产ESBLs肠杆菌科细菌感染的治疗

产ESBLs肠杆菌科细菌感染的治疗浙江大学医学院附属邵逸夫医院感染科俞云松社区革兰阴性菌感染肠杆菌科细菌70%46%17%13%8%6%4%2%1%1%2%E.coliKlebsiellaspp.PseudomonasaeruginosaEnterobacterspp.,Serratiaspp.,andCitrobacterspp.Acinetobacterspp.ProteusmirabilisIndole-positiveProteusspp.OthernonfermentersStenotrophomonasmaltophiliaOthersAntimicrobAgentsChemother.2006Jan;50(1):374-8.浙江大学医学院附属邵逸夫医院3医院革兰阴性菌感染肠杆菌科细菌50%-60%0102030405060708090100201020112012非发酵菌肠杆菌科细菌94.9795.9697.43CHINET2010-2012肠杆菌科细菌最需关注的-内酰胺酶是ESBLsESBLs是肠杆菌科细菌最重要的耐药机制•超广谱-内酰胺酶(ESBLs)•高产头孢菌素酶(AmpC酶)•极少数菌株产碳青霉烯酶(碳青霉烯酶KPC)MDRXDRorPDR超广谱-内酰胺酶（extendedspectrum-lactamases，ESBLs）•是一类由质粒介导的2be类-内酰胺酶，能水解氧亚氨基-内酰胺抗生素，大多数能被-内酰胺酶抑制剂如克拉维酸（CA）所抑制。NS+NH3CNOCH3CNHONSCOO-R头孢噻肟、头孢他啶、头孢吡肟等CommonESBLproducers:•Klebsiellapneumoniae•Escherichiacoli•Proteusmirabilis•Enterobactercloacae•Non-typhoidalSalmonella(insomecountries)–FirstdescribedinGermany(1983)andFrance(1985)amongKlebsiellaspp•Pseudomonasaeruginosa•Acinetobacterbaumannii–PER-typeandOXA-typeenzymesaremorecommoninPseudomonaseruginosaandAcinetobacterspp.ESBLsarerarein:GuangzhouZhejiangShanghaiBeijingWuhanHenanHongKong社区获得感染ESBLs流行情况1.2002-2003年2.中国7个地区3.社区获得性感染病人分离的革兰阴性菌共2099株肠杆菌科细菌产ESBLsAll(1651)E.coli(953)Klebsiella(357)EnterobacterCitrobacter,Serratia(175)ESBL+??1617??Imipenem0000Ertapenem0000Cefotaxime14.714.415.425.1Ceftazidime(5.9)(2.7)(8.1)20.0Pip/taz9.57.113.221.7Ciprofloxacin40.850.625.222.9AntimicrobAgentsChemother.2006Jan;50(1):374-8.ESBLs–anemergingproblemGlasswelletal,Healthcare-associatedInfectionandAntimicrobialResistanceDept&AntimicrobialResistanceMonitoringandReferenceLaboratory,HealthProtectionAgency,Colindale,LondonSpeciesDistributionofGNBCausingIAIs2,292Isolates,China,SMART,2002-200749%17%9%6%4%3%1%11%EscherichiacoliKlebsiellapneumoniaePseudomonasaeruginosaEnterobactercloacaeAcinetobacterbaumanniiCitrobacterfreundiiStenotrophomonasmaltophiliaothers腹腔社区感染肠杆菌科细菌产ESBLsAsia-PacificRegion（SMART2007）大肠埃希菌和肺炎克雷伯菌的ESBLs发生率SMART,2002-2012,IAI,ChinaDatanotpublished北京协和医院杨启文教授提供大肠埃希菌ESBLs发生率(HAvsCA)0.010.020.030.040.050.060.070.080.0E.coli(All)E.coli(HA)E.coli(CA)P0.001P0.001P=0.001北京协和医院杨启文教授提供肺炎克雷伯菌ESBLs发生率(HAvsCA)0.010.020.030.040.050.060.070.080.0K.pneumoniae(All)K.pneumoniae(HA)K.pneumoniae(CA)P=0.177P=0.404P=0.181北京协和医院杨启文教授提供浙江大学医学院附属邵逸夫医院15产ESBLs比例（Chinet监测2005-2012）0.0%10.0%20.0%30.0%40.0%50.0%60.0%2005200620072008200920112012E.coliK.pneumoniae我国耐药监测ESBLs的发生率（主要是院内分离菌）28.645.75954.657.86060.260.261.325.734.947.736.640.451.53845.740.6010203040506070200120022003200420052006