感染病患者多重耐藥菌感染風(fēng)險(xiǎn)的分層

感染病患者多重耐藥菌感染風(fēng)險(xiǎn)的分層第1頁/共50頁抗感染藥物發(fā)展簡史1929AlexanderFleming發(fā)現(xiàn)青霉素

HowardFlorey和ErnstChain分離獲得青霉素，用于動(dòng)物試驗(yàn)青霉素首次用于救治戰(zhàn)傷患者，拯救了許多人的生命1950’s大量抗生素用于臨床AposterfromWorldWarII,dramaticallyshowingthevirtuesofthenewmiracledrug,andrepresentingthehighlevelofmotivationinthecountrytoaidthehealthofthesoldiersatwar.第2頁/共50頁DiscoveryofAntibacterialAgentsCycloserineErythromycinEthionamideIsoniazidMetronidazolePyrazinamideRifamycinTrimethoprimVancomycinVirginiamycinImipenem19301940

195019601970198019902000PenicillinProntosilCephalosporinCEthambutolFusidicacidMupirocinNalidixicacidOxazolidinonesCecropinFluoroquinolonesNeweraminoglycosidesSemi-syntheticpenicillins&cephalosporinsNewercarbapenemsTrinemsSyntheticapproachesEmpiric

screeningNewermacrolides&ketolidesRifampicinRifapentineSemi-syntheticglycopeptidesSemi-syntheticstreptograminsNeomycinPolymixinStreptomycinThiacetazoneChlortetracyclineGlycylcyclinesMinocyclineChloramphenicol第3頁/共50頁臨床關(guān)注的耐藥問題

ResistancesofClinicalConcerns革蘭陽性細(xì)菌金匍菌–

MRSA,VISA,VRSAVRE(地理上差別)肺炎鏈球菌

–青霉素和大環(huán)內(nèi)酯耐藥

革蘭陰性細(xì)菌腸桿菌科ESBLs-喹諾酮,頭孢菌素,青霉素類,氨基糖苷類碳青霉烯酶（KPC,NDM-1?）-碳青酶烯耐藥在中國出現(xiàn)和蔓延非發(fā)酵菌(假單孢菌/不動(dòng)桿菌)喹諾酮,頭孢菌素,青霉素類,氨基糖苷,碳青霉烯類第4頁/共50頁InfectionControlAntibioticstewardshipVREMRSAABESBLK.pneumoniaeAntibioticControlandInfectionControl:TheTwoSidesoftheResistance“Coin”RekhaMurthy.ImplementationofStrategiestoControlAntimicrobialResistanceChest2001;119;405-411ControlofAntibioticResistance第5頁/共50頁NosimplisticpolicyHomogenousprotocolMixing√×第6頁/共50頁經(jīng)驗(yàn)性抗感染治療的基本原則耐藥背景下的個(gè)體化治療理性回歸/責(zé)任所在第7頁/共50頁經(jīng)驗(yàn)性抗感染治療的基本原則

-耐藥背景下的個(gè)體化治療合理使用碳青霉烯類藥物

-指南VS

臨床實(shí)踐內(nèi)容安排第8頁/共50頁慢性咳嗽和黃痰-原因哮喘后鼻腔鼻漏病毒感染后氣道高反應(yīng)性胃酸返流吸煙相關(guān)的慢性支氣管炎支氣管擴(kuò)張癥彌漫性泛細(xì)支氣管炎肺泡蛋白沉積癥

急性發(fā)熱

-WBC不高/淋巴增高（無感染灶）－病毒！

-WBC增高/中性粒增高/核左移－可能細(xì)菌?。课?病原體？－原發(fā)性菌血癥？慢性發(fā)熱

－IE、布病、慢性感染灶？結(jié)核??？－非感染性發(fā)熱藥物熱、風(fēng)濕病、惡性腫瘤正確診斷是正確治療的前提發(fā)熱的診斷與鑒別診斷第9頁/共50頁27-year-oldmanwithacutelymphocyticleukemia.51-year-oldmanwithchronicmyelogenousleukemia.22-year-oldwomanwithadultT-cellleukemia.67-year-oldwomanwithadultT-cellleukemia.61-year-oldmanwithinterstitialfibrosis;patientwasreceivingchlorambucilforchroniclymphocyticleukemia.COP第10頁/共50頁RapidtestsWhenavailable.Gramstain!!!Startadequateantibioticcoverage(within1hour?)TillouAetal.AmSurg2004;70:841-4DrainpurulentcollectionSamplingIncludinginvasiveprocedureswhenneeded(BAL…)

