(MIC--MBC--MPC--and-SBT-Clinical-Application)临床应用.ppt

(MIC--MBC--MPC--and-SBT-Clinical-Application)临床应用.ppt

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MIC,MBC,MPC,andSBTClinicalApplication临床应用,Po-RenHsueh（薛博仁）NationalTaiwanUniversityHospital国立台湾大学医院,MICMinimumInhibitoryConcentration（最小抑菌浓度）MBCMinimumBactericidalConcentration（最小杀菌浓度）MPCMutationPreventionConcentration（预防突变浓度）,M“X”C,SBTSerumBactericidalTiter（血清细菌滴度）,Theclinicalmicrobiologylaboratoryplaysanimportantroleinantibioticselectionandusethroughperformanceofroutineantimicrobialsusceptibilitytestingonpatientsclinicalisolates临床微生物实验室通过对患者分离的菌株进行常规抗菌药物敏感性试验，从而在抗菌药物选择和应用方面起到重要作用,DiskDiffusionMethod纸片扩散法,ASTReport药敏报告Staphylococcusspp.,OxacillinRErythromycinRClindamycinRVancomycinSTeicoplaninS,MinocyclineSCefazolinRGentamicinRTrimethoprim/Rsulfamethoxazole,PharmacologyofAntimicrobialTherapy抗菌疗法的药理学,DosingRegimen定量疗法,Concentrationsinserum血清药物浓度,Concentrationsintissuesandbodyfluids组织与体液药物浓度,Concentrationsatsiteofinfection感染灶药物浓度,Pharmacologicandtoxicologiceffect药理学和毒理学作用,Antimicrobialeffect抗菌作用,Absorption吸收Distribution分布Elimination消除,Pharmacokinetics（PK）药代动力学,Pharmacodynamics（PD）药效动力学,MIC,MBC,MPCCmax/MIC,TMIC,AUIC,MICMinimumInhibitoryConcentration（最小抑菌浓度）MBCMinimumBactericidalConcentration（最小杀菌浓度）MPCMutationPreventionConcentration（预防突变浓度）,M“X”C,SBTSerumBactericidalTiter（血清细菌滴度）,Contents,Drug-Bugrelationship:

MICMICversusDiskSusceptibilityClinicalApplications,MIC与纸片敏感性的比较,临床应用,Drug-Bug关系：

MIC,BrothDilutionMethod肉汤稀释法,Etest,BDPhoenix,BDXpertSystem,Range范围MIC50抑制半数细菌生长的最小抑菌浓度MIC90抑制90细菌生长的最小抑菌浓度Geometricmean几何平均数MICDistributionMIC分布,MICs,MICDistributionS.pneumoniae,2001-2002,Taiwan台湾，2001-2002，肺炎链球菌的MIC分布,No.ofisolates,MIC90,Levofloxacin,Moxifloxacin莫西沙星,Cipofloxacin环丙沙星,HsuehPRetal.AntimicrobAgentsChemother2005,左氧氟沙星,0.03,%ofisolates,MIC（g/ml）,MICDistributionofEnterobacteriaceae419Isolates,Taiwan,2003台湾，2003，肠杆菌科的MIC分布,MIC90,ChengNC,HsuehPRetal.MicrobDrugResist2006,亚胺培南美罗培南厄他培南,InhibitoryQuotient（IQ）TherapeuticIndex,Averagepeaklevel（blood,urine,bile,CSF）IQ=MICIndicatingmultipleoftheMICcanbeexpectedwiththelowestusualdosage（IV）employedclinically指示了采用临床常规最低剂量药物时，可预测的药物平均峰值对MIC的倍数。

SerumIQ,CSFIQ,bileIQ,urineIQ（血清、脑脊液、胆汁、尿液的IQ）HigherIQhigherprobabilityofasuccessfulclinicaloutcome（atleastIQ,4-8）较高的IQ，良好临床效果的可能性较高（至少IQ为48）Ingeneral:

IQ4一般：

IQ4Endocarditis,osteomyelitis,meningitis:

