IDSA指南2004年到2009年的对比

From2004to2009IDSA念珠菌病实践指南解读指南修订的背景：新的抗真菌药物上市024681012141618195019551960196519701975198019851990199520002005ABCDL-AmBABLCTerbinafine#ofdrugsNystatinAmphotericinBGriseofulvin5-FCMiconazoleKetoconazoleYearFluconazoleItraconazoleCaspofunginVoriconazoleMicafunginAnidulafunginPosaconazole2006AmphotericinBinCandidiasisAmB及其脂质衍生物具有完全相同的抗真菌谱和活性LFAmB显著降低AmB的肾毒性但仍然保留了部分输液相关的不良反应三种LFAmB具有不同的药动学特征和不良反应发生率,不可随意相互替换AmB-d:治疗念珠菌病的常规剂量：0.5–0.7mg/kg/d治疗克柔念珠菌及光滑念珠菌的推荐剂量：1mg/kg/dLFAmB对大多数念珠菌病而言，无证据证实LFAmB的疗效优于AmB-dLFAmB不宜用于泌尿系念珠菌感染低的肾组织浓度和尿浓度有治疗失败的动物试验证据和临床报道L-AmB治疗中枢神经系统感染的疗效可能优于AmB-dAzolesinCandidiasisFluconazoleCandidemia:与AmB-d相似的疗效粘膜念珠菌病：咽部、食道及阴道念珠菌病的标准治疗CNS感染：最佳的脑脊液穿透性眼内感染：最佳的玻璃体穿透性泌尿系感染：尿液浓度是血浆浓度的10-20倍Itraconazole通常用于粘膜感染的治疗,尤其是Fluconazole治疗失败者评价Itraconazole治疗侵袭性感染的资料较少AzolesinCandidiasisVoriconazole对粘膜感染和侵袭性感染均有效优秀的脑脊液和玻璃体穿透性主要用于特殊耐药念珠菌感染的降级治疗C.kruseiFluconazole-resistant,voriconazole-susceptibleC.glabrataPosaconazole对念珠菌属的体外活性与voriconazole相似治疗念珠菌病的循证医学证据缺乏（仅有治疗咽部念珠菌病的研究数据）目前不推荐做为治疗念珠菌病的首选药物EchinocandinsinCandidiasis广谱抗念珠菌活性光滑、克柔、近平滑的敏感性低于其他念珠菌近平滑念珠菌的耐药问题近年来备受关注所有品种均有高级别的循证医学证据侵袭性念珠菌病食道念珠菌病高安全性FlucytosineinCandidiasis广谱抗念珠菌活性（C.krusei除外）原则上不推荐单药使用：快速继发耐药可与AmB联用治疗侵袭性感染念珠菌心内膜炎念珠菌脑膜炎特殊情况下可用于敏感菌株引起的泌尿系感染高的尿液浓度指南修订背景：新的流行病学数据SpeciesdistributionofCandidafromcasesofinvasivecandidiasisCLIN.MICROBIOL.REV.2007；20：133–163ChangesinBloodstreamCandidaSpeciesDistributioninHeme-OncPatientsatMDACCC.albicans22%C.albicans27%C.glabrata5%C.glabrata25%1998-2001N=144cases2001-2006N=174casesC.tropicalis9%Other5%C.parapsilosis

23%C.parapsilosis

26%C.tropicalis

23%C.krusei12%C.krusei17%Other6.9%Antoniadouetal.Medicine2003;82:309-321.Sipsasetal.ECCMID2008.指南修订的背景：念珠菌耐药模式的变迁

09指南vs04指南念珠菌属时间氟康唑伊曲康唑伏立康唑泊沙康唑氟胞嘧啶AmBCandins白念珠菌04年SSS-SSS09年SSSSSSS热带念珠菌04年SSS-SSS09年SSSSSSS近平滑念珠菌04年SSS-SSS(-I？)09年SSSSSSS-R光滑念珠菌04年S-DD至RS-DD至RS-I-SS-IS09年S-DD至RS-DD至RS-DD至RS-DD至RSS-IS克柔念珠菌04年RS-DD至RS-I-I-RS-IS09年RS-DD至RSSI-RS-IS葡萄牙念珠菌04年SSS-SS-RS09年SSSSSS-RSIDSAGuidelines.ClinInfectDis2004;39:161-89//ClinicalInfectiousDiseases2009;48:503–35指南修订的背景：新的循证医学证据新的循证医学证据主要集中在如何恰当使用棘白菌素或广谱三唑类药物治疗常见的念珠菌病方面念珠菌血症其他常见的侵袭性念珠菌病粘膜念珠菌病对于少见的侵袭性念珠菌病的治疗，级别较高的新的循证医学依据仍然非常有限慢性播散性念珠菌病念珠菌骨髓炎中枢神经系统念珠菌病Rexetal.NEJM,1994Phillipsetal.EJCMID,1997Rexetal.CID2003Abele-Hornetal.Infection,1996Tuiletal.ISICEM,2003Global150-6082005FLUdAMBFLUdAMB+5FCFLUdAMBFLUdAMB+FLUFLUITRVORdAMB