合格標(biāo)本進(jìn)行微生物學(xué)檢查開始經(jīng)驗(yàn)性抗感染治療

目標(biāo)治療經(jīng)驗(yàn)性治療和目標(biāo)治療的統(tǒng)一第11頁/共50頁選擇哪種抗菌藥物

感染部位的常見病原學(xué)選擇能夠覆蓋病原體的抗感染藥物

-抗菌譜/組織穿透性/耐藥性/安全性/費(fèi)用考慮藥代動(dòng)力學(xué)/藥效動(dòng)力學(xué)考慮病人生理和病理生理狀態(tài)

高齡/兒童/孕婦/哺乳腎功不全/肝功不全/肝腎功能聯(lián)合不全其它因素

殺菌和抑菌/單藥和聯(lián)合/靜脈和口服/療程

經(jīng)驗(yàn)性抗感染治療－合理選擇藥物

-considerationsinchoosingantibioticforempirictherapy

評估病原體

-有的而放矢！評估耐藥性

-到位不越位！病情嚴(yán)重性評估+第12頁/共50頁-個(gè)體化評估-特殊修正因子

先期抗菌藥物對細(xì)菌學(xué)及其耐藥性影響

不同部位感染-病原體的流行病學(xué)從病原學(xué)認(rèn)識(shí)感染性疾病MouthPeptococcusPeptostreptococcusActinomycesSkin/SoftTissueS.aureusS.pyogenesS.epidermidisPasteurellaBoneandJointS.aureusS.epidermidisStreptococciN.gonorrhoeaeGram-negativerodsAbdomenE.coli,ProteusKlebsiellaEnterococcusBacteroidessp.UrinaryTractE.coli,ProteusKlebsiellaEnterococcusStaphsaprophyticusUpperRespiratoryS.pneumoniaeH.influenzaeM.catarrhalisS.pyogenesLowerRespiratoryCommunityS.pneumoniaeH.influenzaeK.pneumoniaeLegionellapneumophilaMycoplasma,ChlamydiaLowerRespiratoryHospitalK.pneumoniaeP.aeruginosaEnterobactersp.Serratiasp.S.aureusMeningitisS.pneumoniaeN.meningitidisH.influenzaGroupBStrepE.coliListeria第13頁/共50頁抗菌譜(coverage)組織穿透性(tissuepenetration)耐藥性(resistance,specificallylocalresistance)－參考代表性資料/依靠當(dāng)?shù)刭Y料安全性(safetyprofile)－藥物本身/制劑/工藝/雜質(zhì)費(fèi)用/效益(cost/effectiveness)－失敗或副作用致再治療費(fèi)用更高經(jīng)驗(yàn)性抗感染治療－藥物選擇的基本原則第14頁/共50頁評價(jià)病原體耐藥可能？是否耐藥菌？

-了解耐藥病原體流行狀況

參考代表性治療/依靠當(dāng)?shù)刭Y料

-個(gè)體化用藥-合理用藥的精髓

病人來源：社區(qū)、養(yǎng)老院、醫(yī)院高齡、基礎(chǔ)疾病、近期抗菌藥物、近期住院、侵襲性操作、晚發(fā)醫(yī)院感染

第15頁/共50頁S.aureusPenicillin[1944]Penicillin-resistantS.aureus金黃色葡萄球菌耐藥的發(fā)生發(fā)展過程Methicillin[1962]Methicillin-resistantS.aureus(MRSA)Vancomycin-resistantenterococci(VRE)Vancomycin[1990s][1997]VancomycinintermediateS.aureus(VISA)[2002]Vancomycin-resistantS.aureusCDC,MMWR2002;51(26):565-567[1960]第16頁/共50頁評價(jià)病原體耐藥可能？是否耐藥菌？

-了解耐藥病原體流行狀況

參考代表性治療/依靠當(dāng)?shù)刭Y料

-個(gè)體化用藥-合理用藥的精髓

病人來源：社區(qū)、養(yǎng)老院、醫(yī)院高齡、基礎(chǔ)疾病、近期抗菌藥物、近期住院、侵襲性操作、晚發(fā)醫(yī)院感染

第17頁/共50頁中國大陸ESBL的發(fā)生率%year細(xì)菌耐藥監(jiān)測結(jié)果如何解讀？

WangH,ChenM.DiagnosMicrobiolInfectDis,2005,51,201-208CMSS/SEANIR/CARES.第18頁/共50頁實(shí)驗(yàn)室藥物敏感性監(jiān)測的解讀意義

