血液病患者真菌感染预防策略

血液病患者真菌感染

预防策略预防性抗真菌治疗的定义一级预防（primaryprophylaxis）国内IFI的治疗原则仍推荐一级预防治疗；对高危人群预防性治疗，可降低IFI发病率及病死率二级预防（secondaryprophylaxis）

是指曾经确诊或临床拟诊真菌感染患者在接受骨髓抑制性化疗以及造血干细胞移植患者的预防性治疗，以防止IFI在患者免疫抑制阶段复发，降低死亡率。血液病化疗患者真菌感染与预防现状血液科患者侵袭性真菌感染发病率高血液科患者真菌感染发病率约为4.6%，急性白血病患者发病率高，占到IFI感染患者的69%；肺曲霉9%-15%(Blood2014;124(26):3858-3869))PaganoLetal.Haematologica.2006Aug;91(8):1068-75.一项对意大利18家血液病房进行的多中心、回顾性、队列研究，入组1999-2003年期11802例血液肿瘤患者(急、慢性白血病、淋巴瘤、多发性骨髓瘤)患者进行病原学分析。IFI发病率(%)373/301277/117315/5966/110454/34576/8447/1616538/11802血液科患者侵袭性真菌感染危害严重历年数据显示，真菌感染归因死亡率高达70%以上ChamilosG,etal.Haematological.2006;91:986-989.一项对美国得克萨斯大学三级肿瘤监护中心1989-2003年期间的1017例血液肿瘤患者的尸检结果分析(P=0.5700)113/14768/8360/821989-1993年1994-1998年1999-2003年IFI归因死亡率(%)Fig1.Kaplan-MeiercurvesforAMLpatientsreceivinginductionchemotherapy,accordingtoIFIstatus.(A)ForallpatientswithorwithoutanyIFIs.(B)ForallpatientswithdifferentcategoriesofIFIs.(C)Forpatientsreceivingstandardinductionchemotherapy.(D)Forpatientsreceivinglow-intensityregimensasinductionchemotherapy.PLOSONEDOI:10.1371/journal.pone.0128410June10,2015HighIncidencesofInvasiveFungalInfectionsinAcuteMyeloidLeukemiaPatientsReceivingInductionChemotherapywithoutSystemicAntifungalProphylaxis:AProspectiveObservationalStudyinTaiwanPLOSONEDOI:10.1371/journal.pone.0128410June10,2015预防性抗真菌治疗不足Intotal,827/4,889(16.9%)casesweretreatedwithprimary(689,83.3%)orsecondary(138,16.7%)antifungalprophylaxisforamedianof11.0days(Q1,Q3;6.0,17.0).AML：29.3%，MDS28.4%.Triazoles(94.3%)：fluconazole48.4%,itraconazole26.0%,voriconazole23.5%and37.5%IV.In93(11.2%),treatmentwasultimatelyswitchedtoadifferentantifungalagentduetoconfirmedorsuspectedIFI.TumorBiol.DOI10.1007/s13277-014-2649-7血液病患者真菌病发生机会大，与患者生存率低有关。预防性抗真菌治疗不足。预防可以降低真菌病的发生率。小结预防性抗真菌药物适用人群中国侵袭性真菌感染工作组

血液病／恶性肿瘤患者侵袭性真菌病的诊断标准

与治疗原则(第四次修订版)急性白血病初次诱导或挽救化疗的患者预计中性粒细胞减少持续大于1周(如骨髓增生异常综合征)的患者伴有严重中性粒细胞缺乏或接受抗胸腺球蛋白(ATG)治疗或造血干细胞移植的重症再生障碍性贫血(再障)患者等。中华内科杂志2013，52（8）：704-708.侵袭性霉菌病个体危险因素抗生素老年人中心静脉置管铁过载近期CMV再激活更昔洛韦的使用下呼吸道病毒感染霉菌的环境暴露InternalMedicineJournal2014,44:1283-1297高危人群（IFD>10%）ANC<0.1X10^9/L>3周或<0.5X10^9/L>5周糖皮质激素:强的松龙1mg/kg+ANC<1.0X10^9/L>1周

