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 CLSI AST Standards January 2012vM100-S22 Tables(2012)*vM02-A11 Disk Diffusion Method(2012)*vM07-A9 MIC Method(2012)*vM11-A7 Anaerobe MIC Testing(2007)2012主要变化v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）v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v葡萄球菌增加金葡菌青霉素抑菌圈周边试验检测（penicillin disk zone edge test）-内酰胺酶产生M100-S22.P22CLSI Breakpoint Additions/Revisions Since 2010Antimicrobial AgentDate of Revision*(M100 version)CommentsEnterobacteriaceae AztreonamJanuary 2010(M100-S20)CefazolinJanuary 2010(M100-S20)January 2011(M100-S21)Breakpoints were revised twice since 2010CefotaximeJanuary 2010(M100-S20)CeftazidimeJanuary 2010(M100-S20)CeftizoximeJanuary 2010(M100-S20)CeftriaxoneJanuary 2010(M100-S20)DoripenemJune 2010(M100-S20U)No previous CLSI breakpoints for doripenemCLSI Breakpoint Additions/Revisions Since 2010Antimicrobial AgentDate of Revision*(M100 version)CommentsPseudomonas aeruginosaPiperacillin-tazobactamJanuary 2012(M100-S22)Ticarcillin-clavulanateJanuary 2012(M100-S22)TicarcillinJanuary 2012(M100-S22)PiperacillinJanuary 2012(M100-S22)肠杆菌科：碳靑霉烯类美国碳靑霉烯类耐药肠杆菌科（CRE）的分布黄色：黄色：KPC酶；酶；蓝点：蓝点：IMP、VIM黄点：黄点：NDMCLSI使用以下数据建立/修订折点v“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v与临床预后相关的MIC对于老药很少有“新”数据 v药物代谢-药效学(PK-PD)分析Time(hours)Organism%Time MIC肠杆菌科35%绿脓30%DMID 2009年CLSI DocumentMIC(g/ml)Disk Diffusion(mm)SuscIntResSuscIntResM100-S20(Jan.2010)*2481916-1815M100-S20U(June 2010)0.250.512320-2219M100-S22(Jan 2012)*0.51.022219-2118肠杆菌科 厄他培南CLSI 折点更新过程*目前和目前和FDA折点相同折点相同为何多次进行修改?v2011 breakpoints primarily based on:MIC distributionsPK/PD(conservatively went with 0.25 g/ml)Very limited clinical data(no patients with MICs at 0.5 g/ml)v2012 breakpoints primarily based on:Additional surveillance data showed isolates with MICs of 0.5 g/ml did not have carbapenemasesFurther review of PK/PDAdditional clinical data(including ESBL-producing E.coli with 0.5 g/ml MICs suggested clinical response)Also,lowest ertapenem concentration on some commercial panels is 0.5 g/ml thus allowing labs to use CLSI ertapenem breakpoints(following verification)if breakpoint is 0.5 g/ml but not if 0.25 g/ml510152025303540Ertapenem Disk Zone Diameter(mm)8Ertapenem MIC(g/ml)11111111111111111111111111111122222222222222222333333333334444444455556666677777777788999910101213131415192024263137374751545664101Ertapenem MIC vs.Disk(All)n=948y=16.3-0.37xr=-0.93Susc.:0.5 g/ml/22 mm Res.:2 g/ml/18 mm VM=0.0%Ma=0.0%Mi=6.1%FOR NEW BREAKPOINTS APPROVED June 2011Modified Hodge Test(MHT)(Table 2A Supplemental Table 2 and 3)“NOTE:Not all carbapenemase-producing isolates of Enterobacteriaceae are MHT positive and MHT-positive results may be encountered in isolates with carbapenem resistance mechanisms other than carbapenemase production.”4 Select CRE Examples:Carbapenem MICs&MHT&-Lactam Resistance MechanismOrganismMIC(g/ml)1MHTResistancemechanismErtapImipMeroE.coli216 R4 R4 RPos4 Plasmid ampCK.pneumoniae216 R0.25 S8 RPos5 ESBL blashvE.coli316 R8 R16 RNeg5 NDM-16K.pneumoniae32 R1 S2 IPos5 IMP-461 Interpreted with current breakpoints2 Anderson,KF et al.2009.ICAAC.D-719.3 Limbago,BM.CLSI Agenda book.January 2011.4 MHT positive only with ertapenem disk5 MHT same result with ertapenem and meropenem(and imipenem)disks Carbapenemases(metallo -lactamases)旧的模式新的模式（22）解释标准基于每）解释标准基于每8小时一次，每次小时一次，每次500mg的给药方案。的给药方案。（23）解释标准基于每天一次，每次）解释标准基于每天一次，每次1g的给药的给药方案。方案。（24）解释标准基于每）解释标准基于每6小时一次，每次小时一次，每次500mg或每或每8小时一次，每次小时一次，每次1g的给药方案。的给药方案。（25）解释标准基于每）解释标准基于每8小时一次，每次小时一次，每次1g的的给药方案。给药方案。碳青霉烯类药物MIC 报告策略例#1例#2美罗培南 MIC(g/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)*耐药耐药中介中介敏感中介耐药旧4816新 124如果用如果用 旧折点旧折点和和碳青霉烯酶筛选试碳青霉烯酶筛选试验阳性验阳性如果用如果用当前折点当前折点和和 需要流行病学的需要需要流行病学的需要进行进行MHT进行进行MHT为何做为何做 MHT?