IQ8心内膜炎，骨髓炎，脑（脊）膜炎：

IQ8,抑制商数,治疗指数,MICBreakpointsHowtoDefine,PharmacologicalConsiderationsClinicalEvaluationEpidemiologicalData,如何规定MIC折点,药理学方面的考虑,临床评价,流行病学数据,QuinolonesPenetrationintoLung渗透到肺中的喹诺酮类,AntibioticconcentrationBrochialEpithelialAlveolarSerummucosaliningfluidmacrophageAntibiotics（mg/L）（mg/kg）（mg/L）（mg/L）Ciprofloxacin1.191.853.013.39Levofloxacin4.16.010.927.7Moxifloxacin4.525.54.4113.6Azithromycin0.5-0.68.12.223.0Cefuroxime3.4-4.63.8-Amoxicillin/6.3-6.9/3.0/1.70.9/1.00/0.8clavulinicacid4.3-5.3,WiseandHoneybourneEurRespirJ1999,血清支气管粘膜上皮细胞内衬液肺泡巨噬细胞,抗菌素浓度,EffectofIncreasingConcentrationsonKillingofPseudomonasaeruginosa,增加浓度对铜绿假单胞菌的杀菌效果,AntimicrobialActivityThreePatterns抗菌活性的三种模式,Concentration-dependentTime-dependentPersistenteffect（+）Persistenteffect（）Persistenteffect（+）AminoglycosidesAll-lactamsMacrolidesQuinolonesflucytosineglycopeptidesKetolidesstretograminsAmphotericinBlinezolid,fluconazoleMaximizeconc.OptimizedurationOptimizeamountAUIC,Cmax/MICTimeaboveMICAUIC,浓度依赖性,持续作用（+）持续作用（+）持续作用（+）,时间依赖性,最大浓度,优化持续时间,优化持续时间,Time,MIC,logConcentration,Peak（Cmax）,Concentration-Dependent浓度依赖性（AchieveHighestPossibleDoseWithoutToxicity）（无毒性作用所能达到的最大可能剂量）,MaximizeBactericidalCmax/MIC,8-10:

1,MIC,Time,MIC,logConcentration,TimeMIC,Time-Dependent时间依赖性（MaximizetimeaboveMIC）（药物浓度高于MIC的最大时间）,MaximumkillingTMIC,40-50%Cmax=3-4xMIC,TMIC,MIC,Peak（Cmax）,Time,MIC90,LogConcentration,24h-AUC,24h-AUC/MIC90（24h-AUIC）,AreaundertheSerum-TimeCurveAUC血清时间曲线下面积,MIC,Dose,Dose,Peak（Cmax）,AUC,40,30,20,10,0,0,4,8,12,16,20,24,TMIC,MIC,Time（h）,Concentration（mg/L）,PK/PDSurrogateRelationships药代动力学/药效动力学的替代关系,24h-AUC/MICCmax/MIC:

10-12xTimeMIC:

40-50%,MIC90,Definitetherapy确诊治疗,Empiricaltherapy,经验性治疗,FluoroquinolonesPK/PD-OptimizedTherapy氟喹诺酮类PK/PD优化治疗,Cmax/MICratio824-hAUC/MICratio125（GPB,GNB）;25-30（GPB?

）125（all）:

resistancepreventionDonotover-fractionatethedailydose,Relationshipbetween24-HourAUC/MICandMortalityinAnimalsforFluoroquinolonesagainstS.pneumoniae采用氟喹诺酮类治疗肺炎链球菌感染，24-HourAUC/MIC与动物死亡率间的关系,2.5,10,25,100,250,1000,0,20,40,60,80,100,24-HourAUC/MIC,Mortality（%）,1,AndesD,CraigWA.IntJAntimicrobAgents.2002;19:

261-8.,Daysoftherapy,02468101214,0,100,75,50,25,AUIC125-250,AUIC250,AUIC125,Patientsremainingculture-positive（%）,ForrestAetal.AntimicrobAgentsChemother1993;37:

1073-81.,AUIC:

