个体化抗菌治疗策略.ppt

,经验性抗感染治疗的基本原则与临床实践个体化抗感染治疗,Casestudyacutefever,既往健康急性发热、无器官系统感染的临床表现WBC正常阿奇霉素、红霉素、白霉素、洁霉素.(基层)二代头孢、三代头孢、喹诺酮类、酶抑制剂复合制剂、厄他培南.(大医院),TheMimicsofPneumonia,感冒样症状轻咳、少痰渐进性气短各种抗菌药物-广谱+联合呼吸衰竭,慢性咳嗽和黄痰-原因,哮喘后鼻腔鼻漏病毒感染后气道高反应性胃酸返流吸烟相关的慢性支气管炎支气管扩张症弥漫性泛细支气管炎肺泡蛋白沉积症,急性发热-WBC不高/淋巴增高（无感染灶）-病毒！-WBC增高/中性粒增高/核左移-细菌?部位/病原体？原发性菌血症？慢性发热-IE、布病、慢性感染灶？结核病？-非感染性发热药物热、风湿病、恶性肿瘤,正确诊断是正确治疗的前提,发热的诊断与鉴别诊断,Mortality*AssociatedWithInitialInadequateTherapyinCriticallyIllICUPatients,0%,20%,40%,60%,80%,100,%,Luna,1997,Ibrahim,2000,Kollef,1998,Harbarth,2003,Rello,1997,Alvarez-Lerma,1996,Initialadequatetherapy,Initialinadequatetherapy,*Mortalityreferstocrudeorinfection-relatedmortality.Alvarez-LermaFetal.IntensiveCareMed1996;22:387-394.RelloJetal.AmJRespirCritCareMed1997;156:196-200.HarbarthSetal.AmJMed2003;115:529-535.KollefMHetal.Chest1998;113:412-420.IbrahimEHatal.Chest2000;118:146-155.LunaCMetal.Chest1997;111:676-685.VallesJetal.Chest2003;123:1615-1624.,Mortality*,Valles,2003,InadequateTherapyWasCloselyAssociatedWithAntibioticResistance,%OccurrenceofPathogen,KollefMH.ClinInfectDis2000;31(Suppl4):S131-S138.,充分初始治疗改善预后/不充分治疗与耐药紧密相关,2001年在欧洲危重病会议和ICC从“猛击策略”到“降阶梯策略”,开始的广覆盖-对于重症感染开始即使用广谱抗生素以覆盖所有可能致病菌随后的降阶梯-48-72小时后根据微生物学检查结果调整抗生素的使用/使之更有针对性,目的和意义:防止病情迅速恶化VS防止细菌产生耐药/降低费用“广覆盖”与“降阶梯”的有机统一,对VAP最初治疗应针对G-和G+包括MRSA，Gram涂片发现G+球菌与培养金葡萄阳性率之间高度一致。故涂片见G+菌应加用万古霉素代表方案-泰能万古,48岁、男性、同种异体肾移植术后3.5个月13天前出现发热（T38.9），继之咳嗽/无痰、进行性气短胸片先后:头孢呋辛(3d)、莫西沙星(3d)、哌拉西林/他唑巴坦(3d)、亚胺培南/西司他丁万古霉素(3d)查体:发绀、RR24/分、P118/分、双肺未闻及干湿罗音ABG:PH7.48、PO256mmHg、PCO230mmHg,Casestudy-PCP,58岁、男性、既往身体健康11天前出现发热（T38.7），继之咳嗽，少痰；胸片(见右)先后头孢唑林(3d)、哌拉西林/他唑巴坦(3d)，无效病情继续加重，呼吸衰竭ALT/AST/Bilirubins/LDH/CK-MBUrinalysis-pro(+)WBC/RBC/CAST(+)再次胸片(见右)换用碳青酶烯抗MRSA抗真菌无效，呼吸衰竭，转诊,Casestudy-LD,58岁、女性、自述既往身体“健康”1天前突然出现上消化道出血诊断:肝炎后肝硬化，食道静脉曲张出血急诊行门脉断流手术术后第二天出现发热（T38.9），继之咳嗽、咳痰，胸片(见右)血气分析:PaO2=56mmHg（吸空气）碳青酶烯+抗MRSA+抗真菌临床转归-呼吸衰竭好转，下一步？,Casestudy-POP,问题在哪里？,经验性抗感染治疗的基本原则与临床实践,FightingInfectionInTheFirsthours,RapidtestsWhenavailable.Gramstain!,Startadequateantibioticcoverage(within1hour?)TillouAetal.AmSurg2004;70:841-4,Drainpurulentcollection,SamplingIncludinginvasiveprocedureswhenneeded(BAL),经验性治疗和目标治疗的统一留取标本进行微生物学检查开始经验性抗感染治疗目标治疗,选择哪种抗菌药物(whichantibiotic?)