从PKPD看抗菌药物的合理应用

从PK/PD看抗菌药物的合理应用DefenitionPK…..Whatthebodydoestothedrug Absorbtion Cmax Metabolism AUC Elimination Half-lifePD…..Whatthedrugdoestothebody DirecteffectsMIC,MBC Post-drugeffectsPAE SelectioneffectsResistancePharmacokineticsConcentrationvsTime

FromPKtoPDConc.TimePharmacodynamicsEffetvsTimeEffectConc.PK/PDEffectvsTimeEffectTimePeak/MICAUICAUC/MICAUC>MICPALECmax/MICT>MICPAEPA-SMEMPC抗菌药药效学细菌对抗菌药的敏感性纸片扩散法（K-B法）最低抑菌浓度(MIC)最低杀菌浓度(MBC)

药物敏感试验琼脂扩散法(纸片法，Kirby-bauer)－测抑菌圈大小画分S,I,R稀释法－琼脂稀释法，肉汤稀释法，微量稀释法E测定法(Epsilometertest)－测MIC值判断标准：通常根据CLSI判断结果4.

自动化药敏测MIC－ATB系统，Vitek系统，MicroScan等药敏试验的临床意义敏感(S)－常规剂量时的平均血浓度超过MIC的5倍以上，用常规剂量通常有效中介(I)－常规剂量时的平均血浓度等于或略高于MIC，需用高剂量或对药物浓缩部位的感染可能有效耐药(R)－药物的MIC高于其常规剂量时的血浓度，通常治疗无效CHINET2012年15家医院31277株肠杆菌科细菌耐药率（%）抗菌药物耐药敏感亚胺培南5.092.2美罗培南4.494.6厄他培南6.391.8阿米卡星7.490.7磷霉素12.284.9哌拉西林/他唑巴坦8.484.2头孢哌酮/舒巴坦10.573.9头孢他啶29.165.3头孢吡肟20.273.2庆大霉素CHINET2012年15家医院19613株非发酵菌耐药率（%）抗菌药物耐药敏感头孢哌酮/舒巴坦26.552.8阿米卡星28.967.9头孢他啶41.952.9头孢吡肟40.453.3哌拉西林/他唑巴坦38.552.5美罗培南44.252.8亚胺培南45.152.0环丙沙星40.055.0各种酶抑制剂复方制剂的比较AM-SBAM-CLTC-CLCPZ-SBPIP-TAZ商品名优力新力百汀特美汀舒普深特治星肠杆菌科2＋2＋2＋～3＋3＋2＋～3＋绿脓、沙雷菌－－2＋～3＋3＋3＋不动杆菌2＋－－3＋－肠球菌2＋2＋2＋－3＋嗜麦芽窄食单胞菌－－3＋3＋2＋头孢哌酮/舒巴坦与头孢菌素、亚胺培南特性比较肠杆菌科细菌铜绿假单胞菌鲍曼不动杆菌厌氧菌链球菌属MRSA特点头孢哌酮/舒巴坦+++±++++++++±－不动及铜绿耐药低适用于经验治疗链球菌属作用差头孢他啶+++++±±－耐药率高，适用于病原治疗；链球菌属、厌氧菌作用差，不适用于吸入肺炎的治疗头孢吡肟++±++++±+++－耐药率与头孢他啶基本相仿，对链球菌的作用增强亚胺培南+++++++±+++++－抗菌谱广，VAP经验治疗需注意不动杆菌耐药性对于革兰阴性菌：++++,R<10%;+++,R<20%;++,R<50%;+,R<80%抗菌药药效学

——MICandMBC参数的不足MIC和MBC反映体外活性，但不反映活性在体内的时间过程MBC不能提供抗菌药的杀菌速度，不能预言增加药物浓度是否可以提高杀菌速度MIC也不能反映细菌在接触抗菌药后，被抑制的状态能持续多少时间抗菌药药效学杀菌曲线(time-killcurves)杀菌曲线反映抗菌药杀灭细菌的动态过程与杀菌效率当抗菌药浓度≥MIC时，杀菌曲线有两种菌量随时间延长逐渐减少，表明具有杀菌作用，为杀菌剂菌量随时间变化不明显，曲线呈近水平状，表明仅具抑菌作用，为抑菌剂Effectofincreasingconcentrationsoftobramycin(a),

