革兰阳性菌感染诊治进展南宁XX0407.doc

革兰阳性菌感染诊治进展南宁XX0407 超级细菌时代革兰阳性菌感染诊治进展李光辉复旦大学附属华山医院2BAD BUG,NO DRUG,NO ESKAPE EEnterocous S S taphylocousK Klebsiella A A ciobacterP Pseudomonas EE nterobacter1998Marchxx;total of3,209,413bacterial isolatesfrom300clinical laboratoriesacross the United StatesStyers D,et al.Ann Clin Microbiol Antimicrobxx,5:2.Staphylocous aureusEscherichia coliEnterocous spp.Coagulase-negative staphylocoiPseudomonas aeruginosaKlebsiella pneumoniaeProteus mirabilisEnterobacter cloacaeSerratia marcescensAciobacter baumanniEscherichia coliStaphylocous aureusEnterocous spp.Pseudomonas aeruginosaCoagulase-negative staphylocoiKlebsiella pneumoniaeProteus mirabilisEnterobacter cloacaeStreptocous pneumoniaeCitrobacter freundiiPercentage ofall bacterialisolates encounteredPercentage ofall bacterialisolates encounteredTop ten pathogens amonginpatients Toptenpathogensamong outpatients12.712.717.318.805101520253035401.01.014.938.60510152025303540S.aureus isa leadingcause ofbacterial infectionsin hospitals and in the munity部分地区MRSA流行现状(SENTRY Program,1997-xx，60,000菌株)0102030405060耐药比率（%）Europe LatinAmerica United States1997199819992000xxxxxxxxxxxxMRSA在全球Inpatient(IP)and outpatient(OP)rates of methicillin-resistant Staphylocous aureus infection,by USCensus BureauStyers D,Sheehan DJ,Hogan P,Sahm DF.Laboratory-based surveillanceof currentantimicrobial resistancepatterns andtrends amongStaphylocous aureus:xxstatus in the United States.Ann ClinMicrobiol Antimicrobxx;5:2门诊36.3%63.0%，住院49.9%63.0%xxCHINET耐药监测革兰阳性菌菌种分布细菌株数金葡菌445232.81肠球菌属404629.82凝固酶阴性葡萄球菌307822.69（血液脑脊液等无菌体液）肺炎链球菌9446.96?-溶血性链球菌8085.96草绿色链球菌（血液及无菌体液）1861.37其他540.40合计13568100.0xx年CHINET监测网各医院金葡菌MR菌株检出率医院金黄色葡萄球菌医院金黄色葡萄球菌MR株数/总株数（%）MR株数/总株数（%）华山医院265/40964.8上海儿科医院/42/36511.5瑞金医院274/44361.9上海儿童医院/115/47024.5协和医院243/56043.4重庆医大一附院/78/12562.4同济医院361/57862.5甘肃省人民医院/85/14259.9浙医一附院103/20949.3医大一附院/207/34959.3广州一附院66/10165.3安徽医大一附院169/27761.0北京医院191/24677.6昆明医大一附院103/17857.9总计2302/445251.70102030405060708090儿童眼耳鼻科皮肤科内科门急诊高干烧伤科外科ICUMRSA不同病房中的MRSA的检出率（1995xx38388株金葡菌MRSA检出率64.8%）检出率（检出率（%）MRSA在中国.上海CA-MRSA?當地檢出率高?有MRSA感染或定植病史?與感染患者有密切接觸?群聚/不健康的生活方式?監獄?軍營?免疫功能地下?某些體育運動?共用器械/毛巾?吸毒Graffunder EM,Venezia RA.J AntimicrobChemother.xx;49:999-1005.Safdar N,Maki DG.Ann InternMed.xx;136:834-844.Moran GJ,et al.N EnglJ Med.xx;355:666-74.MRSA感染的危險因素HA-MRSA?当地检出率高?有MRSA感染或定植病史?与感染患者有密切接触?长期住院?生活在护理院?侵袭性治疗?透析?插管?肠道外营养?近期使用抗生素（氟喹诺酮类/氨基糖苷类/头孢菌素类）Frequent ContactCleanliness CompromisedSkin CrowdingContaminated Surfacesand SharedItems CA-MRSA:Factors forTransmission金葡菌感染骨髓炎食物中毒皮肤烫伤综合征T中毒休克综合征脓疱病疖肺炎眼内炎心内膜炎蜂窝织炎Annual DeathRates in theUnited States SelectedInfectious Diseases15,798579366xx9,00002,0004,0006,0008,00010,00012,00014,00016,00018,00020,000MRSAinfection (xx)AIDS (xx)Viralhepatitis (xx)Tuberculosis (xx)SARS(all)Avianinfluenza(all)No.of patientsdied BoucherHW andCorey GR.Clin Infect Disxx;46:S344-9.