(MIC,MBC,MPC,and SBT Clinical Application)臨床應(yīng)用課件

MIC,MBC,MPC,andSBT

ClinicalApplication

臨床應(yīng)用Po-Ren

Hsueh（薛博仁）NationalTaiwanUniversityHospital國立臺灣大學(xué)醫(yī)院MIC

MinimumInhibitoryConcentration（最小抑菌濃度）MBC

MinimumBactericidalConcentration（最小殺菌濃度）MPC

MutationPreventionConcentration（預(yù)防突變濃度）M“X”CSBTSerumBactericidalTiter（血清細菌滴度）

Theclinicalmicrobiologylaboratoryplaysanimportantroleinantibioticselectionandusethroughperformanceofroutineantimicrobialsusceptibilitytestingonpatients’clinicalisolates臨床微生物實驗室通過對患者分離的菌株進行常規(guī)抗菌藥物敏感性試驗，從而在抗菌藥物選擇和應(yīng)用方面起到重要作用DiskDiffusionMethod紙片擴散法ASTReport藥敏報告

Staphylococcusspp.Oxacillin RErythromycin RClindamycin RVancomycin STeicoplanin SMinocycline SCefazolin RGentamicin RTrimethoprim/ RsulfamethoxazolePharmacologyofAntimicrobialTherapy

抗菌療法的藥理學(xué)DosingRegimen定量療法Concentrationsinserum血清藥物濃度Concentrations

intissuesand

bodyfluids組織與體液藥物濃度Concentrations

atsiteofinfection感染灶藥物濃度Pharmacologic

andtoxicologic

effect藥理學(xué)和毒理學(xué)作用Antimicrobial

effect抗菌作用Absorption吸收Distribution分布

Elimination消除Pharmacokinetics(PK)藥代動力學(xué)Pharmacodynamics(PD)藥效動力學(xué)MIC,MBC,MPCCmax/MIC,T>MIC,AUIC…MIC

MinimumInhibitoryConcentration（最小抑菌濃度）MBC

MinimumBactericidalConcentration（最小殺菌濃度）MPC

MutationPreventionConcentration（預(yù)防突變濃度）M“X”CSBTSerumBactericidalTiter（血清細菌滴度）ContentsDrug-Bugrelationship:MICMICversusDiskSusceptibilityClinicalApplicationsMIC與紙片敏感性的比較臨床應(yīng)用Drug-Bug關(guān)系：MICBrothDilutionMethod肉湯稀釋法EtestBDPhoenix?BDXpertSystemRange

范圍MIC50

抑制半數(shù)細菌生長的最小抑菌濃度MIC90

抑制90％細菌生長的最小抑菌濃度Geometricmean

幾何平均數(shù)MICDistribution

MIC分布MICsMIC

DistributionS.pneumoniae,2001-2002,Taiwan臺灣，2001-2002，肺炎鏈球菌的MIC分布No.ofisolatesMIC90LevofloxacinMoxifloxacin莫西沙星Cipofloxacin環(huán)丙沙星HsuehPRetal.AntimicrobAgentsChemother2005左氧氟沙星

0.03%ofisolatesMIC(g/ml)MICDistributionofEnterobacteriaceae419Isolates,Taiwan,2003臺灣，2003，腸桿菌科的MIC分布MIC90ChengNC,HsuehPRetal.MicrobDrugResist2006亞胺培南美羅培南厄他培南InhibitoryQuotient(IQ)

TherapeuticIndex Averagepeaklevel(blood,urine,bile,CSF)IQ= MIC IndicatingmultipleoftheMICcanbeexpectedwiththelowestusualdosage(IV)employedclinically

指示了采用臨床常規(guī)最低劑量藥物時，可預(yù)測的藥物平均峰值對MIC的倍數(shù)。SerumIQ,CSFIQ,bileIQ,urineIQ

(血清、腦脊液、膽汁、尿液的IQ)HigherIQhigherprobabilityofasuccessfulclinicaloutcome(atleastIQ,4-8) 較高的IQ，良好臨床效果的可能性較高（至少IQ為4－8）Ingeneral:IQ