强的松龙2mg/kg>2周大剂量阿糖胞苷高度难治CLL或低度淋巴瘤使用氟达拉滨阿莱组单抗，特别是高度难治CLL或淋巴瘤ALLAML中危人群（IFD10%以下）ANC

（0.1-0.5）X10^9/L>3-5周ANC

（0.1-0.5）X10^9/L<3周+ALC<0.5X10^9/L低危人群（IFD2%以下）淋巴瘤侵袭性真菌病危险分组InternalMedicineJournal2014,44:1283-1297Leukemia-relatedLowerprobabilityofCR：AML-adversecytogenetic/genemutationprofiles,WBC50X10^9/L，secondaryleukemia,MDSorantecedenthematologicdisorder>6moALL-adversecytogenetic/genemutationprofiles,WBC30X10^9/LBaselineneutropenia：ANC0.5X10^9/L≥7d,MDS-relatedphagocyticdysfunctionLeukemiastatus：Relapse-refractory>firstinduction>consolidationTreatment-related

Corticosteroids(>3wkof>1mg/kgperdofprednisoneequivalent

Highlymucotoxicregimen;CumulativemyelotoxicityfromrapidlycyclingchemotherapycoursesHost-related:Age>65y(AML),>35Y(ALL);Downsyndrome;Immunitypolymorphisms;pharmacogenomicsofantineoplasticdrugsOrgandysfunction:Highcomorbidityscoresande-TRMrisk;Chronicobstructivepulmonarydisease;smoking;respiratoryviralinfection;Poorphysicalfunctioning(ECOG/WHOscore;physiologicstatus,functionalreserve,activitiesofdailyliving,gaitspeed,andothers;Hyperglycemia>200mg/dL>2wk)Exposuretopathogenicfungi:PrioraspergillosisairwaycolonizationbyAspergillussppRoomwithoutHEPAfiltrationBuildingconstructionsorrenovationRoomwithoutwaterprecautions.AML、ALL治疗前危险因素AML、ALL治疗后危险因素NetstateofimmunosupressionNeutropenia,severeandprolonged(ANC<100/mL>10d)ExpectedsevereandprolongedneutropeniaAML:lowCRscore,d15blasts>5%,noCRbyendofinductionALL:noCRin4wk,persistentMRDPersistentlymphopenia(cells<300uL)withnormalWBC/ANCOrgandysfunction:Mucositis-Severe,grade≥3≥7d,especiallyifinvolvinglowergutExposuretopathogenicfungi：PrioraspergillosisairwaycolonizationbyAspergillusspp，RoomwithoutHEPAfiltration；BuildingconstructionsorrenovationRoomwithoutwaterprecautions；MultisitecolonizationbyCandidaspecies；CentralvenouscatheterHowwetreatinvasivefungaldiseasesinpatientswithacuteleukemia:theimportanceofanindividualizedapproach.Blood.2014;124(26):3858-3869.小结一级预防急性髓系白血病诱导化疗阶段急性淋巴细胞白血病诱导阶段淋巴瘤接受利妥昔单抗或嘌呤类似物联合化疗，出现粒细胞及淋巴细胞双重减少的患者等持续中性粒细胞缺乏患者：重症再生障碍性贫血、MDS等化疗后重度黏膜炎、累积骨髓毒性强暴露环境中心静脉置管二级预防既往有确诊、临床诊断、拟诊的侵袭性真菌感染史并接受化疗患者预防性抗真菌药物种类和特点抗真菌药物分类作用位点类别药物作用机制真菌细胞膜多烯类两性霉素B制霉菌素多马霉素结合真菌细胞膜麦角固醇，导致细胞膜去极化，对蛋白质和一、二价阳离子通透性增加，导致真菌细胞死亡直接导致真菌细胞氧化损伤唑类咪唑类：酮康唑克霉唑益康唑咪康唑奥昔康唑硫康唑噻康唑三唑类（一代）：氟康唑伊曲康唑抑制CYP3A依赖性酶14α-固醇去甲基化酶作用，从而抑制真菌细胞膜麦角固醇的生物合成，使得麦角固醇缺乏，而毒性中间产物14α-甲基固醇蓄积，导致细胞膜通透性增强和生长抑制三唑类（二代）：伏立康唑泊沙康唑烯丙胺类阿莫罗芬布替萘芬萘替芬特比萘芬唑类药物也可抑制哺乳动物细胞CYP450系统依赖性染色体合成和药物代谢，因此常与其他药物发生临床相关的药物间相互作用真菌细胞壁棘白菌素类卡泊芬净米卡芬净阿尼芬净通过抑制1,3-β葡聚糖合成酶，抑制真菌细胞壁合成。抑制该酶可导致真菌细胞壁葡聚糖聚合物缺乏，从而不能对抗渗透压力DNA/RNA合成抗代谢药5-氟胞嘧啶（5-FC）可通过胞嘧啶透酶转运进入真菌细胞，在胞浆中经胞嘧啶脱氨酶转化生成5-氟尿嘧啶（5-FU），5-FU可抑制真菌RNA和DNA合成其他其他类灰黄霉素通过阻断有丝分裂纺锤体形成，抑制真菌细胞有丝分裂常用抗真菌药物作用位点与安全性抗真菌药物