抗MRSA的抗菌药物14万古霉素/替考拉宁vanycin利奈唑胺linezolid达托霉素daptomycin类型糖肽类噁唑烷酮类环脂肽类抗菌类型慢性杀菌剂（葡萄球菌）*抑菌剂（肠球菌/葡萄球菌）快速杀菌剂Cidal vs.G(+)抗菌谱G(+)G(+)G(+)作用部位细胞壁核糖体RNA亚基细胞膜*总体而言,对肠球菌是抑菌剂,对葡萄球菌和链球菌是慢性杀菌剂Agents forInfections Causedby ResistantGram-Positive Organisms15Ana MariaRivera,Helen W.Boucher.Mayo ClinProc.xx;86 (12):1230-1242Vanycin?Vanycin has been themainstay ofparenteral therapy for MRSA infections.?However,its efficacyhas einto question,with concernsover itsslow bactericidalactivity,the emergence of resistantstrains,and possibleMIC creepamong susceptiblestrains.?Vanycin killsstaphylocoi moreslowly thando-lactams in vitro,particularly athigher inocula(1077-1099cfu)and isclearly inferiorto-lactams forMSSA bacteremiaand IE.?Tissue perationis highlyvariable anddepends uponthe degreeof inflammation.In particular,it haslimited perationinto bone,lung epitheliallining fluidand CSF.?Vanycin isconsidered pregnancy category C.Vanycin MIC creep17Journal of Antimicrobial Chemotherapy (xx)60,78879405101520253035404550xxxxxxxxxxtotalxx-xx美国99个医疗中心未发现万古霉素对金葡菌MIC的漂移Sader HS,Fey PD,Limaye AP,et al.Evaluation of vanycin anddaptomycin potencytrends(MICcreep)against methicillin-resistant Staphylocous aureus isolatescollected innine U.S.medical centersfromxxtoxx.AACxx,53 (10):4127-4132-0.625菌株所占比例19Journal ofClinical MicrobiologyFebruaryxxVolume50Number2p.318325CONCLUSION Inconsistentevidence onvanycin MICcreep and the relevanceof the MIC toclinical outemay arisefrom differencesin susceptibility testing methods,including storageof isolates.There isa needto standardizeand streamlinesusceptibility testingof vanycin against MRSAEfficacy ofNafcillin VersusVanycin inPreventing PersistentBacteremia andRelapse inMSSA Bacteremia*005510152025Persistent3days Persistent7days RelapseBacteriologic FailureNafcillin(n=18)Vanycin(n=70)6621001100770019MSSA=methicillin-susceptible Staphylocousaureus.*Excludes patientswith infectiveendocarditis.Chang FY,Peacock JEJr,Musher DM,et al.Staphylocousaureusbacteremia:recurrence andthe impactof antibiotictreatment in a prospectivemulticenter study.Medicine(Baltimore).xx;82:333-339.Therapeutic Efficacyof Vanycinin Relationto MICor BactericidalActivity MIC=minimum inhibitoryconcentration.Hidayat LK,Hsu DI,Quist R,Shriner KA,Wong-Beringer A.High-dose vanycin therapy formethicillin-resistant Staphylocousaureus infections:efficacy andtoxicity.Arch InternMed.xx;166 (19):2138-2144.Clinical Suess(%)060408010020P=.021(n=39)2(n=40)8562MIC(?g/mL)Prospective CohortSingle-Center Study?Target vanycintrough levels,1520?g/mL Howshould resultsof vanycinsusceptibilitytestingbe usedto guidetherapy?For isolateswith avanycin MIC5mg/L）?77例存在持续血流感染（血培养持续阳性55天以上），12例（75）死亡，其中88例与hVISA的感染直接相关。 ?