绿脓杆菌Pseudomonas aeruginosa Breakpoint(MIC g/ml)RevisionsAgentOld(M100-S21)New M100-S221SuscIntResSuscIntResPiperacillin 64-1281632-64128Piperacillin-tazobactam64/4-128/416/432/4-64/4128/4Ticarcillin64-1281632-64128Ticarcillin-clavulanate64/2-128/216/232/2-64/2128/2Pseudomonas aeruginosa 2012年CLSI 绿脓杆菌折点变化BPiperacillin-tazobactam 211520 14 16/432/464/4 128/4(7)Interpretive criteria for piperacillin(alone or with tazobactam)are based on a piperacillin dosage regimen of at least 3 g every 6 h.OTicarcillin-clavulanic acid 241623 15 16/232/264/2 128/2(8)Interpretive criteria for ticarcillin(alone or with clavulanate)are based on a ticarcillin dosage regimen of at least 3 g every 6 h.BDoripenem 191618 15 24 8(12)Interpretive criteria for doripenem are based on a dosage regimen of 500 mg every 8 h.BImipenem/Meropenem 191618 15 24 8(13)Interpretive criteria for imipenem and meropenem are based on a dosage regimen of 1 g every 8 h.Section III.Therapy-Related Comments“In cases where specific dosage regimens are important for proper application of breakpoints,the dosage regimen is listed.These dosage regimen comments are not intended for use on individual patient reports.”Pseudomonas aeruginosa Penicillins+/-lactamase Inhibitors vP.aeruginosa breakpoints originally set higher than those for Enterobacteriaceae based in part on FDA label noting that these drugs should be considered in combination therapy with aminoglycosidevDeleted comment from Table 2B-1-“Rx:The susceptible category for penicillins,-lactam/-lactamase inhibitors implies the need for high-dose therapy for serious infections caused by P.aeruginosa.For these infections,monotherapy has been associated with clinical failure”vP.aeruginosa MIC breakpoints are now the same as those for Enterobacteriaceae(slight differences in disk diffusion breakpoints)Outcomes of bacteremia(N=34 episodes)due to P.aeruginosa with reduced susceptibility to piperacillin-tazobactamTam et al.2008.Clin Infect Dis.46:862.22.2%85.7%30.0%20.5%Pseudomonas aeruginosa Breakpoint(MIC g/ml)Revisions AgentOld(M100-S21)New M100-S221SuscIntResSuscIntResDoripenem2 None248Imipenem34816248Meropenem34816248 提醒!v美国同时有 CLSI和FDA 折点vCLSI and FDA建立折点的过程略有不同v商业系统 MUST 使用FDA折点v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S.typhi and Extraintestinal Salmonella spp.and FluoroquinolonesStaphylococcus spp.-PenicillinInduced-lactamase TestIsolates A-D are all-lactamase positiveABCDStaphylococcus aureus Disk Zone Edge Test(10 U penicillin disk and standard disk diffusion method)CLSI vs FDA Interpretive CriteriavIf the regulatory authority changes breakpoints,commercial device manufacturers may have to conduct a clinical laboratory trial,submit the data to the regulatory authority,and await review and approval.For these reasons,a delay of one or more years may be required if an interpretive breakpoint change is to be implemented by a device manufacturer.vIn the United States,laboratories that use Food and Drug Administration(FDA)approved susceptibility testing devices are allowed to use existing FDA interpretive breakpoints.vEither FDA or CLSI susceptibility interpretive breakpoints are acceptable to clinical laboratory accrediting bodies.Policies in other countries may vary.vLaboratories should check with the manufacturers of their antimicrobial susceptibility test system for additional information on the breakpoints used in their systems software.CLSI vs FDAvFollowing discussions with appropriate stakeholders,such as infectious disease practitioners and the pharmacy department,as well as the Pharmacy and Therapeutics and Infection Control committees of the medical staff,newly approved or revised breakpoints may be implemented by clinical laboratories.vCLSI disk diffusion test breakpoints may be implemented as soon as they are published in M100.If a device includes antimicrobial test concentrations sufficient to allow interpretation of susceptibility and resistance to an agent using the CLSI breakpoints,a laboratory could,after appropriate validation,choose to interpret and report results using CLSI breakpoints.“感染性疾病的病原学诊断及临床应用新进展学习班感染性疾病的病原学诊断及临床应用新进展学习班”通知通知v北京 6月27-7月1日v国家级继续教育学分10分 临床微生物学检验和感染疾病诊治指导意义ISO15189与微生物检验寄生虫病的临床和实验室诊断进展真菌病的实验室诊断和新进展不明原因肺炎的临床和实验室诊断进展下呼吸道标本采集、运送和处理规范无菌体液微生物检验的规范流程临床不常见菌的培养和快速鉴定药敏试验折点建立和抗菌药物的PK/PD2012年CLSI药敏试验更新细菌耐药监测和药敏谱统计的规范方法最新CLSI推荐的分枝杆菌、奴卡菌、其他需氧放线菌的药敏试验规程病原微生物的快速分子诊断进展病原菌的分子进化研究进展实验室的生物安全、质量控制和质量保证厌氧菌和弯曲菌的培养、鉴定和药敏试验新进展微生物检验与Lis系统