作用位点结论两性霉素B及其相关制剂细胞膜：麦角固醇人体细胞膜上有胆固醇，两性霉素B对真菌固醇和胆固醇的鉴别力较差，抗真菌机制存在一定安全性问题伏立康唑氟康唑伊曲康唑泊沙康唑艾沙康唑细胞内：细胞膜重要成分麦角固醇合成路径上的14-α-固醇去甲基酶人体无14-α-固醇去甲基酶，抗真菌机制本身无安全性问题卡泊芬净米卡芬净阿尼芬净细胞膜：ß(1,3)葡聚糖合成酶（合成细胞壁重要成分ß(1,3)葡聚糖）人体无ß(1,3)葡聚糖合成酶，抗真菌机制本身无安全性问题预防性抗真菌药物应用策略预防性抗真菌药物起始和结束时间合适起始时间不清楚：

住院？

化疗开始？

化疗结束？结束时间：

危险因素解除，一般ANC>0.5或1.0X10^9/L。

初级预防（一级预防）推荐的抗真菌药物：(1)化疗中中性粒细胞缺乏患者：氟康唑(50～400mg／a)、伊曲康唑、泊沙康唑(200mg3次／d)。再次预防（二级预防）：再次预防推荐的抗真菌药物首选既往抗真菌治疗有效的药物，包括伊曲康唑(200mg／d输液序贯口服200mg2次／d)、伏立康唑(200mg2次／d静脉或口服)以及卡泊芬净、米卡芬净或两性霉素B及其脂质体。。中国侵袭性真菌感染工作组

血液病／恶性肿瘤患者侵袭性真菌病的诊断标准

与治疗原则(第四次修订版)InternalMedicineJournal2014,44:1283-1297InternalMedicineJournal2014,44:1283-1297Leukemia-relatedLowerprobabilityofCR：AssessprobabilityofCRande-TRMDetermineriskforIFDs:high,intermediate,orlow,andmanageaccordingly.Primarymold-activeprophylaxisforhigh-riskpatients.Serials-GMItestsLowercytarabineconsolidationforpatientswithfavorablecytogeneticsBetter-toleratedantileukemicregimentsifhighriskfore-TRMBaselineneutropenia：ManageashighriskforIFDsincludingmold-activeprophylaxisG-CSFforpatientswithALL,andGM-CSFforthosewithAMLLeukemiastatus：ManageashighriskforIFDsexceptforconsolidationTreatment-related