结论hVISA感染的预后差Maor Y,J ClinMicrobiol,xx,45:15114Vanycin resistancein S.aureus?Twevle casesfrom USA?Eight fromMichigan?One fromPennsylvania?One fromNew York?Two fromDelaware?Two strainsreported fromIndia(BMC InfectDis.xx;6:156)?Two strainsreported fromIran(Med PrincPractxx;17:432434)?Positive for the vanAgene?All patientshad priorMRSA colonisationor infection?All hadsevere underlyingfactors CDCreminds clinicallaboratories andhealthcare infectionpreventionists oftheir rolein thesearch andcontainment ofvanycin-resistant Staphylocousaureus(VRSA).Centers forDisease Controland PreventionWeb site.health.ri/materialbyothers/xx05CDCAdvisoryVRSA.pdf.MayxxDPH investigatessecond DelawareVRSA case.ttp:/.dhss.delaware/dhss/pressreleases/xx/vrsacase-090310.html.Delaware Healthand SocialServices Web site Increasingthe Doseof Vanycinto ReachHigher TroughLevels MayNot ImproveClinical OutesMIC=minimum inhibitoryconcentration.Hidayat LK,Hsu DI,Quist R,Shriner KA,Wong-Beringer A.High-dose vanycintherapyformethicillin-resistant Staphylocousaureus infections:efficacy andtoxicity.Arch InternMed.xx;166 (19):2138-2144.Clinical Suess(%)060408010020P=.021(n=39)2(n=40)8562MIC(?g/mL)Prospective CohortSingle-Center Study?Target vanycintrough levels,1520?g/mL VanycinNephrotoxicity Initial Vanycin TroughLodise TP,et al.Clin InfectDis.xx;49 (4):507-514Single-Center,Retrospective StudyStratified Kaplan-Meier Analysis of Timeto NephrotoxicityInitialVanycinTrough ValueandtheRate of Nephrotoxicity RateofNephrotoxicity(%)010204030Probability ofRemaining Nonnephrotoxic01.00.6Initial TroughValue(mg/L)101520Days209/445/953/154/12215203305101520mg/L P.01P88周(A-II)?一些专家建议添加利福平(B-III)?如果同时出现菌血症,菌血症治愈后添加利福平?一些专家建议添加11-33月以上的以利福平为主的口服联合治疗(C-III)?脓毒性关节炎?关节间隙的清创或引流(A-II);使用33-44周的抗生素(A-III)治疗MRSA骨髓炎或者脓毒性关节炎的抗生素总结药剂成人用量等级*评论万古霉素15-20mg/kg/剂IV每88-12小时B B-I II一些专家建议添加使用600mg QD或300-450mg BID的利福平治疗骨髓炎达托霉素6mg/kg/剂IV每天一次B B-I II利奈唑胺600mg PO/IV每日两次B B-I II克林霉素600mg PO/IV每日三次B B-III TMP-SMX+利福平3.5-4.0mg/kg/剂PO/IV每88-12小时B B-I II如果是脓毒性关节炎(B-III)，就只使用TMP-SMX36MRSA=methicillin-resistant Staphylocousaureus;TMP-SMX=trimethoprim-sulfamethoxazole1.Liu C,Bayer A,Cosgrove SEet al.Clinical practiceguidelines bythe InfectiousDiseases Societyof Americaforthe药剂ofmethicillin-resistant Staphylocousaureus infectionsin成人sandchildren.Clin InfectDis.xxJan4Epub aheadof print中枢神经系统MRSA感染的治疗疾病成人推荐剂量其他治疗脑膜炎万古霉素IV(B)、利奈唑胺PO/IV(B)、TMP-SMX IV(C)或万古霉素+利福平(B)S分流装臵感染时，建议移除装臵直到CSF培养阴性(A)脑脓肿、硬脑膜下积脓、硬脊膜外脓肿外科切开引流评估(A)海绵体或硬脑膜静脉窦脓毒性血栓症感染邻近部位或脓肿切开引流(A)Catherine Liuet al.Clinical InfectiousDiseases.xx;52:138.Linezolid?Linezolid isa syntheticoxazolidinone andinhibits initiationof proteinsynthesis atthe50S ribosome.?FDA-approved forthe treatment of SSTI,CAP andHAP dueto MRSA.?It hasinvitro activity againstVISA andVRSA.?It has100%oral bioavailability;?Linezolid resistance is rare?Resistance typicallyours duringprolonged usevia amutation inthe23S rRNAbinding sitefor linezolidor cfrgene-mediated methylationof adenosineat position2503in23SrRNA Catherine Liuet al.Clinical InfectiousDiseases.xx;52:138.Linezolid?Long-term useis limitedby