies/mLPast History of Hepatitis BnHe took Lamivudine 100mg/d，，and witnessed a reduction of viral load to 3.8×103 copies/mL. 15 months later he developed YMDD mutation and viral load rebounded to 1.0×107copies/mLnSince 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 6.19×108 copies/mL in July 2005. Adefovir 10mg/d was added to lamivudineLiver CTHow can I initially treat this patient?nAmBnL-AmBnFluconazolenItraconazolenPosaconazolenFlucytosine RoadmapnClinical studies in the pre-HIV EranClinical studies in the AIDS EranRecent studies for cryptococcal meningitisClinical studies in the pre-HIV EraAmBnPrior to the availability of AmB, cryptococcal meningitis 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 eventsLandmark 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 compared       The first milestone clinical trialnAmB (0.4 mg/kg.d) vs. AmB (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 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 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. 317:334Clinical studies in the 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 --Saag et al. N Engl J Med.  1992. 326: 83The 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 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: 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 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.nConsolidation 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 suppressionThe treatment of cryptococcal meningitis in HIV-negative patientsRecent studiesUpdate on maintenance     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/µL (and greater than 10 percent CD4)nThese patients should be monitored closely, and fluconazole maintenance reinstituted if the CD4 count falls below 100 cells/µL (and below 10 percent CD4 cells)Mussini et al. Clin Infect Dis. 2004. 38: 565 Cryptococcal IRIS in AIDS patientsnTreatment with HAART during antifungal therapy can cause cryptococcal IRIS (Immune Reconstitution Inflammatory Syndrome) Increased CSF OP, increased CSF glucose levels and WBCnantiretroviral drug-naïve patientsnHAART in close proximity to OI diagnosis nRapid decline in HIV RNA levels--Shelburne et al. Clin Infect Dis. 2005. 40: 1049.                                                                                                     --Shelburne et al. AIDS. 2005. 19 : 399.Cryptococcal IRIS in AIDS patientsn30% of patients with cryptococcosis have IRIS nIRIS commonly occurs within the first 1 to 2 months after starting HAARTnAfter starting antifungal therapy for cryptococcal diseases, 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Cryptococcosis/Immune Syndrome Inflammatory Reconstitution/Organ TransplantnIRIS 5.5% (3/54) nWorsening symptoms despite negative cultures nEtiology: effective antifungal treatment and/or cessation of immunosuppresive therapy (tacrolimus, mycophenolate, prednisone)nTemporal association of graft loss Singh et al Clin Infect Dis. 2005. 40: 1756 Singh et al Transplantation. 2005. 80: 1131      Fluconazole as first-line therapy?nIn a South African trial, 27 patients with cryptococcal meningitis were treated with fluconazole as first-line therapynTwo-thirds of the patients had a clinical relapse associated with positive culturesnThe majority of these isolates had reduced susceptibility to fluconazolenDespite the subsequent administration of AmB therapy, mortality was high  Retrospective study in non-AIDS patientsn306 non-HIV-infected patiens with cryptococcosis, among whom 157 patients had CNS diseasen90% of patients receiving an AmB-containing regimen as initial therpaynThe 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 daysnThe total amount of AmB given as antifungal therapy was approximately 800 mg, and the total daily dose of 5-FC was approximately 100 mg/kgnFluconazole was given as initial therapy at doses of 400 to 800 mg in only a few patientsnFluconazole was given in two thirds of patients following a successful induction regimen containing AmBnThese patients received fluconazole at a median dose of 400 mg for a median duration of 10 weeksnOther initial regimens were uncommon and could not be adequately assessed Pappas et al. Clin Infect Dis. 2001. 33: 690AmB lipid formulationsnLiposomal AmB the same effective as AmBnLess toxic than AmB nCSF 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 AmB lipid complexnThe use of AmB lipid complex 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: S409nCompared with AmB, AmB lipid complex produces higher clinical response rates (86% vs. 65%) and less toxicity --Sharkey et al. Clin Infect Dis. 1996. 22:315 Collaborative Exchange of Antifungal Research (CLEAR) studyn83 patients with CNS cryptococcosisn65% for those with CNS disease n56% for those whose disease was refractory to prior antifungal therapy --Baddour et al. Clin Infect. Dis. 2005. 40: S409Lipid formulations of AmB to be effective and less toxicnTo be particularly useful for patients developing significant infusional toxicities or renal failure on conventional AmB therapyOther new antifungal drugs Voriconazole n18 patients with both cryptococcal meningitis and AIDSnResponse rate 39%（7/18）n10 out of the 11 patients that did not respond were stablenSurvival rate at 3 months >90% --Perfect et al. Clin Infect Dis. 2003. 36: 1122PosaconazolenAn open-label international multicenter clinical trialn29 patients with cryptococcal meningitis received posaconazole oral suspension （（800mg/d））nMost patients were refractory to prior therapy of conventional AmB, AmB lipid formulations or fluconazole therapynResponse rate 48%（（14/29））nMay be suitable as consolidation or maintenance therapy for cryptococcal meningitis --Pitisuttithum et al. J Aantimicrob Chemother. 2005. 56: 745Role of Combination Therapy nRandomized controlled trial of initial combination antifungal therapies for treatment of cryptococcal meningitisn64 patients enrolled (2-3 per week) n4 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 nFluconazole 400mg/d 8weeksnFluconazole 200 mg/d thereafter Brouwer et al. Lancet. 2004. 363:1764 ResultsnAll treatments well-tolerated no drug discontinuation in first 2 weeksnOverall mortality 2 weeks - 14% 10 weeks - 22%nThe most rapidly fungicidal regimen AmB + 5-FC nRecommendations for induction therapy AmB + 5-FCCase Study for Treatment ScheduleCase Study for Treatment SchedulenInduction Intravenous itraconazole 200mg/d for 21d. Body temperature returned normal, headache disappearednConsolidation Intravenous fluconazole 200mg/d for 10w. CSF cytology and chemistry turned normalnMaintenance oral fluconazole 200mg/dnThe patient had kept afebrile and symptom-free thereafterChanging of the TemperatureChanging of the TemperatureCranial MRI (after treatment)Liver function test 10 months follow-up after discontinuationnALT 23 U/LnTB 74 µ mol/LnDB 20.8 µ mol/LnA/G 26/ 46 g/LnHBV DNA (-)ConclusionnAmB-based therapy remains the gold standardnAmB + 5-FC: more effective and more rapid clearance of the fungus from CSFnAdherence to the guideline has been shown to generally improve outcomenSpecific clinical situations may dictate creative management plansThanks for your attention!。