感染部位的常见病原学(possiblepathogensonsiteofinfection)选择能够覆盖病原体的抗感染药物(antibioticsrequirement)-抗菌谱/组织穿透性/耐药性/安全性/费用考虑药代动力学/药效动力学(PK/PD)考虑病人生理和病理生理状态(physiologicandpathophysiology)高龄/儿童/孕妇/哺乳(advancedage/children/pregnantwomen/breastfeeding)肾功能不全/肝功能不全/肝肾功能联合不全(renal/hepticdysfunction/combined)其它因素(otherconsiderations)杀菌和抑菌/单药和联合/静脉和口服/疗程(cidalvsstatic/monovscombination/IVvsPO/duration),经验性抗感染治疗药物选择-considerationsinchoosingantibioticforempirictherapy,培养结果前依据基本信息选择抗感染药物choosingAbxbeforecultureresult感染部位和可能病原体的关系associationofpathogenwithsiteofinfectionGram染色结果-与上述病原体是否符合？Gramstain-inaccordancewithsuspectedpathogen?某些病原体易于造成某些部位的感染Somepathogeneasilycausesomesiteofinfection,经验性抗感染治疗药物选择-considerationsinchoosingantibioticforempirictherapy,不同感染部位的常见感染性病原体Possiblepathogensonsiteofinfection,注意特殊修正因子/特别是先期抗菌药物对细菌学的影响,不同感染部位的常见感染性病原体Possiblepathogensonsiteofinfection,关注特殊病原体,肺孢子菌肺炎-免疫缺陷-相对特异临床-积极病原学检查,重症军团菌肺炎发热、少痰多肺叶、多肺段受累肺外表现,抗菌谱(coverage)组织穿透性(tissuepenetration)耐药性(resistance,specificallylocalresistance)参考代表性资料/依靠当地资料安全性(safetyprofile)药物本身/制剂/工艺/杂质费用/效益(cost/effectiveness)失败或副作用致再治疗费用更高,经验性抗感染治疗药物选择的基本原则,评价病原体耐药可能？,是否耐药菌？-了解耐药病原体流行状况参考代表性治疗/依靠当地资料-个体化用药病人来源：社区、养老院、医院高龄、基础疾病、近期抗菌药物、近期住院、侵袭性操作、晚发医院感染,S.aureus,Penicillin,1944,Penicillin-resistantS.aureus,金黄色葡萄球菌耐药的发生发展过程,Methicillin,1962,Methicillin-resistantS.aureus(MRSA),Vancomycin-resistantenterococci(VRE),Vancomycin,1990s,1997,VancomycinintermediateS.aureus(VISA),2002,Vancomycin-resistantS.aureus,CDC,MMWR2002;51(26):565-567,1960,评价病原体耐药可能？,是否耐药菌？-了解耐药病原体流行状况参考代表性治疗/依靠当地资料-个体化用药病人来源：社区、养老院、医院高龄、基础疾病、近期抗菌药物、近期住院、侵袭性操作、晚发医院感染,中国大陆ESBL的发生率,%,WangH,ChenM.DiagnosMicrobiolInfectDis,2005,51,201-208CMSS/SEANIR/CARES.,year,细菌耐药监测结果如何解读？,2002-2004:SMART-ESBLincommunityinChina,StudydoneinreferraltertiaryuniversityhospitalsinChinaPreviousantibioticexposuremayselectmoreESLB-producerSMARTChinamightoverestimateESBLprevalenceinChina,实验室药物敏感性监测的意义及缺陷,意义-反映了耐药趋势/告诫我们要慎重使用抗菌药物-在制定用药方案时考虑耐药性导致的治疗失败缺陷-实验室收集到的菌株/大型教学医院/ICU抗生素选择压力导致耐药性高估！-没有临床背景资料/不利用于个体化用药(年龄、基础疾病、社区/医院感染、前期抗菌药物使用),PrevalenceofrectalcarriageofExtended-Spectrum-lactamase-producingEscherichiaColiamongelderlypeopleinacommunitysettinginShenyang,Crosssectionalstudy-276elderly、rectalswab/Ecoliisolation/ESBLscreening、genotypingandPEGFResult:prevalenceofESBLpositiveEColi7.0%（19/270）CTX-Mtype-CTX-M-1463.2%,other:CTX-M-22andCTX-M-24，2CTX-M-57-like-GAsubstitutionin865pointleadingtoDNsubsitutionin289pointinAA(new,sequenceNo.EF426798),TianSF,ChenBY.PrevalenceofrectalcarriageofExtended-Spectrum-lactamase-producingEscherichiaColiamongelderlypeopleinacommunitysettinginShenyang,China.CanadianJournalofmicrobiology2008;54:15,评价病原体耐药可能？