《革兰阴性菌耐药折点问题》

革兰阴性菌耐药折点问题北京大学人民医院检验科王辉whuibj@整理课件

CLSIASTStandards

January2012M100-S22Tables(2012)*M02-A11DiskDiffusionMethod(2012)**M07-A9MICMethod(2012)**M11-A7AnaerobeMICTesting(2007)New!3整理课件M100-S22PartialTableofContentsM100-S22.Page9.4整理课件更新的的总结

M100-S22.Page13.5整理课件2012主要变化肠杆菌科修订厄他培南折点增加环丙沙星折点（伤寒沙门菌和胃肠外沙门菌）绿脓杆菌降低哌拉西林、哌拉西林/他唑巴坦、替卡西林、替卡西林/克拉维酸折点降低亚胺培南、美罗培南折点；增加多利培南折点葡萄球菌

增加金葡菌青霉素抑菌圈周边试验检测（penicillindiskzoneedgetest）β-内酰胺酶产生New!6整理课件M100-S22.P222010年后折点变化过程New!7整理课件CLSIBreakpointAdditions/RevisionsSince2010AntimicrobialAgentDateofRevision*(M100version)CommentsEnterobacteriaceaeAztreonamJanuary2010(M100-S20)CefazolinJanuary2010(M100-S20)January2011(M100-S21)Breakpointswererevisedtwicesince2010CefotaximeJanuary2010(M100-S20)CeftazidimeJanuary2010(M100-S20)CeftizoximeJanuary2010(M100-S20)CeftriaxoneJanuary2010(M100-S20)DoripenemJune2010(M100-S20U)NopreviousCLSIbreakpointsfordoripenemErtapenemJune2010(M100-S20U)January2012(M100-S22)Breakpointswererevisedtwicesince2010.ImipenemJune2010(M100-S20U)MeropenemJune2010(M100-S20U)Cipro–SalmonellaonlyJanuary2012(M100-S22)整理课件CLSIBreakpointAdditions/RevisionsSince2010AntimicrobialAgentDateofRevision*(M100version)CommentsPseudomonasaeruginosaPiperacillin-tazobactamJanuary2012(M100-S22)Ticarcillin-clavulanateJanuary2012(M100-S22)TicarcillinJanuary2012(M100-S22)PiperacillinJanuary2012(M100-S22)整理课件肠杆菌科：

碳靑霉烯类

整理课件整理课件美国碳靑霉烯类耐药肠杆菌科（CRE）的分布黄色：KPC酶；蓝点：IMP、VIM黄点：NDM整理课件CLSI使用以下数据建立/修订折点“野生菌群”或常规菌群的MIC分布野生菌群=未携带获得性“耐药”机制与临床预后相关的MIC对于老药很少有“新”数据

药物代谢-药效学(PK-PD)分析CLSIM23-A3(2008)“体外药敏实验标准和质量控制参数的发展;批准的指南”描述了CLSI建立和修订折点的过程。整理课件Piperacillin-tazobactam

MICdistributionexampleBlue=wildtype

isolatesRed=isolateswithacquired“R”mechanism10整理课件SerumConcentration(µg/ml)Time(hours)MICTimeaboveMICdosedoseCmax(peakconcentration)PK/PDGoal(“Target”)forβ-lactams=(%T>MIC)12Organism%Time>MIC肠杆菌科35%绿脓30%整理课件DMID2009年整理课件整理课件整理课件整理课件CLSIDocumentMIC(µg/ml)DiskDiffusion(mm)SuscIntResSuscIntResM100-S20(Jan.2010)*≤24≥8≥1916-18≤15M100-S20U(June2010)≤0.250.5≥1≥2320-22≤19M100-S22(Jan2012)**≤0.51.0≥2≥2219-21≤18肠杆菌科–厄他培南

CLSI折点更新过程*目前和FDA折点相同NewNew!28整理课件为何多次进行修改?2011breakpointsprimarilybasedon:MICdistributionsPK/PD(conservativelywentwith≤0.25µg/ml)Verylimitedclinicaldata(nopatientswithMICsat0.5µg/ml)2012breakpointsprimarilybasedon:AdditionalsurveillancedatashowedisolateswithMICsof0.5µg/mldidnothavecarbapenemasesFurtherreviewofPK/PDAdditionalclinicaldata(includingESBL-producingE.coliwith0.5µg/mlMICssuggestedclinicalresponse)Also,lowestertapenemconcentrationonsomecommercialpanelsis0.5µg/mlthusallowinglabstouseCLSIertapenembreakpoints(followingverification)ifbreakpointis≤0.5µg/mlbutnotif≤0.25µg/ml29整理课件CLSIAgendaBookJune201130整理课件CLSIAgendaBookJune201131整理课件Susc.:≤0.5µg/ml/≥22mmRes.:≥2µg/ml/≤18mmVM=0.0%Ma=0.0%Mi=6.1%FORNEWBREAKPOINTSAPPROVEDJune2011整理课件ModifiedHodgeTest(MHT)

(Table2ASupplementalTable2and3)

“NOTE:Notallcarbapenemase-producingisolatesofEnterobacteriaceaeareMHTpositiveandMHT-positiveresultsmaybeencounteredinisolateswithcarbapenemresistancemechanismsotherthancarbapenemaseproduction.”