hematologictoxicity,with thrombocytopeniaourring morefrequently thananemia andneutropenia,peripheral andoptic neuropathy,and lacticacidosis.?Although myelosuppressionis generallyreversible,peripheral andoptic neuropathyare notreversible orare onlypartially reversible.?Linezolid isa weak,nonselective,reversible inhibitorof monoamineoxidase andhasbeenassociated withserotonin syndromein patientstaking concurrentselective serotoninreceptor inhibitors.?Linezolid causesless bonemarrow suppressionin childrenthan itcauses in adults.?It isconsidered pregnancycategory C.CatherineLiuet al.Clinical InfectiousDiseases.xx;52:138.万古霉素抑制细胞壁的合成11万古霉素影响细胞膜的通透性11万古霉素抑制细菌浆内RNA合成115050503030核糖体(mRNA)细菌细胞301.实用抗感染治疗学主审戴自英.主编汪复张婴元.人民卫生出版社xx年11月第1版.第二篇第十一章其他抗菌药物:P400.2.夏梦岩等.细菌对利奈唑胺的耐药机制及检测方法研究进展.微生物与感染xx;4 (3):170-173.3.李娟.利奈唑胺及其耐药机制研究进展.西部医学xx;21 (4):667-668.单一抑菌机制导致利奈唑胺耐药事件频发利奈唑胺作用位点50S核糖体亚基23S rRNA第55功能区结合核50S亚基，抑制70S复合物形成，从而抑制细菌蛋白质合成，对DNA与RNA无影响3341Ian M.Gould.J AntimicrobChemotherxx;66Suppl4:iv17iv21利奈唑胺耐药的MRSA临床暴发感染?华盛顿xx年10月28日讯已有报道发现12例耐甲氧西林金黄色葡萄球菌同时对利奈唑安（商品名斯沃）呈双重耐药，这似乎是首次利奈唑胺耐药株的暴发。 ?此次爆发中11例均为全面爆发感染，包括5例呼吸机相关肺炎、5例菌血症及1例导管相关性败血症。 而余下的1例仅为细菌简单定植，并未致病。 ?因为已成功分离获得耐药菌株，桑切斯博士说?据我们所知，这是首次发现对利奈唑胺耐药的MRSA临床暴发感染事件。 ?.medpagetoday./MeetingCoverage/ICAAC-IDSA/115001.Tsiodras S,et al.Linezolid resistancein aclinical isolateof Staphylocousaureus.Lancetxx;358:207-208.2.Pillai SK,et al.Linezolid Resistancein Staphylocousaureus:Characterization andStability ofResistant Phenotype.JIDxx;186:1603-1607.3.Peeters MJ,Sarria JC.Clinical characteristicsof linezolid-resistant Staphylocousaureus infections.Am JMed Scixx;330 (2):102-4.4.Roberts SM,et al.Linezolid-resistant Staphylocousaureus in two pediatricpatients receivinglow-dose linezolidtherapy.Pediatr InfectDis Jxx;25 (6):562-4.5.Brauers J,et al.Surveillance of linezolid resistancein Germany,xx-xx.ClinMicrobiolInfectxx;11 (1):39-46.6.Wong A,et al.Polyphyletic Emergence of Linezolid-Resistant StaphylocoiintheUnitedStates.Antimicrobial Agentsand Chemotherapyxx;54 (2):742-748.7.Endimiani A,Blackford M,Dasenbrook EC,et al.Emergence of Linezolid-Resistant Staphylocousaureus afterProlonged Treatmentof CysticFibrosis Patientsin Cleveland,Ohio.Antimicrobial Agentsand Chemotherapyxx;55 (4):1684-16922.8.Hentschke M,et al.Emergence of Linezolid Resistanceina Methicillin Resistant StaphylocousaureusStrain.Infectionxx;36 (1):85-87.9.Gales AC,et al.Emergenceoflinezolid-resistant Staphylocousaureus duringtreatmentofpulmonary infectioninapatient withcystic fibrosis.International JournalofAntimicrobialAgentsxx;27:300-302.10.Ikeda-Dantsuji Y,et al.Linezolid-resistant Staphylocousaureus isolatedfromxxthroughxxat sixhospitals inJapan.J InfectChemotherxx;17:45-51.11.Sanchez Garca M,et al.Clinical Outbreakof Linezolid-Resistant Staphylocousaureus inan IntensiveCare Unit.JAMAxx;303 (22):2260-2264.12.Yoshida K,et al.Linezolid-resistant