AUC24/MIC.,TimetoBacterialEradicationvsAUIC细菌根除时间vsAUIC,46,16,120,QuinolonePharmacodynamicsS.pneumoniae,2001,Taiwan治疗肺炎链球菌，喹诺酮药效动力学,AUC/MIC90,AUC:

MIC30Gram-positiveorganisms,CIPRO=ciprofloxacin,LEVO=levofloxacin,GREPA=grepafloxacin,GATI=gatifloxacin,MOXI=moxifloxacin,192,2,1,0.25,0.25,0.03,310,AUC:

MIC125Gram-negativeorganisms,TimeaboveMICPredictsEfficacy药物浓度高于MIC的时间的预测效能,Penicillins青霉素类:

TimeaboveMIC40%ofdosinginterval药物浓度高于MIC的时间需达到或超过给药间歇时间的40Cephalosporins头孢菌素类:

TimeaboveMIC50%ofdosinginterval药物浓度高于MIC的时间需达到或超过给药间歇时间的50,Craig26:

112,DaganRetal.LancetInfectDis2002;2:

593-604.,AssociationbetweenTimeaboveMICinSerumversusBacteriologicalSuccessfor-LactamAntibioticsintheTreatmentofAOM,TMICof40-50%Predict85-100%clinicalsuccess,CraigWA.PediatrInfectDisJ1996;15:

255-9.,DeterminationofMBCBrothDilutionMethod采用肉汤稀释法确定最小杀菌浓度,Isolatedbacterium,NovelAgentsagainstGram-PositiveBacteriaBactericidalvs.Bacteriostatic杀菌vs.抑菌,（n=10）,（n=10）,（n=10）,（n=10）,Vancomycin-R,Vancomycin-R,MBC/MIC32,0,0,0,0,x,x,x,x,DaptomycinMIC90MBC90MSSA0.52MRSA12VRE.faecalis28VRE.faecium48,MPCMutationPreventionConcentration突变预防浓度,Timepost-administration,MIC,MPC,Serumortissuedrugconcentration,MutantSelectionWindow（MSW）突变选择窗口,MSW,MPC90/MIC90=8-16MPCCmax,UrbanCetal.JInfectDis2001;184:

794-8.,Cmax,MPC,mutationpreventionconcentration,FluoroquinolonePotencyBasedonPK/PDParametersS.pneumoniae基于PK/PD参数，氟喹诺酮治疗肺炎链球菌的效能,MIC90MPC90CmaxAUICAgent（g/ml）（g/ml）（g/ml）Ciprofloxacin2163.016Levofloxacin185.745Moxifloxacin0.2524.5192Gatifloxacin0.544.260Gemifloxacin0.030.5-11.2-1.5310BlondeauJMetal.AntimicrobAgentsChemother2001;45:

433-8.UrbanCetal.JInfectDis2001;184:

794-8.,MICBreakpointsHowtoDefine如何规定MIC的折点,PharmacologicalConsiderationsClinicalEvaluationEpidemiologicalData,药理学方面的考虑,临床评价,流行病学数据,ClinicalOutcomevs.MIC,Survival（%）,MIC（g/mL）,BolivarR,etal,RevInfectDis1983,R,I,S,临床结果vs.MIC,MICvs.ClinicalOutcomeCefoperazoneTreatmentfor276PatientsMICvs.临床效果,MICs（g/ml）ofpathogen%ofclinicalfailure14161632326444Cefoperazone:

S,16g/ml;I,32g/ml;R,64g/mlCraigWA.DiagnMicrobiolInfectDis1993.TurnidgeJD.ClinInfectDis1998.,CefotaximeSusceptibilityBreakpoints头孢噻肟的药敏折点,MICZonediameterCategory（g/ml）（mm）Susceptible823Intermediate16-3215-22Resistant6414ForStaphylococci,Enterobacteriaceae,P.aeruginosa,Acinetobacterspp.M100-S13NCCLS2003,Susceptible（S）敏感Definition,Aninfectionduetothestrainmaybeappropriatelytreatedwiththedosageofantimicrobialagentrecommendedforthattypeofinfectionandinfectingspecies,unlessotherwisecontraindicated某菌株导致的感染能够被推荐的用于该类型感染和该种感染株的抗菌素剂量进行适当的治疗，除非有其它的禁忌症。