Ciprofloxacin(b)andTicarcillin(c)onthebacterial

activityagainstPseudomonasAeruginosaLog10cfu/ml(a)9Time(h)1234567802460246024681MIC4MIC0.5MICControl16MIC64MIC(b)(c)抗菌药药效学抗生素后效应（PAE）是指细菌暴露于抗菌药后，在洗去抗菌药的情况下，数量增加十倍（1log10单位）所需的时间（与对照组的差）PAE的大小反映抗生素作用后细菌再生长延迟相的长短，亦反映抗菌药作用于细菌后的持续抑制作用，故而又称持续效应（Persistenteffects）抗菌药药效学抗生素后效应（PAE）PAE在不同抗菌药、不同细菌持续时间有很大差异，且受抗菌药浓度、作用时间等影响对于GPC，所有抗菌药均有PAE；对于GNB，抑制蛋白和核酸合成的抗菌药具有PAEβ内酰胺类对GNB几乎无PAE或短，但亚胺培南对铜绿假单胞菌的PAE为1-2hPost-AntibioticEffect(PAE)RemovalofAntibioticViableCount(cfu/ml)Control1.6hourstoincrease1log10

1log10increase3.1hourstoincrease1log10

AntibioticInduceddeathPAE=3.1-1.6=1.5hoursDuetoantibioticeffectonly药效学/药动学（PK/PD）原则——根据杀菌活性对抗菌药物进行分类第一大类：时间依赖型在药物浓度超过MIC4-5倍以上时杀菌活力不再增加代表药物：β内酰胺类、大环内酯类、克林霉素和万古霉素第二大类：浓度依赖型药物的杀菌活力在很大范围内随药物浓度的增高而增加代表药物：氨基糖苷类、氟喹诺酮类和甲硝唑等

PK/PDparameterscorrelatingwith

antibacterialefficacyPatternofactivityAntimicrobialsGoaloftherapyandPK/PDparameterscorrelatingwithefficacyTime-dependentkillingandminimalornopersistenteffectsPenicillin,cepholosporins,carbapenems,aztreonam,BL/BLI,SMZ/TMPMaximizedurationofexposure;Time>MICTime-dependentkillingandminimalormoderateprolongedpersistenteffectsMacrolides,azithromycin,clindamycin,streptogramins,tetracyclines,glycopeptides,oxazolidinonesMaximizeamountofdrug;24-hrAUC/MICConc.-dependentkillingandprolongedpersistenteffectsAminoglycosides,fluoroquinolones,daptomycin,ketolides,metronidazoleMaximizeconc.;24-hrAUC/MICandpeak/MIC根据PK/PD原理制订的给药方案可以达到更高的疗效和清除病原菌的作用，并可能防止疗程中细菌产生耐药性与时间依赖型药物杀菌活力有关的PK/PD参数是T＞MIC，即血药浓度达到或超过MIC持续的时间占2次给药间期的百分比与浓度依赖型药物杀菌活力有关的主要参数是AUC24/MIC或Cmax/MIC药效学/药动学（PK/PD）原则——PK/PD参数的意义PharmacodynamicsParameters&OutcomeRybakMJ.AmJMed2006;119:S37-S44.TimeConc.Cmax=PeakCmin=TroughMICPAET>MICAUC/MICCmax/MICBeta-lactamsTetracyclineOxazolidinonesAminoglycosideFluoroquinolonesDaptomycinFluoroquinolonesMacrolidesKetolidesGlycopeptidesLipopeptidesTime-dependentagentsTimeAntibacterialconcentration

(µg/ml)2DrugADrugBADrugApresentatconcentrationof2µg/mlfor50%ofdosingintervalDrugBpresentatconcentrationof2µg/mlfor30%ofdosinginterval4680TimeaboveMICXBDosingintervalTimeaboveMIC

CorrelationofserumpharmacokineticswithMIC(susceptibility)ofanorganism

MIC

ScandJInfectDisSuppl96:11-16,1995抗菌药发挥作用所必需的

Time>MIC抗生素B／A（%）

碳青霉烯类

头孢菌素类

青霉素类30-40%50-60%50-60%给药间隔的多少%合适？＜B／A（%）＞

B:TimeaboveMIC时间A:给药间隔时间PharmacodynamicGoals(T>MICaspercentofInterval)withBeta-Lactams MaximumClass Organism Stasis KillingCephalosporins GNR,pneumo 40-50 70-80 Staph 20-30 40-50Penicillins GNR,pneumo30-40 60-70 Staph 20-3040-50Carbapenems GNR,staph 20-30 40-50 Pneumo 10-20 25-40Craig1999020406080100020406080100TimeaboveMIC(%)PenicillinsCephalosporinsMortalityafter4daysoftherapy(%)Craig.DiagnMicrobiolInfectDis1996;25:213–217RelationshipbetweenTimeaboveMIC