methicillin-resistant Staphylocousaureus isolatedafter long-term,repeated useoflinezolid.J InfectChemotherxx;15 (6):417-9.13.Hill RL,et al.Linezolid-resistant ST36methicillin-resistant Staphylocousaureus associated with prolongedlinezolid treatmentintwopaediatric cysticfibrosis patients.J AntimicrobChemotherxx;65:442-445.14.Hong SB.Co-emergenceoflinezolid-resistant Staphylocousaureus andEnterocous Faeciuminapatient withmethicillin-resistant S.aureus pneumonicsepsis.Diagnostic Microbiologyand InfectiousDiseasexx;69:232-233.15.Morales G,Picazo JJ,Baos E,et al.Resistance to Linezolid IsMediated bythe cfrGene inthe First Report ofan Outbreakof Linezolid-Resistant Staphylocousaureus.Clinical InfectiousDiseasesxx;50:821-825.16.中日友好医院病原菌资料甲氧西林耐药金黄色葡萄球菌药敏分析(xx.9-xx.2).单一抑菌机制药物利奈唑胺的耐药报道不断LRSA=耐利奈唑胺金葡菌2000年利奈唑胺上市xx-xx年(日本)13株LRSA10xx年(西班牙)12株LRSA，6例死亡11xx年(美国)5株LRSA2xx年(德国)1株LRSA8xx年(巴西)1株LRSA9xx年(美国)3株LRSA1xx-xx年(美国)6株LRSA6xx-xx年(美国)40株LRSA7xx-xx年(德国)26株LRSA5xx年(美国)6株LRSA3xx年(美国)2株LRSA4xx年(日本)1株LRSA12xx年(英国)2株LRSA13xx年(西班牙)4株LRSA15xx年(韩国)6株LRSA14xx年(中国)29株LRSA161.Snchez Garca M,De laTorre MA,Morales G,Clinical Outbreakof Linezolid-Resistant Staphylocousaureus inan IntensiveCare Unit.JAMA.xxJun9;303 (22):2260-4.治疗LRSA的感染抗生素LRSA患者的预后Resistance toLinezolid IsMediated bythe cfrGene inthe FirstReport ofan Outbreakof Linezolid-Resistant Staphylocousaureus45Clinical InfectiousDiseasesxx;50:821825万古霉素有效治疗耐利奈唑胺金葡菌感染患者LRSA感染患者的存活率1.Snchez GarcaM,De laTorre MA,Morales G,Clinical OutbreakofLinezolid-ResistantStaphylocousaureus inan IntensiveCare Unit.JAMA.xxJun9;303 (22):2260-4.文章关键点?日本利奈唑胺上市仅短短两年，就出现了13例利奈唑胺耐药的MRSA株，本文111株，另外会议报道22株。 48美国xx-xx耐利奈唑胺的金葡菌发生率逐年上升Farrell DJ,et al.LEADER ProgramResults forxx:an Activityand SpectrumAnalysisofLinezolid Using6,414Clinical Isolatesfrom56Medical CentersintheUnitedStates.Antimicrobial agentsand chemotherapyxx;55 (8):3684-3690.0.000.030.030.060.100.150xxxxxxxxxxxx耐药率(%)N=18537近年中国利奈唑胺耐药报告情况1.中日友好医院病原菌资料甲氧西林耐药金黄色葡萄球菌药敏分析(xx.9-xx.2).2.药小萍,吴学勇,翁丽贞等.耐甲氧西林金黄色葡萄球菌感染的流行病学及耐药性研究.中华医院感染学杂志xx;21 (16):3483-3485.3.浙江省医院细菌耐药监测年鉴(xx年版).P23.北京(xx-xx)2株LRSA1上海(xx-xx)9株LRSA2浙江 (xx)18株LRSA(发生率达1%)3xx年CLSI公布了利奈唑胺耐药折点标准?利奈唑胺耐药金葡菌达到0.05%，报告时无须复杂的确认流程金葡菌利奈唑胺增加了?耐药?折点CLSI M100-S19xxCLSI M100-S20xx敏感中介耐药敏感中介耐药MIC(g/ml)444488纸片法(mm)212120新！Mendes,et al.FirstReportof cfr-Mediated ResistancetoLinezolidin HumanStaphylocoal ClinicalIsolates RecoveredintheUnitedStates.Antimicrob AgentsChemotherxx;52 (6):2244-2246.美国FDA多次对利奈唑胺发出警告?xx年向辉瑞公司发出警告信31指出其广告和宣传材料夸大其词，暗示比对照药万古霉素效果好，实际并无证据没有明确指出利奈唑胺有骨髓抑制、乳酸酸中毒和无羟色胺综合征等严重不良反应擅自扩大适应症，应明确利奈唑胺只能用于规定情况下治疗肺炎和皮肤感染?xx年FDA向医生发出警告32治疗导管相关感染的研究表明利奈唑胺治疗首次用药后84天内的死亡率21.5%(78/363)，而对照组为16.0%(58/363)，差异有统计学意义，要求停止用于治疗导管相关感染 31、ALERT DEPARTMENTOF HEALTH&HUMAN SERVICES 32、FDA ALERT3/16/xx利奈唑胺受到美国FDA的警告11xx年FDA向医生发出警告?治疗导管相关感染的研究表明22利奈唑胺治疗首次用药后84天内的死亡率21.5%(78/363)，而对照组为16.6%(58/363)。 1,Wilcox MH,Tack KJ,Bouza E,etal.Complicated skin