-反映了耐藥趨勢/告誡要謹(jǐn)慎使用抗菌藥物

-影響選擇藥物/考慮耐藥性對療效的影響不足

-實(shí)驗(yàn)室收集菌株/大型教學(xué)醫(yī)院/ICU

抗生素選擇壓力導(dǎo)致耐藥性高估！

-沒有臨床背景資料/不能用于指導(dǎo)個(gè)體化用藥

（年齡、基礎(chǔ)疾病、社區(qū)/醫(yī)院感染、前期抗菌藥物使用情況）

第19頁/共50頁NoRiskFactors

forMDROsRiskFactors

forMDREnterobacteriaceaeaRiskFactorsfor

MDRPseudomonasHealthcare

contact

NoYes!(eg,recenthospitaladmission,nursinghome,dialysis)withoutinvasiveprocedureYes,Longhospitalizationand/orinfectionfollowinginvasiveprocedures(>5days)RecentAbx

NoYes!(≥14daysinpast90days)Yes!

(≥14daysinpast90days)對Patient

characteristics

Youngfewcomorbidities≥65yrscomorbiditiessuchasTPNorrenalinsufficiencyco-morbiditiessuchasCF,structurallungdisease,advancedAIDS,neutropenia,orothersevereimmunodeficiencyDrugsofchoiceAmoxi/calvAmpicillin/sulb2ndor3rdGFQsPip/tazoCefaperazone/sulbactamertapenemCeftazidine

cefepimePip/tazoCefperazone/sulbactamImipenem

meropenemaExceptnonfermenters/non-Pseudomonasspecies.AdaptedfromCarmeliY.Predictivefactorsformultidrug-resistantorganisms.In:RoleofErtapenemintheEraofAntimicrobialResistance[newsletter].Availableat:www.invanz.co.il/secure/downloads/IVZ_Carmeli_NL_2006_W-226364-NL.pdf.Accessed7April2008;DimopoulosG,FalagasME.EurInfect

Dis.2007;49–51;Ben-AmiR,etal.ClinInfectDis.2006;42(7):925–934;Pop-VicasAE,D’AgataEMC.ClinInfectDis.2005;40(12):1792–1798;ShahPM.ClinMicrobiolInfect.2008;14(suppl1):175–180.StratificationforRiskforMDRGram-NegativePathogens第20頁/共50頁重癥感染≠耐藥菌感染！重癥感染≠革蘭陰性腸桿菌科細(xì)菌感染！肺炎鏈球菌、化膿性鏈球菌、軍團(tuán)菌、肺孢子菌等均可致重癥感染PCPLD對于選擇抗菌藥物-耐藥性

VS

嚴(yán)重性哪個(gè)更重要？第21頁/共50頁P(yáng)CPLD耐藥菌感染

VS

嚴(yán)重感染-PCP和LD告訴我們什么？觀點(diǎn):

-耐藥性判斷對于合理選擇抗菌藥物更重要！

[包括重癥感染]-即使重癥感染,抗感染治療方案仍需根據(jù)病原體及其耐藥性評估來制定第22頁/共50頁經(jīng)驗(yàn)性抗感染治療的基本原則

-耐藥背景下的個(gè)體化治療合理使用碳青霉烯類藥物

-指南VS

臨床實(shí)踐內(nèi)容安排第23頁/共50頁CAP－……碳青霉烯HAP－……碳青霉烯CNS感染－……碳青霉烯中性粒細(xì)胞減少性發(fā)熱

－……碳青霉烯外科感染－……碳青霉烯抗感染指南中碳青霉烯的地位

所有抗感染指南都推薦碳青霉烯作為治療選擇之一！如何恰到好處地個(gè)體化應(yīng)用碳青霉烯？第24頁/共50頁Effectiveness-roleofcarbapenem？-Why？When？Which？Empirictherapycoverscloseto100%ofsuspectedpathogensDirectedtherapyClinicalsuccessSafetyprofileAdverseeventsCost/effectivenessMinimizingresistanceSelfresistance/ResistancetootheragentsConsiderations

inChoosingAntibioticforOptimalTherapy第25頁/共50頁ChangeofparadigmWearelivinginaneraofhighresistanceG-vesresistantto