4

一般：IQ≥4Endocarditis,osteomyelitis,meningitis:IQ

8心內(nèi)膜炎，骨髓炎，腦(脊)膜炎：IQ≥8

抑制商數(shù)治療指數(shù)MICBreakpoints

HowtoDefinePharmacologicalConsiderationsClinicalEvaluationEpidemiologicalData如何規(guī)定MIC折點藥理學(xué)方面的考慮臨床評價流行病學(xué)數(shù)據(jù)Quinolones

PenetrationintoLung

滲透到肺中的喹諾酮類

Antibioticconcentration

Brochial Epithelial Alveolar Serum mucosa liningfluid macrophage

Antibiotics (mg/L) (mg/kg) (mg/L) (mg/L) Ciprofloxacin 1.19 1.85 3.0 13.39 Levofloxacin 4.1 6.0 10.9 27.7 Moxifloxacin 4.52 5.5 4.4 113.6 Azithromycin 0.5-0.6 8.1 2.2 23.0Cefuroxime 3.4-4.6 3.8 - - Amoxicillin/ 6.3-6.9/ 3.0/1.7 0.9/1.0 0/0.8clavulinicacid4.3-5.3 WiseandHoneybourneEurRespirJ1999血清支氣管粘膜上皮細胞內(nèi)襯液肺泡巨噬細胞抗菌素濃度EffectofIncreasingConcentrations

onKillingofPseudomonasaeruginosa增加濃度對銅綠假單胞菌的殺菌效果AntimicrobialActivity

ThreePatterns

抗菌活性的三種模式Concentration-dependent Time-dependentPersistenteffect(++)Persistenteffect(

)Persistenteffect(+)Aminoglycosides All-lactams Macrolides

Quinolones flucytosineglycopeptidesKetolides stretograminsAmphotericinB linezolid,fluconazoleMaximizeconc. Optimizeduration OptimizeamountAUIC,Cmax/MIC TimeaboveMIC AUIC

濃度依賴性持續(xù)作用（++）持續(xù)作用（+）持續(xù)作用（++）時間依賴性最大濃度優(yōu)化持續(xù)時間優(yōu)化持續(xù)時間TimeMIClogConcentrationPeak(Cmax)Concentration-Dependent

濃度依賴性(AchieveHighestPossibleDoseWithoutToxicity)（無毒性作用所能達到的最大可能劑量）MaximizeBactericidalCmax/MIC,8-10:1MICTimeMIClogConcentrationTime>MICTime-Dependent

時間依賴性(MaximizetimeaboveMIC)（藥物濃度高于MIC的最大時間）MaximumkillingT>MIC,40-50%Cmax=3-4xMICTMICMICPeak(Cmax)TimeMIC90LogConcentration24h-AUC24h-AUC/MIC90(24h-AUIC)AreaundertheSerum-TimeCurve

AUC血清－時間曲線下面積MICDoseDosePeak(Cmax)AUC40302010004812162024TMICMICTime(h)Concentration(mg/L)PK/PDSurrogateRelationships藥代動力學(xué)/藥效動力學(xué)的替代關(guān)系24h-AUC/MICCmax/MIC:>10-12xTime>MIC:>40-50%MIC90Definitetherapy確診治療Empiricaltherapy經(jīng)驗性治療Fluoroquinolones

PK/PD-OptimizedTherapy

氟喹諾酮類PK/PD－優(yōu)化治療Cmax/MICratio824-hAUC/MICratio125(GPB,GNB);25-30(GPB?)125(all):resistancepreventionDonotover-fractionatethedailydoseRelationshipbetween24-HourAUC/MICandMortalityinAnimalsforFluoroquinolonesagainstS.pneumoniae

采用氟喹諾酮類治療肺炎鏈球菌感染，

24-HourAUC/MIC與動物死亡率間的關(guān)系2.51025100250100002040608010024-HourAUC/MICMortality(%)1AndesD,CraigWA.IntJAntimicrobAgents.2002;19:261-8.Daysoftherapy0 2