M100-S16NCCLS2006,Resistant（R）耐药Definition,Strainsarenotinhibitedbytheusuallyachievablesystemicconcentrationoftheagentwithnormaldosageschedules采用常规疗程剂量通常所能达到的系统浓度对菌株无法抑制。

StrainswithMICfallintherangewherespecificmicrobialresistancemechanismsarelikelyandclinicalefficacyhasnotbeenreliableintreatmentstudies菌株的MIC符合某范围，该范围内细菌可能产生特异性的耐药机制，并且在治疗研究中临床效能是不可靠的。

M100-S16NCCLS2006,Intermediate（I）中介Definition,IsolateswithMICsapproachingusuallyattainablebloodandtissuelevel菌株具有接近于通常可达到的血液与组织水平的MICs。

Responseratesmaybelowerthanforsusceptibleisolates反应率可能比敏感菌株低。

Clinicalapplicabilityininfectedsiteswherethedrugsarephysiologicallyconcentratedorhighdosageofadrugcanbeused临床适用于药物能生理性浓缩或能采用高剂量药物的感染灶。

“Bufferzone”缓冲地带M100-S16NCCLS2006,StreptococcuspneumoniaePenicillinSusceptibilityCriteria肺炎链球菌青霉素敏感标准,MIC（g/ml）AgentSIRMeningitisPenicillin0.060.12-12Penicillin（OX-1）20mm19mmCefotaxime（CRO,FEP）0.512Non-meningitisPenicillin248Amoxicillin（-clav）2（2/1）4（4/2）8（8/4）Cefotaxime（CRO,FEP）124,M100-S18NCCLS（CLSI）2008,MICDataMIC值SelecttheLowestMICDrugisOftenNotAppropriate选择具有最低MIC的药物常常并不合适,AnorganismwithanMICof8g/mlofadrugismoreresistantthananorganismwithanMICof2g/mlofthesamedrug对某药物具有8g/mlMIC的菌株比对同一药物具有2g/mlMIC的菌株更加耐药。

AnorganismwithanMICof8g/mltoonedrugandof2g/mltoaseconddrugisnotnecessarilymoreresistanttothefirstdrug对第一种药物具有8g/mlMIC，对第二种药物具有2g/mlMIC的菌株不一定对第一种药物更加耐药。

AgentamicinMICof16g/mlcannotbedirectlycomparedtoacephalosporinMICof16;thelaterleveliseasilyachieved,theformerisdifficultandtoxic对庆大霉素16g/ml的MIC不能直接与头孢菌素16g/ml的MIC相比较；后者的水平容易达到，前者是困难的且有毒性。

MICsvs.S,I,RAreMICsperseMoreValuabletoPhysicians（?

）MICS是否本质上对医生更有价值？

Non-infectiousdiseasespecialistscaninterpretaccuratelytheMICs（?

）非感染科专家能准确的解释MICs（?

）DeterminationofMICsissuperiortocategoryresultsinpatientmanagement（?

）noclearproof!

在病人治疗中，MICs的确定应优先于类别结果（?

）无明确的证据！

ShouldwereportMICvaluesaloneorwithS,I,R我们是否只需要单独报告MIC值或是连同S,I,R?

MarginalIntereststoClinicians,MadeinChina,CefotaximeSusceptibilityBreakpoints头孢噻肟敏感性折点,MICZonediameterCategory（g/ml）（mm）Susceptible823Intermediate16-3215-22Resistant6414ForStaphylococci,Enterobacteriaceae,P.aeruginosa,Acinetobacterspp.M100-S12NCCLS2002,MICTestinginClinicalMicrobiologyLaboratoryIndications临床检验科MIC检测的指征,Consultationwithaninfectiousdiseasespecialistisrecomme