-penicillins/cephalosporins-quinolones-aminoglycosides-TMP/SMX

ThinkMDRratherthanresistance第26頁/共50頁IncreasingproportionofMDRGNRD’AgataE.ICHE2004%MDR第27頁/共50頁SppESBLciprogentamicinTMP/sulPip/tzKlebsiellaN=90+49%16%30%40%KlebsiellaN=158-97%97%91%99%E.coliN=70+16%14%11%71%E.coliN=535-93%96%71%99%SusceptibilitiesESBLvsnon-ESBLSchwaberM.AAC2005ESBLcontributemosttoMDRpathogens第28頁/共50頁FailureESBLvsnon-ESBL0%20%40%60%80%100%Schwaber,2005*Kim,2002*PattersonDL,2001ArrifinH,2000*non-ESBLESBLFailure*failure=mortality第29頁/共50頁Susceptibilitiesof1030ESBLproducingE.coli&Klebsiellaspp.ColodnerR.ICAAC2005第30頁/共50頁Mortalityamong60patientswithESBLproducingKlebsiellaBacteremiaPatersonDL.AnnInternMed第31頁/共50頁Whetherwelikeitornot…AccumulationofESBLs&quinoloneresistancewilldrivecarbapenemuse…Whenandwhich?第32頁/共50頁選擇哪種抗菌藥物(whichantibiotic?)

感染部位的常見病原學(xué)(possiblepathogensonsiteofinfection)選擇能夠覆蓋病原體的抗感染藥物(antibioticsrequirement)

-抗菌譜/組織穿透性/耐藥性/安全性/費(fèi)用考慮藥代動(dòng)力學(xué)/藥效動(dòng)力學(xué)(PK/PD)考慮病人生理和病理生理狀態(tài)(physiologicandpathophysiology)

高齡/兒童/孕婦/哺乳(advancedage/children/pregnantwomen/breastfeeding)腎功能不全/肝功能不全/肝腎功能聯(lián)合不全(renal/hepticdysfunction/combined)其它因素(otherconsiderations)

殺菌和抑菌/單藥和聯(lián)合/靜脈和口服/療程

(cidalvsstatic/monovscombination/IVvsPO/duration)經(jīng)驗(yàn)性抗感染治療－怎樣選擇碳青霉烯？評估病原體－有的而放矢！評估耐藥性－到位不越位！MDREnterobacteriaceae（ESBL-producer)？MDRP.aeruginosa/A.acinetobacter？第33頁/共50頁入院即可能有MDROs感染的高風(fēng)險(xiǎn)人群老年人誤吸(對于肺炎而言)基礎(chǔ)內(nèi)科疾病-結(jié)構(gòu)性肺病/粒缺/嚴(yán)重免疫缺陷除外-銅綠風(fēng)險(xiǎn)過期三個(gè)月使用任何靜脈抗生素

-特別是FQ和二、三代頭孢菌素過期一年內(nèi)多次(>2次)住院先期手術(shù)住LCTF長期血液透析實(shí)體臟器移植第34頁/共50頁RiskfactorsforinfectionwithESBLproducersoutsidehospitalFactorOddsratioRx3genceph15.8Rx2genceph10.1Hospitalinlast3months8.95Rx

quinolone4.1Rx

penicillins4.0AntibioticRxinlast3months3.23Age>60years2.65Diabetes2.57ColodneretalEJCMID200423,163.第35頁/共50頁WhatpatientscanbenefitmostfromertapenemtreatmentGnegatives-IncludingESBL+CAPinadvancedageCAPwithaspirationCAPSevereHowtopredict?-bacteria-resistance第36頁/共50頁醫(yī)院獲得性肺炎細(xì)菌學(xué)演變-抗生素選擇性壓力的體現(xiàn)早期(Early)中期(Middle)

晚期(Late)135101520肺鏈流感嗜血桿菌MSSAMRSA腸桿菌科細(xì)菌(抗生素敏感)

腸桿菌科細(xì)菌(抗生素不敏感)肺克,大腸肺克,大腸銅綠假單胞菌MDRXDRPDR不動(dòng)桿菌MDRXDRPDR嗜麥芽窄食單胞菌抗生素選擇性壓力

二代頭孢菌素三代頭孢菌素/酶抑制劑復(fù)合制劑碳青霉烯+抗MRSA135101520第37頁/共50頁選擇哪種抗菌藥物(whichantibiotic?)

