《革兰阴性菌耐药折点问题》

CLSIASTStandards

January2012M100-S22Tables(2012)*M02-A11DiskDiffusionMethod(2012)**M07-A9MICMethod(2012)**M11-A7AnaerobeMICTesting(2007)New!3现在是1页\一共有56页\编辑于星期四M100-S22PartialTableofContentsM100-S22.Page9.4现在是2页\一共有56页\编辑于星期四更新的的总结

M100-S22.Page13.5现在是3页\一共有56页\编辑于星期四2012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现在是4页\一共有56页\编辑于星期四M100-S22.P222010年后折点变化过程New!7现在是5页\一共有56页\编辑于星期四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)现在是6页\一共有56页\编辑于星期四CLSIBreakpointAdditions/RevisionsSince2010AntimicrobialAgentDateofRevision*(M100version)CommentsPseudomonasaeruginosaPiperacillin-tazobactamJanuary2012(M100-S22)Ticarcillin-clavulanateJanuary2012(M100-S22)TicarcillinJanuary2012(M100-S22)PiperacillinJanuary2012(M100-S22)现在是7页\一共有56页\编辑于星期四肠杆菌科：

碳靑霉烯类

现在是8页\一共有56页\编辑于星期四现在是9页\一共有56页\编辑于星期四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现在是10页\一共有56页\编辑于星期四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。现在是11页\一共有56页\编辑于星期四Piperacillin-tazobactam

MICdistributionexampleBlue=wildtype

isolatesRed=isolateswithacquired“R”10现在是12页\一共有56页\编辑于星期四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%现在是13页\一共有56页\编辑于星期四DMID2009年现在是14页\一共有56页\编辑于星期四现在是15页\一共有56页\编辑于星期四现在是16页\一共有56页\编辑于星期四现在是17页\一共有56页\编辑于星期四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现在是18页\一共有56页\编辑于星期四为何多次进行修改?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现在是19页\一共有56页\编辑于星期四CLSIAgendaBookJune201130现在是20页\一共有56页\编辑于星期四CLSIAgendaBookJune201131现在是21页\一共有56页\编辑于星期四Susc.:≤0.5µg/ml/≥22mmRes.:≥2µg/ml/≤18mmVM=0.0%Ma=0.0%Mi=6.1%FORNEWBREAKPOINTSAPPROVEDJune2011现在是22页\一共有56页\编辑于星期四ModifiedHodgeTest(MHT)

(Table2ASupplementalTable2and3)

“NOTE:Notallcarbapenemase-producingisolatesofEnterobacteriaceaeareMHTpositiveandMHT-positiveresultsmaybeencounteredinisolateswithcarbapenemresistancemechanismsotherthancarbapenemaseproduction.”

M100-S22.Table2ASupplementalTables2and3.Pages53and57.New!36现在是23页\一共有56页\编辑于星期四4SelectCREExamples: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现在是24页\一共有56页\编辑于星期四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现在是25页\一共有56页\编辑于星期四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.JeanPatelCDC现在是26页\一共有56页\编辑于星期四CLSIM100-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。现在是27页\一共有56页\编辑于星期四M100-S22.Table2ASupplementalTables2and3.Pages52-60.(旧折点)(当前折点)MHT检测碳青霉烯酶35现在是28页\一共有56页\编辑于星期四碳青霉烯类药物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)现在是29页\一共有56页\编辑于星期四如果用

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现在是30页\一共有56页\编辑于星期四现在是31页\一共有56页\编辑于星期四绿脓杆菌57现在是32页\一共有56页\编辑于星期四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现在是33页\一共有56页\编辑于星期四Pseudomonasaeruginosa

M100-S22.Table2B-1.Page63.Dosagecomments(3gevery6halsoforpiperacillinandforticarcillin)59现在是34页\一共有56页\编辑于星期四2012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.现在是35页\一共有56页\编辑于星期四SectionIII. Therapy-RelatedComments