FLUTREATMENTTRIALSOFAZOLEFORINVASIVECANDIDIASISResponsebyTreatmentAllocationTREATMENTTRIALSOFCANDINSFORINVASIVECANDIDIASIS

NEJM.2002;347:2020–2029,NEJM.2007;356:2472–2482,Lancet.2007;369:1519–1527CaspofunginStudy*AnidulafunginStudy*MicafunginStudy*DesignDouble-blind,randomized,controlledDouble-blind,randomized,controlledDouble-blind,randomized,controlledSampleSizeN=239N=245N=537Dose50mgQD(70mgload)100mgQD(200mgload)100to200mg/dayforpatients>40kg2mg/kg/dayforpatients≤40kgComparatorDoseAmphotericinB0.6–1mg/kgFluconazole400mg(800mgload)L-AmB3mg/kg/dayPrimaryEfficacy

EndPointOnlycompleteresolution

ofsignsandsymptoms

MicrobiologicaleradicationCompleteORpartialresponsePresumedordocumentedmicrobiologicaleradicationCompleteORpartialresponsePresumedordocumentedmicrobiologicaleradicationEfficacyPopulationsMITTPP(≥5daysoftreatment)MITTPP(≥5daysoftreatment)Results81%/65%75.6%/60.2%74%/70%Candinvscomparatorforinvasivecandidiasis:

Adverseeventsrequiringdiscontinuation

MayoClinProc.2008;83(9):1011-1021All-causemortalityAdverseeventsrequiringdiscontinuation多个RCT与Meta-分析：

确立了棘白菌素类与三唑类药物的地位棘白菌素类与三唑类药物的疗效；棘白菌素类与三唑类药物的安全性；多个RCT与Meta-分析：

确立了棘白菌素类与三唑类药物的地位09指南的主要变化强调了氟康唑和棘白菌素类药物在念珠菌病治疗中的地位AmB及其脂质复合物在绝大多数情况下退居二线鼓励采用“降级”治疗策略（stepdowntherapy）对疑似侵袭性念珠菌病的经验性治疗提出了建议明确提出单纯下呼吸道标本中发现念珠菌不推荐进行抗真菌治疗(AIII)更细致的建议，更好的可操作性09指南回答的15个核心问题Whatisthetreatmentofcandidemiainnonneutropenicpatients?Whatisthetreatmentofcandidemiainneutropenicpatients?Whatistheempiricaltreatmentforsuspectedinvasivecandidiasisinnonneutropenicpatients?Whatistheempiricaltreatmentforsuspectedinvasivecandidiasisinneutropenicpatients?WhatisthetreatmentforurinarytractinfectionsduetoCandidaspecies?Whatisthetreatmentforvulvovaginal

candidiais?Whatisthetreatmentforchronicdisseminatedcandidiasis?WhatisthetreatmentforosteoarticularinfectionsduetoCandidaspecies?WhatisthetreatmentforCNScandidiasisinadults?WhatisthetreatmentforCandidaendophthalmitis?WhatisthetreatmentforinfectionsofthecardiovascularsystemduetoCandidaspecies?Whatisthetreatmentforneonatalcandidiasis?WhatisthesignificanceofCandidaspeciesisolatedfromrespiratorysecretions?Whatisthetreatmentfornongenital

mucocutaneous

candidiasis?Shouldantifungalprophylaxisbeusedforsolid-organtransplantrecipients,ICUpatients,neutropenicpatientsreceivingchemotherapy,andstemcelltransplantrecipientsatriskofcandidiasis?Whatisthetreatmentofcandidemiainnonneutropenicpatients?选择治疗方案前需要重点考虑的因素近期有无三唑类药物暴露史有无不能耐受抗真菌药物的病史可能的主要致病真菌及其在特定环境中的耐药特点病情的严重程度是否有合并症有无累及CNS、心脏瓣膜或其他内脏器官的证据起始治疗的推荐药物首选药物AnechinocandinisfavoredifModeratelyseveretosevereillness,orRecentazoleusefortreatmentorprophylaxis(AIII),orIsolateisknowntobeC.glabrataorC.krusei(BIII)Fluconazoleforpatientswhoarelesscriticallyilland

