下呼吸道感染的诊治进展.ppt

下呼吸道感染的诊治进展,北京大学第一医院呼吸内科王广发,PathogensofLRTInfection,细菌需氧G+球菌需氧G-杆菌厌氧菌病毒真菌支原体立克次体衣原体原虫Pneumocystiscarinii,TenLeadingCausesofDeath,UnitedStates,2019,1Heartdisease726,9742Malignantneoplasms539,5773Cerebrovascular159,7914Bronchitis,Emphysema,Asthma109,0295Unintentionalinjuryandadverseeffects95,6446Pneumoniaincreaseinmortality,CommunityAcquiredPneumoniaMortality,Changesofhostsinrecentyears,人口老龄化低免疫人群的不断增加肾上腺皮质激素、免疫抑制剂降低了宿主免疫功能有创医疗技术广泛应用增加了细菌入侵的途径某些疾病的日益增多糖尿病、AIDS,ChangesofPathogensinBacterialPneumonia,病原的多样化革兰氏阴性杆菌性肺炎日益多见原先认为不致病的微生物发现具有致病性新病原的出现-军团菌细菌耐药成为日益普遍的现象(MRSA,ESBL),细菌耐药,甲氧西林耐药的金黄色葡萄球菌（MRSA）甲氧西林耐药的表皮葡萄球菌（MRSE）万古霉素中度敏感的金葡菌（VISA）万古霉素耐药的肠球菌（VRE）青霉素耐药的肺炎链球菌（PRSP）超广谱-内酰胺酶（ESBLs）AmpC碳青霉烯酶,多重耐药菌的分离率2019年NNIS调查资料与1994年资料的比较,万古霉素耐药肠球菌：从15%到26%甲氧西林耐药金黄色葡萄球菌：从38%到55%克雷伯菌对三代头孢菌素的耐药率：从7%到9%铜绿假单胞菌对亚胺培南的耐药率：从12%到19%铜绿假单胞菌对喹诺酮类耐药率：从12%到23%肠杆菌属细菌对三代头孢菌素的耐药率：从34%到37%,获得性细菌耐药,直接从另一株细菌获得耐药质粒，质粒上携带有耐药基因通过病毒转染从其他细菌获得耐药基因染色体突变从死细菌中获得DNA,万古霉素耐药的肠球菌,万古霉素的用量,万古霉素的用量Kg,耐药率%,产ESBL菌株分离率的地区差异(2019-2000),0,5,10,15,20,25,30,35,40,45,澳大利亚,日本,台湾,中国,香港,菲律宾,新加坡,大肠杆菌,肺炎克雷伯杆菌,南非,SENTRY,ESBL阳性百分比,产ESBL的地区差异(2019-2000),0,10,20,30,40,50,60,阴沟肠杆菌,粘质沙雷杆菌,澳大利亚,日本,台湾,中国,香港,菲律宾,新加坡,南非,SENTRY,ESBL阳性百分比,在中国十家医院用E-test法评估六种广谱b-内酰胺药对分离细菌株的体外活性,细菌数主要细菌大肠埃希菌107肠杆菌属109阴沟肠杆菌克雷伯菌属120肺炎克雷伯菌沙雷菌属88黏质沙雷菌枸橼酸菌属100弗劳地枸橼酸菌吲哚阳性变形杆菌属76普通变形，摩根绿脓假单胞菌100不动杆菌属99鲍曼不动杆菌金黄色葡萄球菌(Oxs)101凝固酶阴性葡萄球菌37表皮葡萄球菌总计937,北京协和医院陈民钧教授等,937株细菌对六种药物的总体敏感性排序,药物总体敏感率亚胺培南96.5马斯平(头孢吡肟)89.1头孢哌酮/舒巴坦85.8头孢他啶75.5头孢曲松66.9哌拉西林57.1,北京协和医院陈民钧教授等,北京协和医院陈民钧教授等,药名耐药中介MIC50MIC90头孢吡肟17.011.0364头孢他啶18.00.01.564头孢曲松50.047.032512亚胺培南21.07.0332头孢哌酮/舒巴坦17.011.0464哌拉西林23.00.08512,六种抗微生物药对100株铜绿假单胞菌的活性,细菌的进化与耐药,inactivation,impermeability,efflux,A,B,By-pass,Alteredtarget,细菌对抗生素的耐药机制,细胞内药物浓度降低外排增多四环素（tetA）氟喹诺酮类（norA）外膜通透性降低内酰胺类（OmpF;OprD)氟喹诺酮类（OmpF）细胞膜运输能力降低氨基糖甙类（低能量）药物失活内酰胺类（内酰胺酶）氨基糖甙类（修饰酶）磷霉素（谷胱甘肽结合）氯霉素（灭活酶）靶位修饰氟喹诺酮类（旋转酶修饰）利福平（DNA聚合酶结合）内酰胺类（PBP改变）大环内酯类（rRNA甲基化）靶位旁路糖肽类（vanA、vanB）甲氧苄定（胸腺嘧啶缺陷株）,内酰胺酶的分类（1）,1973年Richmond132:621-30,(P=0.022),(P65years(institutionalized)68-114per1000/yearHospitalizationGPsoffice17-35%MortalityOverall1-3%Hospitalizedpatients6-24%RequiringICU22-57%,Niederman,MS,etal(1986).CritCareClin.2(3):471-95.Marrie,TJ(1994).ClinInfectDis18(4):501-13;MarrieTJ9(2019).InfectDisClinNorthAm2(3):723-40,0,5,10,15,20,25,30,S.pneumoniaeC.pneumoniae*ViralM.pneumoniaeLegionellasp.H.influenzaeG-negenterobacteriaCpsittaciCoxiellaburnetiiStaphaureusM.catarrhalisOther,Datafrom26prospectivestudies(5961adults)from10countries.*DatafromsixstudiesWoodhead,MA(2019),CommunityAcquiredPneumonia:BacteriologyinHospitalizedPts,CommonpathogensassociatedwithCAP,*ExcludingPneumocystis.,FileTM,TanJS.CurrOpinPulmMed.2019;3:89-97.,StreptococcusPneumoniae,为G（+）球菌，呼吸道寄生有多糖体荚膜（86种亚型）80%为1-8型多见,以1-3型最多,3型毒力最强不产生具有组织破坏作用的毒素不形成空洞,右上叶后段肺炎,MortalityofPneumococcolPneumoniainPre-antibioticandantibioticera,S.pneumoniae:prevalenceofpenicillin-intermediateand-resistantstrains,SWUSA12%28%,NEUSA10%20%,Brazil29%1%,Mexico27%25%,SouthAfrica55%25%,SaudiArabia44%18%,HongKong6%74%,pen-I(penicillinMIC0.121g/ml),pen-R(penicillinMIC2g/ml),TheAlexanderProject2019,SmithKlineBeechamdataonfile,UK6%8%,Belgium6%13%,Spain10%37%,France17%45%,Germany1%4%,Poland5%17%,Switzerland3%11%,Italy7%6%,Portugal13%10%,CzechRepublic1%2%,SlovakRepublic15%15%,S.pneumoniae:prevalenceofpenicillin-intermediateand-resistantstrains,pen-I(penicillinMIC0.121g/ml),pen-R(penicillinMIC2g/ml),TheAlexanderProject2019,SmithKlineBeechamdataonfile,PenicillinNon-SusceptibleStreptococcuspneumoniaeintheUS,%ofisolatesresistanttopenicillin*,Year,*MIC0.1to1.0g/mL(intermediate)and2.0g/mL(highlevel)penicillinresistance,AppelbaumPC.ClinInfectDis.1992;15:77-83.BreimanRF,etal.JAMA.1994;271:1831-1835.DoernGV,etal.AntimicrobAgentsChemother.2019;40:1208-1213.ThornsberryC,etal.DiagnMicrobiolInfectDis.2019;29:249-257.ThornsberryC,etal.JAntimicrobChemother.2019;44:749-759.ThornsberryC,etal.In:Abstractsofthe39thICAAC,2019,abstract820.Selman,L.In:Abstractsofthe40thICAAC,2000,abstract1789.Selman,L.In:Abstractsofthe40thICAAC,2000,abstract1800.Selman,L.In:Abstractsofthe38thIDSA,2000,abstract201933.DataonfileatOrtho-McNeilPham.,StreptococcuspneumoniaestrainsrecoveredfromLRTwithintermediateandhighlevelsofresistance,DoernGV,EmergingInfectiousDiseases5(6),2019.CDC,多药耐药的肺炎链球菌常见耐药类型,penicillinandTMP/SMX(6.9%)penicillin,macrolide,andchloramphenicol(4.6%)penicillin,macrolide,tetracycline,andTMP/SMX(3.6%)penicillin,macrolide,tetracycline,TMP/SMX,andchloramphenicol(5.4%),DoernGV,EmergingInfectiousDiseases5(6),2019.CDC,Theprevalenceofmacrolide-resistantS.pneumoniae:19922019,Prevalenceofmacrolideresistance(erythroMIC1g/ml;%),Year,Felminghametal.JChemother2019;11:521TheAlexanderProject2019/2019.DataavailableonrequestfromSmithKlineBeechamTheAlexanderProject2019(alexander-network),喹诺酮耐药的肺炎链球菌,喹诺酮耐药逐渐增加(ciproMIC4mg/L)0%in1993,3.7%in2019,成人耐药的增多与氟喹诺酮类使用量相关处方量每年0.8%增至5.5%(1988-2019)喹诺酮耐药存在差异:ciprolevofloxacinsparfloxacingrepafloxacintrovafloxacingatifloxacinmoxifloxacingemifloxacin42.9%对青霉素耐药的肺炎链球菌对环丙沙星也耐药,中国5个城市肺炎链球菌对6种抗生素的敏感率（MIC90）,PenicillinsAlterationinpenicillin-bindingproteins(PBPs)CephalosporinsAlterationsinPBP2x,PBP1aMacrolidesEffluxpumpalteration(mefE)Ribosomalmethylase(ermAM)SpontaneousmutationsFluoroquinolonesAlterationsinDNAgyrase(gyrAandgyrB)AlterationintopoisomeraseIV(parCandparE),MechanismsofAntibioticResistanceinSpneumoniae,肺炎链球菌肺炎的治疗,青霉素G为首选药物青霉素过敏者红霉素、洁霉素、一代头孢菌素对青霉素中中介（MIC0.1-2ug/ml）加大剂量，每日600万单位。对青霉素高度耐药（MIC2ug/ml）头孢曲松/头孢噻肟、新喹诺酮类、万古霉素，亚胺培南、万古霉素、壁霉素、利福平,G-，含荚膜，营养条件要求高，在巧克力平板生长，根据荚膜分为A、B、C、D、E、F6个血清型，B型致病力最强也最常见感染率20%+发病机理：内毒素-致病过程有重要作用荚膜其有抗吞噬作用菌毛粘附定植IgA蛋白酶支气管肺炎，叶或段的浸润影、空洞、脓胸治疗：AM/CL,TMP/SMX,oralceph2/3,Cefotaxime,Ceftriaxone、IMP,MER,Ciprofloxacin,流感嗜血杆菌(Haemophilusinfluenzae),H.influenzaeResistanceTrustIV2000,Abstractsofthe40thICAAC,2000,abstract1800.Selman,L.In:Abstractsofthe38thIDSA,2000,abstract201933DataonfileOrtho-McNeilPharmaceutical,H.influenzaeIncreasingBetaLactamaseProduction,2019-2019年亚欧流感嗜血杆菌药敏检测,AtypicalPneumonia,Thetermatypicalpneumoniaiscommonlyusedtodescribeaformofpneumoniainwhichsystemicsymptomsareusuallymorepronouncedthanrespiratorysymptoms.,AtypicalRespiratoryPathogens,MycoplasmapneumoniaeLegionellaspeciesChlamydiapneumoniaeOthers:respiratoryviruses,(influenzaAandB,parainfluenzaviruses,andrespiratorysyncytialvirus),Chlamydiapsittaci(鹦鹉热衣原体),andCoxiellaburnetii(伯氏柯克斯体),Mycoplasmapneumoniae,为能在无细胞培养基上生长的最小微生物，无细胞壁，结构简单，营养要求高，生长需要胆固醇对四环素和大环内酯类敏感肺炎支原体能产生过氧化氢及超氧化物溶血素与呼吸道上皮粘附获取外源营养物质可以进入细胞内生长造成上皮细胞及其纤毛的损伤容易与其它病原同时感染宿主,美国每年2百万例肺炎支原体感染其中约5%导致肺炎，相当于2例/1000人口/年约20%肺炎支原体的感染没有症状，多数呼吸道症状轻微肺炎支原体可以引起爆发流行（areportbytheCentersforDiseaseControlandPreventionofanoutbreakinColorado）,Mycoplasmapneumoniae,肺炎支原体(Mycoplasmapneumoniae),年轻人及儿童多见，秋季发病多，潜伏期2-3周体温在37.8-39，可伴有头痛、肌痛病理以间质性炎症为主咳痰：少量粘液毯或干咳胸片多表现为斑片状，有时呈网状、云雾状、粟粒状或间质浸润WBC正常或轻度升高冷凝集试验补体依赖性抗体,中耳炎,溶血,神经系统的损害-周围神经炎、脑膜炎、脊髓炎、神经根炎Erythromycin,Tetracycline疗程：7-10d,支原体肺炎,ColdAgglutinin,BloodarecollectedinWassermantubecontainingNaEDTADefinitefloccularagglutinationseenwithunaidedeye(upperpanel)Disappearsuponwarmingto37(bottompanel),LegionellaSpecies,革兰氏阴性杆菌、需氧、不产生芽孢、无荚膜军团菌超过40种嗜肺军团杆菌（Legionellapneumophila）为主要多数军团菌肺炎（军团病）的病原L.pneumophila:15个血清型，1型最常见L.pneumophilaserogroup1可通过尿液检测抗原,Dieterlestainofsputum,Legionella,被吞噬后，在呼吸道巨噬细胞胞体内繁殖释放细胞毒素杀死吞噬细胞释放到细胞外在潮湿环境中繁殖，传播水源、空调器、雾化器污染中央空调系统可引发爆发流行危险因素：高龄、酗酒、吸烟、慢性疾病、器官移植死亡率：免疫功能正常者5-25%,嗜肺军团杆菌(Legionellapneumophila),夏秋发病多，潜伏期2-10天，可伴有消化、神经系统症状、相对缓脉，临床分型流感样型（Pontiacfever）、肺炎型病理：融合的支气管肺炎伴小脓腔形成干咳或血丝痰，WBC1-2万培养方法：BCYE培养基或PCYE培养基抗体：间接荧光抗体大于等于1：128或恢复期血清大于等于1：256，两次抗体滴度增加4倍以上检测痰液、组织和尿中的抗原有重要的诊断价值BAL等的Gimsa染色可以发现细菌并发症：Empyema,Cavitation,Endocarditis,Pericarditis,myositis,ARF红霉素每日2-4g，疗程：3wtrovafloxacin,levofloxacin,moxifloxacinandrifampicin,X线特点：1、病变双侧、多发；2、进展迅速；3、多样性：大片、斑片、斑点结节状、条索、纱网状4、空洞出现快而闭合慢；5、炎症吸收慢,嗜肺军团杆菌(Legionellapneumophila),军团菌肺炎,入院日,入院第3日,入院第5日,Chlamydiapneumoniae,1986年首次发现为呼吸道病原预先存在于细胞内Anobligate,intracellularbacterium.