4 6 8 10 12 140100755025AUIC125-250AUIC>250AUIC<125Patientsremainingculture-positive(%)ForrestAetal.AntimicrobAgentsChemother1993;37:1073-81.AUIC:AUC24

/MIC.TimetoBacterialEradicationvsAUIC

細菌根除時間vsAUIC4616120QuinolonePharmacodynamics

S.pneumoniae,2001,Taiwan

治療肺炎鏈球菌，喹諾酮藥效動力學(xué)AUC/MIC90AUC:MIC~30Gram-positiveorganismsCIPRO=ciprofloxacin,LEVO=levofloxacin,GREPA=grepafloxacin,GATI=gatifloxacin,MOXI=moxifloxacin192210.250.250.03310AUC:MIC~125Gram-negativeorganisms‘TimeaboveMIC’

PredictsEfficacy

‘藥物濃度高于MIC的時間’的預(yù)測效能Penicillins青霉素類:‘TimeaboveMIC’

40%ofdosinginterval藥物濃度高于MIC的時間需達到或超過給藥間歇時間的40％Cephalosporins頭孢菌素類:‘TimeaboveMIC’

50%ofdosinginterval藥物濃度高于MIC的時間需達到或超過給藥間歇時間的50％Craig&Andes.PediatrInfectDisJ1996;15:255–259

Craig.ClinInfectDis1998;26:1–12DaganRetal.LancetInfectDis2002;2:593-604.AssociationbetweenTimeaboveMICinSerumversusBacteriologicalSuccessfor-LactamAntibioticsintheTreatmentofAOMT>MICof>40-50%Predict85-100%clinicalsuccessCraigWA.PediatrInfectDisJ1996;15:255-9.DeterminationofMBCBrothDilutionMethod采用肉湯稀釋法確定最小殺菌濃度IsolatedbacteriumNovelAgents

againstGram-PositiveBacteria

Bactericidalvs.Bacteriostatic

殺菌vs.抑菌(n=10)(n=10)(n=10)(n=10)Vancomycin-RVancomycin-RMBC/MIC320000xxxxDaptomycin MIC90 MBC90MSSA 0.5 2MRSA 1 2VRE.faecalis 2 8VRE.faecium 4 8 MPCMutationPreventionConcentration突變預(yù)防濃度Timepost-administrationMICMPCSerumortissuedrugconcentrationMutantSelectionWindow(MSW)突變選擇窗口MSWMPC90/MIC90=8-16MPC<CmaxUrbanCetal.JInfectDis2001;184:794-8.

CmaxMPC,mutationpreventionconcentrationFluoroquinolonePotency

BasedonPK/PDParameters

S.pneumoniae

基于PK/PD參數(shù)，氟喹諾酮治療肺炎鏈球菌的效能 MIC90 MPC90 CmaxAUIC Agent (g/ml)(g/ml)(g/ml)Ciprofloxacin 2 16 3.0 16Levofloxacin 1 8 5.7 45Moxifloxacin 0.25 2 4.5 192Gatifloxacin 0.5 4 4.2 60Gemifloxacin 0.03 0.5-1 1.2-1.5310

BlondeauJMetal.AntimicrobAgentsChemother2001;45:433-8. UrbanCetal.JInfectDis2001;184:794-8.

MICBreakpoints

HowtoDefine

如何規(guī)定MIC的折點PharmacologicalConsiderationsClinicalEvaluationEpidemiologicalData藥理學(xué)方面的考慮臨床評價流行病學(xué)數(shù)據(jù)ClinicalOutcomevs.MICSurvival(%)MIC(g/mL) BolivarR,etal,RevInfectDis1983RIS臨床結(jié)果vs.MICMICvs.ClinicalOutcome

CefoperazoneTreatmentfor276Patients

MIC

vs.