,是否耐药菌？-了解耐药病原体流行状况参考代表性治疗/依靠当地资料-个体化用药-合理用药的核心病人来源：社区、养老院、医院高龄、基础疾病、近期抗菌药物、近期住院、侵袭性操作、晚发医院感染,RiskfactorsforinfectionwithESBLproducers(MDR)outsidehospital,ColodneretalEJCMID200423,163.,UnivariateanalysisofriskfactorsforcarriageofESBL-producingEscherichiacoliinthecommunity(n=270),PotentialRiskfactorsNo(%)ESBLsTotalNoOddsratio(95%CI)PvalueAge(years)7416(7.4)216753(5.6)540.74(0.21-2.62)0.77GenderFemale12(7.8)153Male7(6.0)1170.81(0.31-2.13)0.81DiabetesNo11(6.3)174Yes8(8.3)961.35(0.52-3.47)0.62HospitalizationinpastoneyearNo18(6.8)264Yes1(16.7)62.73(0.30-24.66)0.34SurgeryinpastoneyearNo19(7.1)268Yes0(0)20.00.8UseofantibioticinpastthreemonthsNo12(5.3)227Yes7(16.3)433.48(1.29-9.44).018,医院感染-产ESBL细菌感染的危险因素,Prospectivestudyof455episodesofK.pneumoniaebacteremia(253nosocomial)in12hospitals30.8%为医院获得,ICU中43.5%产ESBLsESBLs危险因素-先期使用氧亚氨基-内酰胺类抗菌药物-过去14天内使用2d(OR=3.9).其它危险因素TPN,肾功衰竭,烧伤非ESBL危险:碳青霉烯、头孢吡肟、喹诺酮、氨基糖苷类Patersonetal:AnnInternMed2004;140:26-32.,VAP耐药菌感染的危险因素,135次VAPICU变量ORPMV7days6.0.009先期ABs13.57days/priorABs,Trouillet,etal.AmJRespirCritCareMed.1998;157:531,aExceptnonfermenters/non-Pseudomonasspecies.AdaptedfromCarmeliY.Predictivefactorsformultidrug-resistantorganisms.In:RoleofErtapenemintheEraofAntimicrobialResistancenewsletter.Availableat:www.invanz.co.il/secure/downloads/IVZ_Carmeli_NL_2006_W-226364-NL.pdf.Accessed7April2008;DimopoulosG,FalagasME.EurInfectDis.2007;4951;Ben-AmiR,etal.ClinInfectDis.2006;42(7):925934;Pop-VicasAE,DAgataEMC.ClinInfectDis.2005;40(12):17921798;ShahPM.ClinMicrobiolInfect.2008;14(suppl1):175180.,StratificationforRiskforMDRGram-NegativePathogens,EpidemiologyofMRSA,H-MRSAReservoires-hospitals-LTCFs5geneticbackgrouds,H-MRSAincommunity-patientswithriskfactors-contactwithpatientswithriskfactors,Truecommunity-MRSA-nohealthcare-associatedriskfactors-withPVLgenes,healthcare,community,AcquiredOnset,H-MRSA感染危险因素:年龄65岁，严重基础疾病，伤口广谱抗生素使用，住院时间延长，多次住院侵袭性操作（气管插管、切开/植入血管导管）,合理使用抗MRSA药物糖肽类/利奈唑胺,重症感染耐药菌感染！重症感染革兰阴性肠杆菌科细菌感染！PCP、军团菌、肺炎链球菌都可致重症感染,是否重症?-依据临床表现/器官功能状态-氧和、血液动力学、肾功能肠功能,PCP,LD,为什么随意使用广谱抗菌药物和联合使用？