换个角度看药敏

换个角度看药敏---解读当前耐药状况浙江大学医学院附属邵逸夫医院感染科俞云松做药敏的目的预测治疗的效果敏感：常规剂量达到较好疗效中介：较大剂量达到较好疗效耐药：较大剂量一般达不到治疗目的血清中抗菌药物浓度致死量中毒浓度治疗浓度无效浓度最小中毒量常用量极量最小有效量10ug/ml耐药菌敏感菌治疗安全范围不同菌株MIC(ug/ml)5ug/ml3ug/ml人体血清治疗浓度25ug/ml人体血清抗菌药物（庆大霉素）浓度与不同菌株MIC的关系1999年-2008年MYSTIC项目收集E.coli耐药趋势051015202530351999200020012002200320042005200620072008耐药率（%）MeropenemImipenemCeftriaxoneCeftazidimeCefepimePiperacillin/tazobactamTobramycinCiprofloxacinDiagnosticMicrobiologyandInfectiousDiesease,20091999年-2008年MYSTIC项目收集K.pneumoniae耐药趋势0510152025301999200020012002200320042005200620072008耐药率（%）MeropenemImipenemCeftriaxoneCeftazidimeCefepimePiperacillin/tazobactamTobramycinCiprofloxacinDiagnosticMicrobiologyandInfectiousDiesease,20090510152025199920002001200220032004200520072008耐药率（%）MeropenemImipenemCeftriaxoneCeftazidimeCefepimePiperacillin/tazobactamTobramycinCiprofloxacin1999年-2008年MYSTIC项目收集Enterobacterspp.耐药趋势DiagnosticMicrobiologyandInfectiousDiesease,20091999年-2008年MYSTIC项目收集全部Enterobacteriaceae耐药趋势05101520251999200020012002200320042005200620072008耐药率（%）MeropenemImipenemCeftriaxoneCeftazidimeCefepimePiperacillin/tazobactamTobramycinCiprofloxacinDiagnosticMicrobiologyandInfectiousDiesease,20091999年-2008年MYSTIC项目收集P.aeruginosa耐药趋势0204060801999200020012002200320042005200620072008耐药率（%）MeropenemImipenemCeftriaxoneCeftazidimeCefepimePiperacillin/tazobactamTobramycinCiprofloxacinDiagnosticMicrobiologyandInfectiousDiesease,20091999年-2008年MYSTIC项目收集A.baumannii耐药趋势020406080199920002001200220032004200520072008耐药率（%）MeropenemImipenemCeftriaxoneCeftazidimeCefepimePiperacillin/tazobactamTobramycinCiprofloxacinDiagnosticMicrobiologyandInfectiousDiesease,2009MDR-PDR-XDR不断增加MDRMultiDrugResistantPDRPanDrugResistant(泛耐药)XDRExtensiveDrugResistant(大量/广泛/大规模耐药)ExtremeDrugResistant(极端/极度耐药)当今世界主要的MDR、XDR、PDR1.甲氧西林耐药金葡菌(MRSA)2.万古霉素耐药肠球菌(VRE)和金葡菌(VRSA)3.产超广谱β-内酰胺酶(ESBLs)大肠埃希菌和肺炎克雷伯菌4.高产头孢菌素酶的阴沟肠杆菌5.碳青霉烯类抗生素耐药铜绿假单胞菌和鲍曼不动杆菌6.碳青霉烯类抗生素耐药肠杆菌科细菌为改善MDR、XDR、PDR感染的疗效，利用PK/PD相关参数设计给药方案AUC/MIC(AUIC)：药时曲线下面积与MIC90之比值Peak/MIC：血峰浓度与MIC90之比值Cmax/MIC：最高血浓度与MIC90之比值TimeMIC(TMIC)–timeaboveMIC(h)：超过MIC90的浓度维持时间，用小时表示–timeMIC(%)：超过MIC90浓度维持时间占给药间隔时间的百分率（%）成人细菌性脑膜炎给药剂量抗菌药物每日剂量给药方法头孢噻肟头孢曲松头孢他啶12g4g6gQ4hQ12hQ6-8h青霉素氨苄西林奈夫西林苯唑西林哌拉西林24mu12g9-12g9-12g24gQ4hQ4hQ4hQ4hQ4h庆大霉素妥布霉素阿米卡星3-5mg/kg3-5mg/kg15mg/kgQ8-12hQ8-12hQ8-12h万古霉素氯霉素利福平氨曲南环丙沙星SMZ/TMP美罗培南2g4-6g600mg6-8g800mg20mg/kg6gQ12hQ6hQ24hQ6-8hQ12