感染部位的常見病原學(xué)(possiblepathogensonsiteofinfection)選擇能夠覆蓋病原體的抗感染藥物(antibioticsrequirement)

-抗菌譜/組織穿透性/耐藥性/安全性/費(fèi)用考慮藥代動(dòng)力學(xué)/藥效動(dòng)力學(xué)(PK/PD)考慮病人生理和病理生理狀態(tài)(physiologicandpathophysiology)

高齡/兒童/孕婦/哺乳(advancedage/children/pregnantwomen/breastfeeding)腎功能不全/肝功能不全/肝腎功能聯(lián)合不全(renal/hepticdysfunction/combined)其它因素(otherconsiderations)

殺菌和抑菌/單藥和聯(lián)合/靜脈和口服/療程

(cidalvsstatic/monovscombination/IVvsPO/duration)經(jīng)驗(yàn)性抗感染治療－怎樣選擇碳青霉烯？評估病原體－有的而放矢！評估耐藥性－到位不越位！MDREnterobacteriaceae（ESBL-producer)？MDRP.aeruginosa/A.acinetobacter？第38頁/共50頁IDSAGuidelinesonEmpiric

TherapyforCAPRiskfactorsforPseudomonas

-severestructurallungdisease(eg,bronchiectasis)

-recentantibiotictherapyorstayinhospital(especiallyintheICU).AdaptedfromMandellLA,etal.ClinInfectDis.2003;37:1405–1433.第39頁/共50頁VAP－MDR細(xì)菌感染的危險(xiǎn)因素

135次VAP－ICU變量

OR

PMV>7days6.0

.009先期ABs

13.5

<.001廣譜ABs

4.1

.025MV>7days

/

priorABsTrouillet,etal.AmJRespirCritCareMed.1998;157:531第40頁/共50頁Effectiveness-

roleofcarbapenem？-Why？When？Which？Empirictherapycoverscloseto100%ofsuspectedpathogensDirectedtherapyClinicalsuccessSafetyprofileAdverseeventsCost/effectivenessMinimizingresistanceSelfresistance/ResistancetootheragentsConsiderations

inChoosingAntibioticforOptimalTherapy第41頁/共50頁ErtapenemPharmacokinetics:MinimalSelectivity

forResistantPaeruginosaUnderClinicalConditionsMinimalresistanceselectionamongPaeruginosa(MIC90:16mg/L)MinimalresistanceselectionamongEnterobacteriaceae(MIC90:0.03mg/L)N=68healthyvolunteersMRSA=methicillin-resistantSaureus;MSSA=methicillin-susceptibleSaureus.AdaptedfromNixDE,etal.JAntimicrobChemother.2004;53(supplS2):ii23–ii28;FriedlandI,etal.JChemother.2002;14(5):483–491.PlasmaErtapenemConcentration,mg/LTotalFree0.010.1100011010004812162024MIC90,mg/L

Organism16

Paeruginosa, enterococci,MRSA1.0

Anaerobes0.25

MSSA,pneumococci0.12

GroupAstreptococci0.03

EnterobacteriaceaeHoursAfter1gIntravenousDoseofErtapenem第42頁/共50頁SummaryEffectofErtapenemonPaeruginosa,Enterobacteriaceae,andOtherG-vePathogensUseofertapenemnotdecreasesusceptibilitiesofP

aeruginosa,Enterobacteriaceae,orotherG-vepathogenstocarbapenemsAdaptedfromLivermoreDM,etal.JAntimicrobChemother.2005;55(3):306–311;DiNubileMJ,etal.EurJClinMicrobiolInfectDis.2005;24:

443–449;DiNubileMJ,etal.DiagnMicrobiolInfectDis.2007;58:491–494;DiNubileMJ,etal.AntimicrobAgentsChemother.2005;49(8):

3217–3221;CrankC,etal.Posterpresentedat:44thAnnualMeetingoftheInfectiousDiseasesSocietyofAmerica(IDSA);12–15October2006.Toronto,Ontario,Canada;GoffDA,ManginoJE.Posterpresentedat:47thAnnualInterscienceConferenceonAntimicrobialAgentsandChemotherapy(ICAAC);17–20September2007;Chicago,Illinois,USA;GoldsteinEJC,etal.Posterpresentedat:44thAnnualMeetingoftheInfectiousDiseasesSocietyofAmerica(IDSA);12–15October2006;Toronto,Ontario,Canada;CarmeliY,etal.Posterpresentedat:47thAnnualInterscienceConferenceonAntimicrobialAgentsandChemotherapy(ICAAC);17–20September2007;Chicago,Illinois,USA.ClinicalStudiesOASISIandOASISIISTITCHCrankGoffGoldsteinCarmeliBasicScienceStudyLivermore第43頁/共50頁NoRiskFactors

forMDRPathogensRiskFactors

forMDREnterobacteriaceaeaRiskFactorsfor

MDRPseudomonasHealthcare

contactNoYes!(eg,recenthospitaladmission,nursinghome,dialysis)withoutinvasiveprocedureYes,Longhospitalizationand/orinfectionfollowinginvasiveprocedures(>5days)RecentAbx

NoYes!(≥14daysinpast90days)Yes!

(≥14daysinpast90days)Patient

characteristicsYoungfewc