Corticosteroids：Reducecorticosteroiddose,provideantifungalandPneumocystisprophylaxis

Highlymucotoxicregimen：FluconazoleprophylaxiseveniflowriskforIFDsCumulativemyelotoxicityfromrapidlycyclingchemotherapycoursesAdjustdosedensityandintensitybasedonlikelihoodofCRande-TRMAML、ALL治疗前对策Host-related:

ManageashighriskforIFDs,includingmold-activeprophylaxisConsiderbetter-toleratedtherapiesOrgandysfunction:Improveorganfunctionandconsiderbetter-toleratedregimensManageashighriskforIFDs,includingmold-activeantifungalprophylaxisDuringinfluenzaseason:immunizepatientandclosecontactsvsinfluenzaviruses,prophylaxiswithneuraminidaseinhibitors,avoidsickvisitors,smokingcessationPreemptivephysicalandoccupationaltherapyExposuretopathogenicfungiManageashighriskforIFDs,includingmold-activeantifungalsecondaryprophylaxisProvideHEPAfiltrationEnsuresafeconstructionpracticesProvidewaterprecautionsHowwetreatinvasivefungaldiseasesinpatientswithacuteleukemia:theimportanceofanindividualizedapproach.Blood.2014;124(26):3858-3869.AML、ALL治疗后对策NetstateofimmunosupressionManageashighriskforIFDs,includingmold-activeantifungalprophylaxisExpectedsevereandprolongedneutropeniaAML:Day-15bonemarrowbiopsyforblastclearanceandMRDALL:G-CSFforpatientswithALLandG-CSFforthosewithAMLPersistentlymphopenia(cells<300uL)withnormalWBC/ANC：Reducecorticosteroiddose,antifungalandPneumocystisprophylaxisOrgandysfunction:Mucositis-Severe,FluconazoleprophylaxisExposuretopathogenicfungi：PrioraspergillosisairwaycolonizationbyAspergillusspp，RoomwithoutHEPAfiltration；BuildingconstructionsorrenovationRoomwithoutwaterprecautions；MultisitecolonizationbyCandidaspecies：Fluconazoleprophylaxis,unlessamold-activeagentisindicated；

OptimalCentralvenouscatheterHowwetreatinvasivefungaldiseasesinpatientswithacuteleukemia:theimportanceofanindividualizedapproach.Blood.2014;124(26):3858-3869.PolymerasechainreactionbloodtestsforthediagnosisofinvasiveaspergillosisinimmunocompromisedpeopleTheCochraneLibrary2015,Issue9清除真菌感染源重视患者教育，提高医护认识评估患者风险恰当选择预防性药物基础疾病的缓解新方法的探索小结预防性抗真菌药物研究进展BMCInfectiousDiseases2014,14:573WeeklyuseoffluconazoleasprophylaxisinhaematologicalpatientsatriskforinvasivecandidiasisComparativeclinicaleffectivenessofprophylacticvoriconazole/posaconazoletofluconazole/itraconazoleinpatientswithacutemyeloidleukemia/myelodysplasticsyndromeundergoingcytotoxicchemotherapyovera12-yearperiodHaematologica2012;97(3):459-463EAFT:empiricantifungaltreatmentTheincidenceofinvasivefungalinfectionsinneutropenicpatientswithacuteleukemiaandmyelodysplasticsyndromesreceivingprimaryantifungalprophylaxiswithvoriconazoleAm.J.Hematol.88:283–288,20132.2%4.2%EffectivenessofPrimaryAnti-AspergillusProphylaxisduringRemissionInductionChemotherapyofAcuteMyeloidLeukemiaAntimicrobialAgentsandChemotherapyp.2775–27802014Volume58Number5IncidenceDensityofInvasiveFungalInfectionsduringPrimary

AntifungalProphylaxisinNewly