M100-S22.Table2ASupplementalTables2and3.Pages53and57.New!36整理课件4SelectCREExamples:CarbapenemMICs&MHT&-LactamResistanceMechanismOrganismMIC(µg/ml)1MHTResistancemechanismErtapImipMeroE.coli2>16R4R4RPos4

PlasmidampCK.pneumoniae2>16R≤0.25S8RPos5

ESBLblashvE.coli3>16R8R>16RNeg5

NDM-16K.pneumoniae32R1S2IPos5

IMP-461Interpretedwithcurrent

breakpoints2Anderson,KFetal.2009.ICAAC.D-719.3Limbago,BM.CLSIAgendabook.January2011.4MHTpositiveonlywithertapenemdisk5MHTsameresultwithertapenemandmeropenem(andimipenem)disks6Carbapenemases(metallo-lactamases)39整理课件进行耐药机制的初筛试验

(MIC升高至接近“敏感”折点为

“可疑”)进行耐药机制的特异确证试验若检测到耐药机制则更改药敏报告发现一种新型β-内酰胺酶(如ESBL或碳青霉烯酶)旧的模式ESBLMHTCourtesyofDr.JeanPatelCDC整理课件新的模式进行药敏试验并且使用

新的“降低的”折点以治疗为目的报告药敏结果–不更改“敏感”结果仅以感染控制和流行病学研究为目的进行特殊的耐药机制检测试验分离出肠杆菌科菌CourtesyofDr.JeanPatelCDCCLSIM100-S20-U表1A修订的碳青霉烯类药物折点和对应的药物剂量SIRSIR（22）解释标准基于每8小时一次，每次500mg的给药方案。（23）解释标准基于每天一次，每次1g的给药方案。（24）解释标准基于每6小时一次，每次500mg或每8小时一次，每次1g的给药方案。（25）解释标准基于每8小时一次，每次1g的给药方案。整理课件M100-S22.Table2ASupplementalTables2and3.Pages52-60.(旧折点)(当前折点)MHT检测碳青霉烯酶35整理课件碳青霉烯类药物MIC

报告策略例#1例#2美罗培南MIC(µg/ml)4422改良霍奇试验*阳性阴性阳性阴性报告(旧折点)耐药敏感耐药敏感报告(新折点)*耐药耐药中介中介*对常规病人的报告不必做改良霍奇试验;可以为感染控制目的而进行该试验但不要把“敏感”或“中介”改为“耐药”敏感中介耐药旧≤48≥16新≤12≥4折点(µg/ml)整理课件如果用

旧折点和碳青霉烯酶筛选试验阳性如果用当前折点和

需要流行病学的需要进行MHT进行MHT为何做MHT?M100-S22.Comment(23)Page47.Table2ASupplementalTables2and3.Pages52and56.40整理课件整理课件绿脓杆菌57整理课件Pseudomonasaeruginosa

Breakpoint(MICµg/ml)RevisionsAgentOld(M100-S21)NewM100-S221SuscIntResSuscIntResPiperacillin≤64-≥128≤1632-64≥128Piperacillin-tazobactam≤64/4-≥128/4≤16/432/4-64/4≥128/4Ticarcillin≤64-≥128≤1632-64≥128Ticarcillin-clavulanate≤64/2-≥128/2≤16/232/2-64/2≥128/21 Correspondingdiskdiffusionbreakpointsalsorevised

M100-S22.Table2B-1.Page63.New!58整理课件Pseudomonasaeruginosa

M100-S22.Table2B-1.Page63.Dosagecomments(3gevery6halsoforpiperacillinandforticarcillin)59整理课件2012年CLSI绿脓杆菌折点变化BPiperacillin-tazobactam

2115–20

14

16/432/4–64/4

128/4(7)Interpretivecriteriaforpiperacillin(aloneorwithtazobactam)arebasedonapiperacillindosageregimenofatleast3gevery6h.OTicarcillin-clavulanicacid

2416–23

15

16/232/2–64/2

128/2(8)Interpretivecriteriaforticarcillin(aloneorwithclavulanate)arebasedonaticarcillindosageregimenofatleast3gevery6h.BDoripenem

1916–18

15

24

8(12)Interpretivecriteriafordoripenemarebasedonadosageregimenof500mgevery8h.BImipenem/Meropenem

1916–18

15

24

8(13)Interpretivecriteriaforimipenemandmeropenemarebasedonadosageregimenof1gevery8h.整理课件SectionIII. Therapy-RelatedComments

“Incaseswherespecificdosageregimensareimportantforproperapplicationofbreakpoints,thedosageregimenislisted.Thesedosageregimencommentsarenotintendedforuseonindividualpatientreports.”M100-S22.Instructions.Page28.New!60整理课件Pseudomonasaeruginosa

Penicillins+/-β-lactamaseInhibitors

P.aeruginosabreakpointsoriginallysethigherthanthoseforEnterobacteriaceaebasedinpartonFDAlabelnotingthatthesedrugsshouldbeconsideredincombinationtherapywithaminoglycosideDeletedcommentfromTable2B-1-“Rx:Thesusceptiblecategoryforpenicillins,β-lactam/β-lactamaseinhibitorsimpliestheneedforhigh-dosetherapyforseriousinfectionscausedbyP.aeruginosa.Fortheseinfections,monotherapyhasbeenassociatedwithclinicalfailure”P.aeruginosaMICbreakpointsarenowthesameasthosefor

Enterobacteriaceae(slightdifferencesindiskdiffusionbreakpoints)61整理课件Outcomesofbacteremia(N=34episodes)duetoP.aeruginosawithreducedsusceptibilitytopiperacillin-tazobactam…Tametal.2008.ClinInfectDis.46:862.22.2%85.7%30.0%20.5%Clinicaldatasuggestformerbreakpointstoohigh!62整理课件Pseudomonasaeruginosa

Breakpoint(MICµg/ml)Revisions

AgentOld(M100-S21)NewM100-S221SuscIntResSuscIntResDoripenem2

None≤24≥8Imipenem3≤48≥16≤24≥8Meropenem3≤48≥16≤24≥81 correspondingdiskdiffusionbreakpointsalsorevised2 Interpretivecriteriaarebasedondosageregimensof500mgevery8h

3 Interpretivecriteriaarebasedondosageregimensof1gevery8h

M100-S22.Table2B-1.Page63.New!63整理课件提醒!

美国同时有CLSI和FDA折点CLSIandFDA建立折点的过程略有不同商业系统

MUST使用FDA折点临床实验室可以使用

CLSI或FDA折点认证机构接受如果是FDA-批准的商业AST系统,临床实验室使用更新的CLSI折点时，需要验证8整理课件S.typhiandExtraintestinalSalmonellaspp.andFluoroquinolones41整理课件M100-S22.Table2A.Page48.S.typhiandExtraintestinalSalmonellaspp.andFluoroquinolonesNew!45整理课件M100-S22.Table2A.Page48.S.typhiandExtraintestinalSalmonellaspp.andCiprofloxacinNew!47整理课件Staphylococcusspp.-Penicillin68整理课件Inducedß-lactamaseTest苯唑西林(诱导剂)Subisolatetoagar(e.g.,BAP,MHA)Dropß-lactamdisk(e.g.,oxacillin,cefoxitin)IncubateovernightTestcellsfromperipheryofzoneIfβ-lactamasepositive(withorwithoutinduction),reportpenicillinRPosNeg71整理课件CloverleafAssayforβ-lactamase

S.aureus5%sheepbloodagar1unitpenicillindiskS.aureusATCC25923astheindicatorβ-lactamasenegative(penicillinS)strainSomedifficultiesreadingIsolatesA-Dareallβ-lactamasepositiveABCDβ-lactamasenegative75整理课件β-lactamasepositiveβ-lactamasenegative76整理课件Staphylococcus

aureus

DiskZoneEdgeTest(10Upenicillindiskandstandarddiskdiffusionmethod)Fuzzy“beach”=β-lactamasenegativePenicillin-SSharp“cliff”=β-lactamasepositivePenicillin-RS.aureusQC:

Neg-ATCC25923Pos-ATCC29213(supplementalQC)M100-S22.Table2CSupplementalTable1.Page83.New!77整理课件M100-S22.Table2CSupplementalTable1.Page80.β-lactamaseTests–S.aureusandS.lugdunensis80整理课件β-lactamaseTests–CoNSNOTS.lugdunensisM100-S22.Table2CSupplementalTable3.Page88.81整理课件CLSIvsFDAInterpretiveCriteriaIftheregulatoryauthoritychangesbreakpoints,commercialdevicemanufacturersmayhavetoconductaclinicallaboratorytrial,submitthedatatotheregulatoryauthority,andawaitreviewandapproval.Forthesereasons,adelayofoneormoreyearsmayberequiredifaninterpretivebreakpointchangeistobeimplementedbyadevicemanufacturer.IntheUnitedStates,laboratoriesthatuseFoodandDrugAdministration(FDA)–approvedsusceptibilitytestingdevicesareallowedtouseexistingFDAinterpretivebreakpoints.EitherFDAorCLSIsusceptibilityinterpretivebreakpointsareacceptabletoclinicallaboratoryaccreditingbodies.Policiesinothercountriesmayvary.Laboratoriesshouldcheckwiththemanufacturersoftheirantimicrobialsusceptibilitytestsystemforadditionalinformatio