,SepsisSIRSplusDocumentedInfection,重症感染的临床判定,SevereSepsisSepsisplusorganfailure,SepticshockSeveresepsisandHypotensionDespiteadequateressucitation,SIRS-atleast2ofthefollowingsT38or90beats/minRR20breaths/minWBC12,000cells/ml,10%immatureforms,ACCP/SCCMconsensusconference1992,重症感染的临床判定,宿主因素-Hostfactor免疫缺陷高龄、疾病、治疗感染所致临床综合征中枢神经系统-CNS医院获得性肺炎-HAP呼吸机相关肺炎-VAP菌血症-Bacteremia肺炎-pneumonia原发性或不明原因-Primaryorunknown严重软组织感染-Severesofttissueinfection,病原体致病性/耐药性Highvirulenceorresistance金黄色葡萄球菌-S.aureus铜绿假单孢菌-P.aeruginosa化脓性链球菌-S.pyogenes获得感染得场所-Nosocomialinfections病人因素-Patientfactors免疫缺陷-Immunocompromized病情危重-Criticallyill病原体因素-Pathogenfactors高致病性和/或难治性微生物Virulentand/ordifficulttotreatorganisms,PCP,LD,耐药菌感染VS严重感染-PCP和LD告诉我们什么？,观点:耐药性判断对于合理选择抗菌药物更重要！包括重症感染,选择哪种抗菌药物(whichantibiotic?)感染部位的常见病原学(possiblepathogensonsiteofinfection)选择能够覆盖病原体的抗感染药物(antibioticsrequirement)-抗菌谱/组织穿透性/耐药性/安全性/费用考虑药代动力学/药效动力学(PK/PD)考虑病人生理和病理生理状态(physiologicandpathophysiology)高龄/儿童/孕妇/哺乳(advancedage/children/pregnantwomen/breastfeeding)肾功能不全/肝功能不全/肝肾功能联合不全(renal/hepticdysfunction/combined)其它因素(otherconsiderations)杀菌和抑菌/单药和联合/静脉和口服/疗程(cidalvsstatic/monovscombination/IVvsPO/duration),经验性抗感染治疗合理选择药物-considerationsinchoosingantibioticforempirictherapy,评估病原体有的而放矢！评估耐药性到位不越位！,评估严重性广谱VS窄谱？单药VS联合？,选择哪种抗菌药物(whichantibiotic?)感染部位的常见病原学(possiblepathogensonsiteofinfection)选择能够覆盖病原体的抗感染药物(antibioticsrequirement)-抗菌谱/组织穿透性/耐药性/安全性/费用考虑药代动力学/药效动力学(PK/PD)考虑病人生理和病理生理状态(physiologicandpathophysiology)高龄/儿童/孕妇/哺乳(advancedage/children/pregnantwomen/breastfeeding)肾功能不全/肝功能不全/肝肾功能联合不全(renal/hepticdysfunction/combined)其它因素(otherconsiderations)杀菌和抑菌/单药和联合/静脉和口服/疗程(cidalvsstatic/monovscombination/IVvsPO/duration),经验性抗感染治疗药物选择-considerationsinchoosingantibioticforempirictherapy,联合用药的理由,补充单一用药的抗菌谱不足！协同作用如铜绿假单孢菌菌血症减少耐药？,2007ATS/IDSAGuidelines:Inpatients,MandellLA,etal.ClinInfectDis2007,CAPInpatientTherapy,MedicalWard,IntensiveCareUnit,RecentAntibiotic,NoRecentAntibiotic,RespiratoryFQaloneORAdvancedmacrolide+-lactam,NoPseudomonasRisk,No-lactamAllergy,-lactamAllergy,-lactam+advancedmacrolideOR+respiratoryFQ,*RegimendependonnatureofrecentAbxtherapy,RespiratoryFQ+aztreonam,PseudomonasRisk,No-lactamAllergy,-lactamAllergy,Anti-pseudomonal,antipneumococcalb-lactam/penem+Cipro/Levo750ORAnti-pseudomonal,antipneumococcalb-lactam/penem+aminoglycoside+Azithromycin,Aztreonam+respiratoryFQ+aminoglycoside,Advancedmacrolide+-lactamORrespiratoryFQ*,抗菌药物联合药敏,药物联合能够提高铜绿假单胞菌对药物的敏感率(平均增加3.49.2),CID2005，40(Suppl2)：S89一S98,NovelAntibioticCombinationsagainstInfectionswithAlmostCompletel