200720082010大肠埃希菌肺炎克雷伯菌%WangH,ChenM.DiagnosMicrobiolInfectDis,2005,51,201-208CMSS/SEANIR/CARES.CMSS2010,王辉等,中华检验医学杂志,2011,Vol34.No10,897－904year产ESBLs菌株血行感染死亡率显著增加（Meta分析）•产ESBLs菌株与不产ESBLs菌株血行感染死亡率比较的Meta分析–包括16个研究–产ESBLs菌株菌血症死亡率显著增加(–pooledRR1.85,95%CI1.39–2.47,P0.001）Mortalityanddelayineffectivetherapyassociatedwithextended-spectrumb-lactamaseproductioninEnterobacteriaceaebacteraemia:asystematicreviewandmeta-analysis.JournalofAntimicrobialChemotherapy(2007)60,913–920AreESBLproducersassociatedwithhighermortality?•Meta-analysisofmortalityfrombacteremiawithESBLproducers[SchwaberJACNov2007]–16studiesfrom2000-2006–Crudemortality：34%(199/591)forESBLproducersvs.20%(216/1091)fornon-ESBL–PooledRR1.85;95%CIs1.39-2.47•Delayineffectivetherapyinupto44%patientswithESBLproducers[SchwaberJACNov2007;GoffICAAC2006]社区获得（CA）产ESBLs大肠埃希菌尿路感染－危险因素ClinMicrobiolInfect2010;16:147–151复杂性尿路感染尿路结石前列腺疾病最近一年发作3次以上尿路感染最近3个月应用抗菌药物，尤其是β内酰胺类浙江大学医学院附属邵逸夫医院20年龄60岁以上女性糖尿病反复的尿路感染卫生保健相关感染之前抗菌药物的应用（氨基青霉素、头孢菌素、氟喹诺酮类）侵袭性泌尿道操作ArchInternMed.2008Sep22;168(17):1897-902.社区获得性产ESBLs大肠埃希菌感染－危险因素社区获得性产ESBLs大肠埃希菌菌血症－危险因素(注重危险因素评估)JMicrobiolImmunolInfect2010;43(3):240–248年龄性别合并症初始感染部位临床表现长期的照顾机构浙江大学医学院附属邵逸夫医院22医院获得性产ESBLs细菌感染危险因素尿路/血管置管使用抗菌药物曾住院2或3种抗菌药物联用糖尿病气管插管肿瘤肾功能衰竭免疫缺陷曾入住ICUEmergHealthThreatsJ.2012;5.doi:10.3402/ehtj.v5i0.11589.浙江大学医学院附属邵逸夫医院23危险因素的阴性预测值更高加强ESBLs的检测头孢噻肟＋克拉维酸头孢噻肟头孢他啶头孢他啶＋克拉维酸产ESBLs菌株感染治疗药物治疗药物碳青霉烯类复合制剂头霉素类氨基糖苷类氟喹诺酮类磷霉素甘氨酰环类（替加环素）多粘菌素呋喃妥因等也可取得临床疗效，但一般不作为首选。产ESBLs菌株亚胺培南MIC分布亚胺培南和美罗培南的血浆浓度（1g）MIC90DreetzMetal.AntimicrobAgentsChemother1996;40:105-109.亚胺培南美罗培南（常规剂量：0.5Q6H；最小剂量：0.5Q8H）TMICs40%以上产ESBLs菌株血行感染：不同抗菌药物经验性治疗疗效比较ClinicalInfectiousDiseases2003;39:31–7碳青霉烯类抗生素产ESBLs菌株血行感染：不同抗菌药物经验性治疗疗效比较•不同抗菌药物治疗方案30天病死率比较：Thirty-daymortalityrates–碳青霉烯类12.9%(8of62)–头孢菌素26.9%(7of26)–氨基糖苷类26.9%(7of26)选择碳青霉烯类抗生素作为产ESBLs菌株感染的经验性治疗的合理性！BloodstreamInfectionsDuetoExtended-SpectrumBeta-Lactamase-ProducingEscherichiacoliandKlebsiellapneumoniae:RiskFactorsforMortalityandTreatmentOutcome,withSpecialEmphasisonAntimicrobialTherapy.AAC.2004,48,(12),p.4574–4581存活率耐药性逐年增加-CRAB是21世纪的耐药哨兵事件，是21世纪的MRSA%year•耐药性(CHINET数据；不动杆菌）31TheIncreasingResistanceRatesofCarbapenemsinEnterobacteriaceae(CHINETProgram:CHINA2005-2012)EnterobacteriaceaeK.pneumoniae浙江大学医学院附属邵逸夫医院32酶抑制剂复合制剂的地位轻中度感染：可选择头孢哌酮/舒巴坦，哌拉西林/他唑巴坦需加大剂量使用：头孢哌酮/舒巴坦2g/3g，q8h；哌拉西林/他唑巴坦4.5h，q6h其他β-内酰胺/β-内酰胺酶复合制剂不推荐使用产ESBLs菌株感染－不同抗菌药物经验性治疗疗效比较•β内酰胺酶抑制剂合剂–需要高的剂量（PK/PD参数的要求）–存在酶抑制剂不能灭活的染色体介导的AmpC酶（3-5%）不作为产ESBLs菌株严重感染病人治疗的首选！（近10%病人疗效不佳）CurrentOpinioninPharmacology20