臨床效果MICs(g/ml)

ofpathogen %ofclinicalfailure

1 4 16 16 32 32 64 44

Cefoperazone:S,

16g/ml;I,32g/ml;R,64g/ml

CraigWA.DiagnMicrobiolInfectDis1993. TurnidgeJD.ClinInfectDis1998.

CefotaximeSusceptibilityBreakpoints

頭孢噻肟的藥敏折點 MIC ZonediameterCategory (g/ml) (mm)Susceptible 8 23Intermediate 16-32 15-22Resistant 64 14ForStaphylococci,Enterobacteriaceae,P.aeruginosa,Acinetobacterspp.

M100-S13NCCLS2003

Susceptible(S)

敏感

DefinitionAninfectionduetothestrainmaybeappropriatelytreatedwiththedosageofantimicrobialagentrecommendedforthattypeofinfectionandinfectingspecies,unlessotherwisecontraindicated某菌株導(dǎo)致的感染能夠被推薦的用于該類型感染和該種感染株的抗菌素劑量進行適當(dāng)?shù)闹委?，除非有其它的禁忌癥。

M100-S16NCCLS2006Resistant(R)

耐藥

DefinitionStrainsarenotinhibitedbytheusuallyachievablesystemicconcentrationoftheagentwithnormaldosageschedules

采用常規(guī)療程劑量通常所能達到的系統(tǒng)濃度對菌株無法抑制。StrainswithMICfallintherangewherespecificmicrobialresistancemechanismsarelikelyandclinicalefficacyhasnotbeenreliableintreatmentstudies

菌株的MIC符合某范圍，該范圍內(nèi)細菌可能產(chǎn)生特異性的耐藥機制，并且在治療研究中臨床效能是不可靠的。

M100-S16NCCLS2006Intermediate(I)

中介

DefinitionIsolateswithMICsapproachingusuallyattainablebloodandtissuelevel

菌株具有接近于通?？蛇_到的血液與組織水平的MICs。Responseratesmaybelowerthanforsusceptibleisolates

反應(yīng)率可能比敏感菌株低。Clinicalapplicabilityininfectedsiteswherethedrugsarephysiologicallyconcentratedorhighdosageofadrugcanbeused

臨床適用于藥物能生理性濃縮或能采用高劑量藥物的感染灶?！癇ufferzone”

緩沖地帶

M100-S16NCCLS2006Streptococcuspneumoniae

PenicillinSusceptibilityCriteria

肺炎鏈球菌青霉素敏感標(biāo)準(zhǔn) MIC(g/ml)Agent S I RMeningitisPenicillin 0.06 0.12-1 2Penicillin(OX-1) 20mm

19mmCefotaxime(CRO,FEP) 0.5 1 2Non-meningitis

Penicillin

2 4 8Amoxicillin(-clav) 2(2/1) 4(4/2) 8(8/4)

Cefotaxime(CRO,FEP)1 2 4

M100-S18NCCLS(CLSI)2008MICDataMIC值

SelecttheLowestMICDrugisOftenNotAppropriate

選擇具有最低MIC的藥物常常并不合適AnorganismwithanMICof8g/mlofadrugismoreresistantthananorganismwithanMICof2g/mlofthesamedrug

對某藥物具有8g/mlMIC的菌株比對同一藥物具有2g/mlMIC的菌株更加耐藥。AnorganismwithanMICof8g/mltoonedrugandof2g/mltoaseconddrugisnotnecessarilymoreresistanttothefirstdrug

對第一種藥物具有8g/mlMIC，對第二種藥物具有2g/mlMIC的菌株不一定對第一種藥物更加耐藥。AgentamicinMICof16g/mlcannotbedirectlycomparedtoacephalosporinMICof16;thelaterleveliseasilyachieved,theformerisdifficultandtoxic

對慶大霉素16g/ml的MIC不能直接與頭孢菌素16g/ml的MIC相比較；后者的水平容易達到，前者是困難的且有毒性。

MICsvs.S,I,R

AreMICsperseMoreValuabletoPhysicians(?)