hQ6-12hQ8h药敏标准不一致也有差异CLSI与UCARST折点不一样不仅要了解细菌药敏、更需了解MIC值或分布AntibioticSusceptibilityTest,AST不仅要了解细菌药敏、更需了解MIC值或分布AntibioticSusceptibilityTest,AST84021Tetracycline(ug/ml)MIC=2ug/mlDeterminationofMIC不仅要了解细菌药敏、更需了解MIC值或分布AntibioticSusceptibilityTest,AST84021Tetracycline(ug/ml)MIC=2ug/mlDeterminationofMICChlAmpEryStrTetDiskDiffusionTestMICandMortality:Gram-negativeBacteremia23.327.827.356.353.3010203040506012481628-dayMortality(%)CefepimeMIC(mcg/ml)Gram-NegativeBacteremia30.585.720.522.2010203040506070809016=1630-dayMortality(%)Piperacillin/TazobactamMIC(mcg/ml)P.aeruginosaBacteremiaPiperacillin/TazobactamControlBhatSVetal,AntimicrobAgentsChemother2007;51:4390TamVHetal,ClinInfectDis2008;46:862TMIC与疗效的关系对于β-内酰胺类药物，%TMIC的时间达到40-50%，细菌的清除率可达85%以上。青霉素或头孢菌素治疗试验性动物肺炎链球菌肺炎，%TMIC的时间达到40-50%，动物的存活率可达90-100%。CralgWA.DlagnMicrobiolInfectionDis1996,25:213-217PK/PDparameters‘ｈｏｕｒ（μg/mL）CmaxMICTimeaboveMICBC•MIC升高：时间依赖性抗生素：TMIC明显缩短PK/PDparameters‘ｈｏｕｒ（μg/mL）CmaxMICTimeaboveMICBC•MIC升高：时间依赖性抗生素：TMIC明显缩短PK/PDparameters‘ｈｏｕｒ（μg/mL）CmaxMICTimeaboveMICBC•MIC升高：时间依赖性抗生素：TMIC明显缩短突变选择窗口(MSW)敏感菌株被抑制单一靶位突变菌株不被抑制耐药菌株选择性增殖用药后时间MICMPCMSW血清或组织中药物浓度肠杆菌科细菌临床关注的主要-内酰胺酶•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)MDRXDR如何测出ESBLs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)60,913–92051.7%53.0%55.6%39.9%43.4%42.0%45.2%39.1%0%10%20%30%40%50%60%2005200620072008ESBLs产生率％E.coliK.pneumoniaePrevalenceofESBLsCHINETsurveillance,China,2005-2008CHINET产ESBL大肠埃希菌耐药率（%）抗菌药物耐药敏感阿米卡星11.183.2庆大霉素64.934哌拉西林99.10.4哌拉西林/他唑巴坦7.476.2头孢呋辛98.81.1头孢噻肟85.51.4头孢他啶22.667.7头孢吡肟30.650.9头孢哌酮/舒巴坦4.275.3头孢西丁12.577亚胺培南0100美罗培南0.199.9环丙沙星71.524.9复方磺胺甲噁唑75.223.6CHINET产ESBL克雷伯菌属耐药率（%）抗菌药物耐药敏感阿米卡星30.966.5庆大霉素57.741.7哌拉西林97.71.6哌拉西林/他唑巴坦27.644.3头孢呋辛96.22.3头孢噻肟81.92.7头孢他啶48.640.9头孢吡肟36.145.4头孢哌酮/舒巴坦14.658.9头孢西丁25.170.5亚胺培南0.998.5美罗培南0.398.7环丙沙星44.940复方磺胺甲噁唑66.430.3头孢哌酮/舒巴坦对产ESBLs菌株MIC分布哌拉西林/三唑巴坦对产ESBLs菌株MIC分布头孢他啶对产ESBLs菌株MIC分布产ESBLs菌株血行感染：头孢菌素的经验性治疗疗效判断——与MIC的相关性BloodstreamInfectionsDuetoExtended-SpectrumBeta-Lactamase-ProducingEscherichiacoliandKlebsiellapneumoniae:RiskFactorsforMortalityandTreatmentOutcome,withSpecialEmphasisonAntimicrobialTherapy.AAC.2004,48,(12),p.4574–4581Susceptible：MIC=8ug/mlMICs=2ug/ml疗效明显优于MICs=8ug/ml产ESBLs菌株血行感染：头孢菌素的经验性治疗疗效判断——与MIC的相关性BloodstreamInfectionsDuetoExtended-SpectrumBeta-Lactamase-ProducingEscherichiacoliandKlebsiellapneumonia