“Incaseswherespecificdosageregimensareimportantforproperapplicationofbreakpoints,thedosageregimenislisted.Thesedosageregimencommentsarenotintendedforuseonindividualpatientreports.”M100-S22.Instructions.Page28.New!60现在是36页\一共有56页\编辑于星期四Pseudomonasaeruginosa

Penicillins+/-β-lactamaseInhibitors

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

Enterobacteriaceae(slightdifferencesindiskdiffusionbreakpoints)61现在是37页\一共有56页\编辑于星期四Outcomesofbacteremia(N=34episodes)duetoP.aeruginosawithreducedsusceptibilitytopiperacillin-tazobactam…Tametal.2008.ClinInfectDis.46:862.22.2%85.7%30.0%20.5%Clinicaldatasuggestformerbreakpointstoohigh!62现在是38页\一共有56页\编辑于星期四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现在是39页\一共有56页\编辑于星期四提醒!

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现在是40页\一共有56页\编辑于星期四S.typhiandExtraintestinalSalmonellaspp.andFluoroquinolones41现在是41页\一共有56页\编辑于星期四M100-S22.Table2A.Page48.S.typhiandExtraintestinalSalmonellaspp.andFluoroquinolonesNew!45现在是42页\一共有56页\编辑于星期四M100-S22.Table2A.Page48.S.typhiandExtraintestinalSalmonellaspp.andCiprofloxacinNew!47现在是43页\一共有56页\编辑于星期四Staphylococcusspp.-Penicillin68现在是44页\一共有56页\编辑于星期四Inducedß-lactamaseTest苯唑西林(诱导剂)Subisolatetoagar(e.g.,BAP,MHA)Dropß-lactamdisk(e.g.,oxacillin,cefoxitin)IncubateovernightTestcellsfromperipheryofzoneIfβ-lactamasepositive(withorwithoutinduction),reportpenicillinRPosNeg71现在是45页\一共有56页\编辑于星期四CloverleafAssayforβ-lactamase

S.aureus5%sheepbloodagar1unitpenicillindiskS.aureusATCC25923astheindicatorβ-lactamasenegative(penicillinS)strainSomedifficultiesreadingIsolatesA-Dareallβ-lactamasepositiveABCDβ-lactamasenegative75现在是46页\一共有56页\编辑于星期四β-lactamasepositiveβ-lactamasenegative76现在是47页\一共有56页\编辑于星期四Staphylococcus

aureus

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

Neg-ATCC25923Pos-ATCC29213(supplementalQC)M100-S22.Table2CSupplementalTable1.Page83.New!77现在是48页\一共有56页\编辑于星期四M100-S22.Table2CSupplementalTable1.Page80.β-lactamaseTests–S.aureusandS.lugdunensis80现在是49页\一共有56页\编辑于星期四β-lactamaseTests–CoNSNOTS.lugdunensisM100-S22.Table2CSupplementalTable3.Page88.81现在是50页\一共有56页\编辑于星期四CLSIvsFDAInterpretiveCriteriaIftheregulatoryauthoritychangesbreakpoints,commercialdevicemanufacturersmayhavetoconductaclinicallaboratorytrial,submitthedatatotheregulatoryauthority,andawaitreviewandapproval.Forthesereasons,adelayofoneormoreyearsmayberequiredifaninterpretivebreakpointchangeistobeimplementedbyadevicemanufacturer.IntheUnitedStates,laboratoriesthatuseFoodandDrugAdministration(FDA)–approvedsusceptibilitytestingdevicesareallowedtouseexistingFDAinterpretivebreakpoints.EitherFDAorCLSIsusceptibilityinterpretivebreakpointsareacceptabletoclinicallaboratoryaccreditingbodies.Policiesinothercountriesmayvary.Laboratoriesshouldcheckwiththemanufacturersoftheirantimicrobialsusceptibilitytestsystemforadditionalinformationonthe