IDSA指南2004年到2009年的對比

From2004to2009IDSA念珠菌病實踐指南解讀指南修訂的背景：新的抗真菌藥物上市024681012141618195019551960196519701975198019851990199520002005ABCDL-AmBABLCTerbinafine#ofdrugsNystatinAmphotericinBGriseofulvin5-FCMiconazoleKetoconazoleYearFluconazoleItraconazoleCaspofunginVoriconazoleMicafunginAnidulafunginPosaconazole2006AmphotericinBinCandidiasisAmB及其脂質(zhì)衍生物具有完全相同的抗真菌譜和活性LFAmB顯著降低AmB的腎毒性但仍然保留了部分輸液相關(guān)的不良反應(yīng)三種LFAmB具有不同的藥動學(xué)特征和不良反應(yīng)發(fā)生率,不可隨意相互替換AmB-d:治療念珠菌病的常規(guī)劑量：0.5–0.7mg/kg/d治療克柔念珠菌及光滑念珠菌的推薦劑量：1mg/kg/dLFAmB對大多數(shù)念珠菌病而言，無證據(jù)證實LFAmB的療效優(yōu)于AmB-dLFAmB不宜用于泌尿系念珠菌感染低的腎組織濃度和尿濃度有治療失敗的動物試驗證據(jù)和臨床報道L-AmB治療中樞神經(jīng)系統(tǒng)感染的療效可能優(yōu)于AmB-dAzolesinCandidiasisFluconazoleCandidemia:與AmB-d相似的療效粘膜念珠菌病：咽部、食道及陰道念珠菌病的標(biāo)準(zhǔn)治療CNS感染：最佳的腦脊液穿透性眼內(nèi)感染：最佳的玻璃體穿透性泌尿系感染：尿液濃度是血漿濃度的10-20倍Itraconazole通常用于粘膜感染的治療,尤其是Fluconazole治療失敗者評價Itraconazole治療侵襲性感染的資料較少AzolesinCandidiasisVoriconazole對粘膜感染和侵襲性感染均有效優(yōu)秀的腦脊液和玻璃體穿透性主要用于特殊耐藥念珠菌感染的降級治療C.kruseiFluconazole-resistant,voriconazole-susceptibleC.glabrataPosaconazole對念珠菌屬的體外活性與voriconazole相似治療念珠菌病的循證醫(yī)學(xué)證據(jù)缺乏（僅有治療咽部念珠菌病的研究數(shù)據(jù)）目前不推薦做為治療念珠菌病的首選藥物EchinocandinsinCandidiasis廣譜抗念珠菌活性光滑、克柔、近平滑的敏感性低于其他念珠菌近平滑念珠菌的耐藥問題近年來備受關(guān)注所有品種均有高級別的循證醫(yī)學(xué)證據(jù)侵襲性念珠菌病食道念珠菌病高安全性FlucytosineinCandidiasis廣譜抗念珠菌活性（C.krusei除外）原則上不推薦單藥使用：快速繼發(fā)耐藥可與AmB聯(lián)用治療侵襲性感染念珠菌心內(nèi)膜炎念珠菌腦膜炎特殊情況下可用于敏感菌株引起的泌尿系感染高的尿液濃度指南修訂背景：新的流行病學(xué)數(shù)據(jù)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.指南修訂的背景：念珠菌耐藥模式的變遷

09指南vs04指南念珠菌屬時間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熱帶念珠菌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指南修訂的背景：新的循證醫(yī)學(xué)證據(jù)新的循證醫(yī)學(xué)證據(jù)主要集中在如何恰當(dāng)使用棘白菌素或廣譜三唑類藥物治療常見的念珠菌病方面念珠菌血癥其他常見的侵襲性念珠菌病粘膜念珠菌病對于少見的侵襲性念珠菌病的治療，級別較高的新的循證醫(yī)學(xué)依據(jù)仍然非常有限慢性播散性念珠菌病念珠菌骨髓炎中樞神經(jīng)系統(tǒng)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多個RCT與Meta-分析：