双相生长周期在细胞内以网状体形式繁殖释放抗原到上皮表面引起炎症反应并导致纤毛运动障碍C.pneumoniae缺乏细胞壁为成人及儿童肺炎的常见病原超过50%的成人曾有过感染,Chlamydiapneumoniae,并非终生免疫潜伏期：2-4周症状通常轻微，也可病程迁延发热及咳嗽为常见的症状，胸部体检可有湿性罗音C.pneumoniaepneumonia:双相病程咽炎痊愈1-3周后肺炎病死率:住院患者9.8%Chlamydialcomplementfixationantibodytesting：IgMorIgGelevationsthattakeaminimumof2-3weekstoriseafteracuteinfection.,PneumoniaofMixedEtiology,Atypicalpathogensfrequentlyappearasmixedinfections1/32/3arelikelycoinfections,withS.pneumoniaethepresenceofatleastoneotherpathogenin:33-64%ofM.pneumoniaeinfections48-74%ofC.pneumoniaeinfections54-63%ofLegionellainfections,TreatmentofAtypicalpathogens,SinceC.pneumoniaeandM.pneumoniaelackapeptidoglycanwall,-lactamantimicrobialagentsareineffectiveagainstthem.C.pneumoniaeandLegionellaspeciescanresideinorreplicatewithincells,necessitatingtheuseofantimicrobialsthatareactiveintracellularly.Suitabletreatmentoptionsaremacrolides,fluoroquinolones,ormembersofthenewketolideclassofantimicrobials.TetracyclinesmaybeusedtotreatC.pneumoniaeorM.pneumoniae,TreatmentofCAP,Empirictherapyandpathogen-directedtherapyInitiationofpromptantimicrobialtherapyiscrucialtominimizemorbidity,mortality,andhealthcarecosts.Antibioticadministrationwithin8hoursofhospitalarrivalhasbeenassociatedwithalower30-daymortality.Delayingantibioticadministrationmayincreasecomplicationsorresultinprolongedhospitalizations,Community-AcquiredPneumonia(CAP)Year2019AntibioticSelectionandManagementUpdate,Evaluation,RiskStratification,andCurrentAntimicrobialTreatmentGuidelinesforHospital-BasedManagementofCAP:Outcome-EffectiveStrategiesBasedonNewNCCLSBreakpointsandRecentClinicalStudiesTheASCAPPanel*ConsensusReport,2019,AntibioticSelectionforCommunity-AcquiredPnuemonia,FactorsAssociatedwithanIncreasedRiskforMortalityofCAP,Increasingage(65)AlcoholismChroniclungdiseaseImmunodeficiencySpecificlaboratoryabnormalities(azotemiaandhypoxemia),HighRiskforMortality(Radiograph),BilateraleffusionsModerate-sizepleuraleffusionsMulti-lobarinvolvementBilateralinfiltrates,PointScoringSystemforPredictionRule(PneumoniaSeverityIndex,PSI),*Oxygensaturation12,000/ul脓性分泌物,敏感性69%特异性75%尸检研究,TorresA,etal.AmJRespirCritCareMed1994;149:324-331,临床肺部感染评分(CPIS),变量：体温、WBC计数、脓性分泌物、氧饱和度、胸片浸润的范围根据对5个变量的评价，每个变量的得分为0-2,临床肺部感染评分(CPIS),CPIS6，可诊断为肺炎在获得诊断准备抗生素治疗前2天，CPIS从基线值的6一旦开始抗生素治疗，CPIS在以后的9天内渐低，一般在第5天降低到6以下CPIS如果不降低，临床病情恶化往往是由铜绿假单胞菌感染