whohavenorecentazoleexposure(AIII).orwithinfectionduetoC.parapsilosis(BIII)备选药物LFAmBorAmB-dVoriconazole病情稳定者的合理降级治疗（stepdown）致病菌可能对氟康唑敏感Anechinocandintofluconazole(A-II).AmB-dorLFAmBtofluconazole(A-I)致病菌为C.krusei或伏立康唑敏感的C.glabrataAnechinocandintooralvoriconazoletherapy(B-III)AmB-dorLFAmBtooralvoriconazoletherapy(B-III)开始治疗的时机、疗程及其他干预措施开始治疗的时机Earlyinitiationofeffectiveantifungaltherapyiscriticalinthesuccessfultreatmentofcandidemia疗程Recommendeddurationoftherapyforcandidemiawithoutobviousmetastaticcomplicationsisfor2weeksafterdocumentedclearanceofCandidaspeciesfromthebloodstreamandresolutionofsymptomsattributabletocandidemia(A-III).其他措施Removeallintravascularcatheters,ifpossibleOphthalmologicalexaminationisrecommendedforallpts.起始治疗的时间对念珠菌血症的预后非常关键KevinW.etal.ClinInfectDis.2006;43:25–31.*自首次阳性血培养的血标本采集后开始计时P=0.0009采集血培养当天*采集血培养后1天*采集血培养后2天*采集血培养后≥3天*41.4%死亡率(％)氟康唑治疗230例念珠菌血症患者的多中心回顾性队列研究结果延迟治疗增加念珠菌血症的病死率CLINICALMICROBIOLOGYREVIEWS,Jan.2007,p.133–163念珠菌血症的治疗：足疗程的重要性粗死亡率(%)足疗程不足疗程康涅狄格地区JulietteMetal.InfectControlHospEpidemiol2005;26:540-54737/10838/7056/17944/78巴尔的摩地区P<0.05P<0.05拔除静脉导管对念珠菌血症预后的影响KibblerCCetal.JHospInfect.2003;54:18-24.30天内病死率(%)(N=102)(N=91)(N=43)(N=29)一项为期2年6所英国医院参加的监测结果拔除导管治疗拔除导管＋治疗*未拔除导管治疗未拔除导管＋治疗**P<0.05Whatisthetreatmentofcandidemiainneutropenicpatients?起始治疗的推荐药物首选药物EchinocandinCaspofungin(A-II)Micafungin,100mgdaily(A-II)Anidulafungin,(A-III)LFAmB(A-II)备选药物Fluconazole：forptswhoarelesscriticallyillandwhohavenorecentazoleexposure

(B-III)Voriconazole：tobeusedinsituationsinwhichadditionalmoldcoverageisdesired(B-III)CANDINS治疗合并粒缺的念珠菌血症的疗效Mora-DuarteJetal.NEnglJMed.2002;347:2020–2029;KuseE-Retal.Lancet.2007;369:1519–1527;PappasPG,ClinInfectDis2007;45:883–93.粒缺患者：特殊耐药念珠菌的针对性治疗光滑念珠菌(B-III)EchinocandinispreferredLFAmBisaneffectivebutlessattractivealternativebecauseofcostandthepotentialfortoxicity

近平滑念珠菌(B-III)FluconazoleorLFAmB克柔念珠菌(B-III)EchinocandinorLFAmBor

Voriconazole伴粒缺的念珠菌血症：是否必须拔除静脉导管？非粒缺患者Intravenouscatheterremovalisstronglyrecommended(A-II).粒缺患者Intravenouscatheterremovalshouldbeconsidered(B-III)区别对待的原因Distinguishinggut-associatedfromvascularcatheter–associatedcandidemiacanbedifficultinneutropenicpatientsthedataforcatheterremovalislesscompellingtheconsequencesofcatheterremovaloftencreatesignificantintravenousaccessproblemsinneutropenicpatients.伴粒缺的念珠菌血症：抗真菌治疗的疗程血液中致病念珠菌的清除并非唯一标准必须重视粒细胞的恢复指南的推荐：Recommendeddurationoftherapyforcandidemiawithoutpersistentfungemiaormetastaticcomplicationsis2weeksafterdocumentedclearanceofCandidafromthebloodstreamandresolutionofsymptomsattributabletocandidemiaandresolutionofneutropenia(A-III)Whatistheempiricaltreatmentforsuspectedinvasivecandidiasisinnonneutropenicpatients?在04年指南基础上新增加的内容治疗推荐与非粒缺念珠菌血症相同关键是早期、准确识别高危患者哪些患者需要进行经验性抗真菌治疗？需要同时满足以下三条标准病情危重具有发生侵袭性念珠菌病的高危因素不存在可导致发热的其他原因侵袭性念珠菌病高危患者的识别RiskfactorsCandidacolonizationseverityofillness,numberofbroad-spectrumantibioticsusedanddurationofuseprevioussurgery(especiallybowelsurgery)receiptofdialysis,useofcentralvenouscathetersreceiptofparenteralnutr