確立了棘白菌素類與三唑類藥物的地位棘白菌素類與三唑類藥物的療效；棘白菌素類與三唑類藥物的安全性；多個RCT與Meta-分析：

確立了棘白菌素類與三唑類藥物的地位09指南的主要變化強調(diào)了氟康唑和棘白菌素類藥物在念珠菌病治療中的地位AmB及其脂質(zhì)復(fù)合物在絕大多數(shù)情況下退居二線鼓勵采用“降級”治療策略（stepdowntherapy）對疑似侵襲性念珠菌病的經(jīng)驗性治療提出了建議明確提出單純下呼吸道標(biāo)本中發(fā)現(xiàn)念珠菌不推薦進行抗真菌治療(AIII)更細(xì)致的建議，更好的可操作性09指南回答的15個核心問題Whatisthetreatmentofcandidemiainnonneutropenicpatients?Whatisthetreatmentofcandidemiainneutropenicpatients?Whatistheempiricaltreatmentforsuspectedinvasivecandidiasisinnonneutropenicpatients?Whatistheempiricaltreatmentforsuspectedinvasivecandidiasisinneutropenicpatients?WhatisthetreatmentforurinarytractinfectionsduetoCandidaspecies?Whatisthetreatmentforvulvovaginal

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

mucocutaneous

candidiasis?Shouldantifungalprophylaxisbeusedforsolid-organtransplantrecipients,ICUpatients,neutropenicpatientsreceivingchemotherapy,andstemcelltransplantrecipientsatriskofcandidiasis?Whatisthetreatmentofcandidemiainnonneutropenicpatients?選擇治療方案前需要重點考慮的因素近期有無三唑類藥物暴露史有無不能耐受抗真菌藥物的病史可能的主要致病真菌及其在特定環(huán)境中的耐藥特點病情的嚴(yán)重程度是否有合并癥有無累及CNS、心臟瓣膜或其他內(nèi)臟器官的證據(jù)起始治療的推薦藥物首選藥物AnechinocandinisfavoredifModeratelyseveretosevereillness,orRecentazoleusefortreatmentorprophylaxis(AIII),orIsolateisknowntobeC.glabrataorC.krusei(BIII)Fluconazoleforpatientswhoarelesscriticallyilland

whohavenorecentazoleexposure(AIII).orwithinfectionduetoC.parapsilosis(BIII)備選藥物L(fēng)FAmBorAmB-dVoriconazole病情穩(wěn)定者的合理降級治療（stepdown）致病菌可能對氟康唑敏感Anechinocandintofluconazole(A-II).AmB-dorLFAmBtofluconazole(A-I)致病菌為C.krusei或伏立康唑敏感的C.glabrataAnechinocandintooralvoriconazoletherapy(B-III)AmB-dorLFAmBtooralvoriconazoletherapy(B-III)開始治療的時機、療程及其他干預(yù)措施開始治療的時機Earlyinitiationofeffectiveantifungaltherapyiscriticalinthesuccessfultreatmentofcandidemia療程Recommendeddurationoftherapyforcandidemiawithoutobviousmetastaticcomplicationsisfor2weeksafterdocumentedclearanceofCandidaspeciesfromthebloodstreamandresolutionofsymptomsattributabletocandidemia(A-III).其他措施Removeallintravascularcatheters,ifpossibleOphthalmologicalexaminationisrecommendedforallpts.起始治療的時間對念珠菌血癥的預(yù)后非常關(guān)鍵KevinW.etal.ClinInfectDis.2006;43:25–31.*自首次陽性血培養(yǎng)的血標(biāo)本采集后開始計時P=0.0009采集血培養(yǎng)當(dāng)天*采集血培養(yǎng)后1天*采集血培養(yǎng)后2天*采集血培養(yǎng)后≥3天*41.4%死亡率(％)氟康唑治療230例念珠菌血癥患者的多中心回顧性隊列研究結(jié)果延遲治療增加念珠菌血癥的病死率CLINICALMICROBIOLOGYREVIEWS,Jan.2007,p.133–163念珠菌血癥的治療：足療程的重要性粗死亡率(%)足療程不足療程康涅狄格地區(qū)JulietteMetal.InfectControlHospEpidemiol2005;26:540-54737/10838/7056/17944/78巴爾的摩地區(qū)P<0.05P<0.05拔除靜脈導(dǎo)管對念珠菌血癥預(yù)后的影響KibblerCCetal.JHospInfect.2003;54:18-24.30天內(nèi)病死率(%)(N=102)(N=91)(N=43)(N=29)一項為期2年6所英國醫(yī)院參加的監(jiān)測結(jié)果拔除導(dǎo)管治療拔除導(dǎo)管＋治療*未拔除導(dǎo)管治療未拔除導(dǎo)管＋治療**P<0.05Whatisthetreatmentofcandidemiainneutropenicpatients?起始治療的推薦藥物首選藥物EchinocandinCaspofungin(A-II)Micafungin,100mgdaily(A-II)Anidulafungin,(A-III)LFAmB(A-II)備選藥物Fluconazole：forptswhoarelesscriticallyillandwhohavenorecentazoleexposure