MICS是否本質(zhì)上對醫(yī)生更有價值？Non-infectiousdiseasespecialistscaninterpretaccuratelytheMICs(?)

非感染科專家能準(zhǔn)確的解釋MICs(?)DeterminationofMICsissuperiortocategoryresultsinpatientmanagement(?)noclearproof!!!

在病人治療中，MICs的確定應(yīng)優(yōu)先于類別結(jié)果(?)無明確的證據(jù)?。?！ShouldwereportMICvaluesaloneorwithS,I,R我們是否只需要單獨報告MIC值或是連同S,I,R?MarginalIntereststoCliniciansMadeinChinaCefotaximeSusceptibilityBreakpoints

頭孢噻肟敏感性折點 MIC ZonediameterCategory (g/ml) (mm)Susceptible 8 23Intermediate 16-32 15-22Resistant 64 14ForStaphylococci,Enterobacteriaceae,P.aeruginosa,Acinetobacterspp.

M100-S12NCCLS2002

MICTestingin

ClinicalMicrobiologyLaboratory

Indications

臨床檢驗科MIC檢測的指征ConsultationwithaninfectiousdiseasespecialistisrecommendedindeterminingtheneedforMICtestingandininterpretationofresults

建議與感染疾病專家交流決定是否需要檢測MIC，并對結(jié)果進行解釋。Forpathogenscausinginfectioninvolvingtissuewithlowerlevelofantibioticthanserum(endocarditis,osteomyelitis,meningitis,septicarthritis,etc.)

引發(fā)感染的病原菌涉及組織內(nèi)的抗菌素濃度低于血漿（心內(nèi)膜炎、骨髓炎、腦(脊)膜炎、膿毒性關(guān)節(jié)炎等。）AleastforS.pneumoniae,andviridansstreptococciisolatedfromnormallysterilesites

至少對從正常無菌部位分離出的肺炎鏈球菌和草綠色鏈球菌CorrelationofClinicalOutcomeandAntibioticLevelsinBodyFluidsandTissues

體液與組織中抗菌素水平與臨床效果的關(guān)系Bodyfluid Predictivevaluefor ortissue favorableoutcomeSerum Freedrugconc.>MICCSF 10-to30-fold>MICUrine MICRespiratorytract >MIC:bronchialsecretionor tissue,intracellulardrugconc.Bone >MIC:osseoustissueconc.

體液或組織良好療效的預(yù)測值SSSS

andBothsusceptibleBurkholderiapseudomallei

(Blood,Pleuraleffusion,Synovialfluid)

鼻疽伯克霍爾德菌（血、胸腔積液、滑液）Agent MIC(g/ml) MIC(g/ml),S AMC 4/2(S) 8/4(?)Ceftazidime 8(S) 8Imipenem 0.5(S) 4Ciprofloxacin 1(S) 1Streptococcuspneumoniae

PenicillinSusceptibilityCriteria

肺炎鏈球菌青霉素敏感標(biāo)準(zhǔn) MIC(g/ml)Agent S I RMeningitisPenicillin 0.06 0.12-1 2Penicillin(OX-1) 20mm

19mmCefotaxime(CRO,FEP) 0.5 1 2Non-meningitis

Penicillin

2 4 8Amoxicillin(-clav) 2(2/1) 4(4/2) 8(8/4)

Cefotaxime(CRO,FEP)1 2 4

M100-S18NCCLS(CLSI)2008腦(脊)膜炎非腦(脊)膜炎TreatmentGuidelinesforPneumonia

S.pneumoniae

肺炎鏈球菌性肺炎的治療指導(dǎo)方針Penicillin MIC(g/ml) Primary Alternative1 Penicillin 1stgen.cephalosporins(S) AmpicillinorAmoxicillin

2 Penicillin(highdose) 3rdor4thcephalosporins(I) AmpicillinorAmoxicillin4 3rdor4thcephalosporins VancomycinorTeicoplanin(R) VancomycinorTei