(B-III)Voriconazole：tobeusedinsituationsinwhichadditionalmoldcoverageisdesired(B-III)CANDINS治療合并粒缺的念珠菌血癥的療效Mora-DuarteJetal.NEnglJMed.2002;347:2020–2029;KuseE-Retal.Lancet.2007;369:1519–1527;PappasPG,ClinInfectDis2007;45:883–93.粒缺患者：特殊耐藥念珠菌的針對性治療光滑念珠菌(B-III)EchinocandinispreferredLFAmBisaneffectivebutlessattractivealternativebecauseofcostandthepotentialfortoxicity

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

Voriconazole伴粒缺的念珠菌血癥：是否必須拔除靜脈導(dǎo)管？非粒缺患者Intravenouscatheterremovalisstronglyrecommended(A-II).粒缺患者Intravenouscatheterremovalshouldbeconsidered(B-III)區(qū)別對待的原因Distinguishinggut-associatedfromvascularcatheter–associatedcandidemiacanbedifficultinneutropenicpatientsthedataforcatheterremovalislesscompellingtheconsequencesofcatheterremovaloftencreatesignificantintravenousaccessproblemsinneutropenicpatients.伴粒缺的念珠菌血癥：抗真菌治療的療程血液中致病念珠菌的清除并非唯一標(biāo)準(zhǔn)必須重視粒細(xì)胞的恢復(fù)指南的推薦：Recommendeddurationoftherapyforcandidemiawithoutpersistentfungemiaormetastaticcomplicationsis2weeksafterdocumentedclearanceofCandidafromthebloodstreamandresolutionofsymptomsattributabletocandidemiaandresolutionofneutropenia(A-III)Whatistheempiricaltreatmentforsuspectedinvasivecandidiasisinnonneutropenicpatients?在04年指南基礎(chǔ)上新增加的內(nèi)容治療推薦與非粒缺念珠菌血癥相同關(guān)鍵是早期、準(zhǔn)確識別高危患者哪些患者需要進行經(jīng)驗性抗真菌治療？需要同時滿足以下三條標(biāo)準(zhǔn)病情危重具有發(fā)生侵襲性念珠菌病的高危因素不存在可導(dǎo)致發(fā)熱的其他原因侵襲性念珠菌病高?；颊叩淖R別RiskfactorsCandidacolonizationseverityofillness,numberofbroad-spectrumantibioticsusedanddurationofuseprevioussurgery(especiallybowelsurgery)receiptofdialysis,useofcentralvenouscathetersreceiptofparenteralnutr