andefficacyinanimalinfectionmodels

infectedwithS.pneumoniae细菌学疗效：青霉素：T>MIC%>40%头孢菌素：T>MIC%>50%RelationshipBetweenT>MICandEfficacyforCephalosporins(Yellow),Penicillins(Aqua)andCarbapenems(Red)MIC：64mg/LMIC：16mg/L8.OkamuraK,etal.ActaUrolJpn.1989;35:727-734.9.SuzuyamaY,etal.Chemotherapy.1984;32(S-4):355-367.10.AoyamaH,etal.JpnJAntibiot.1988;41:1279-1284.11.TsuyukiK,etal.Chemotherapy.1984;32(S-4):404-41212.ChoN,etal.WorldGynecol.1984;36(8):649-675.13.NakagawaK,etal.SurgCare.1990;32(6):875-879.14.HayasakiM,etal.Chemotherapy.1984;32(S-4):649-665.15CetobidProductMonograph.Physician`sDeskReference(53thed.)16WarnkeIP,etal.IntJClinPharmacolTher1998;36(5):253-25717FouldsG,etal.AntimicrobAgentsChemother1997;31(11):1703-170518StahlJP,etal.RevInfectDis1986;8(5):S612-S616药效学/药动学（PK/PD）原则——头孢哌酮-舒巴坦复合制剂中头孢哌酮PK/PD参数比较不动杆菌属大肠埃希菌铜绿假单胞菌产气肠杆菌T>MIC90(%)头孢哌酮-舒巴坦2克q8h和3克q12h在难治的革兰阴性耐药菌中T>MIC90%均达到50％以上嗜麦芽窄食单胞菌阴沟肠杆菌普深在肺组织内的平均浓度超过常见致病菌的MIC90值舒0.10.5致病菌 MIC90(mg/ml)金黄色葡萄球菌

16(产b-内酰胺酶)铜绿假单胞菌 8金黄色葡萄球菌 2肺炎克雷伯菌 2阴沟肠杆菌 1大肠埃希菌 0.5鲍曼不动杆菌 0.120121020舒巴坦头孢哌酮7.84mg/ml24.60mg/ml肺组织内平均药物浓度(mg/ml)舒普深在静注2g后在肺组织内的平均浓度与对常见致病菌的MIC90值比较*DeguchiK,YokotaN,koguchim,etal,.b-lactamaseactivtyinsputumofpatientswithcommunity-agguiredlowerrespiratorytractinfections.JonJantibiot1994;47:161-169.34舒普深(2:1)3gq6h的PK/PDMIC%T>MIC*64433270169681234150217612030.52300.252560.1252830.0625310*基于舒普深药代动力学参数计算。2.舒普深1.5g说明书；3.REITBERGDP,MARBLEDA,SCHULTZRW,etal.ANTIMICROBIALAGENTSANDCHEMOTHERAPY,1988,p.503-509；5.REITBERGDP,WHALLTJ,CHUNGM,etal.ANTIMICROBIALAGENTSANDCHEMOTHERAPY,Jan.1988,p.42-46头孢哌酮/舒巴坦(2:1)3种给药方案对非发酵菌不同MIC值时%T>MIC（头孢哌酮）给药方案MIC(mg/L)481632643gq8h

(1.5h)1001001006593gq8h

(2h)10010010057153gq6h

(2h)10010010071223gq12h

(2h)1009666354MIC≤16mg/L:3g,q8h、3g,q12h；MIC≥32mg/L:3g,q6h鲍曼：疗程11.2±4.6天，临床治愈率为79.3%（23/29）；微生物学治愈率为69.0%（20/29）铜绿：疗程11.7±4.5天，临床治愈率为68.2%（15/22）；微生物学治愈率为19.0%（4/21），混合感染：临床治愈率：2/3；微生物学治愈率：其中2例铜绿未清除舒普深3g,q8h,疗程14天治疗鲍曼不动杆菌HAP患者PK/PD参数与临床疗效关系的研究（n=12)患者号MICs(μg/mL)%T>MIC临床疗效细菌学疗效综合疗效

CPZSULCPZSUL101.50.75304128治愈清除治愈264226873治愈清除治愈1416821160治愈清除治愈9241210429治愈清除治愈84212360治愈菌交替治愈1621100100治愈菌交替治愈18168680治愈菌交替治愈532166314失败未清除失败1348244410失败未清除失败24824350失败未清除失败74824300失败未清除失败2348245210失败未清除失败Kutietal.AmJHealthSystPharm2002;59:2209–2215Concentration(µg/mL)00.11101004862Time(hours)MIC=2µg/mL;60%T>MICMIC=4µg/mL;46%T>MICMeropenem1gthree-timesdaily:

5000patientMonteCarlosimulation替加环素PK/PD特性

抗生素后效应（PAE）体外PAE金葡菌：3.4～4.0h大肠埃希菌：1.8～2.9h体内PAE大肠杆菌：4.9h肺炎链球菌：8.9h中一长时效的PAEPK/PD参数：AUC24/MIC

CAP患者:fAUC0-24:MIC)of>12.8wereassociatedwithafastertimetofeverresolutionpatientswithlowerdrugexposureshadaslowertimetofeverresolution(P<0.05)替加环素PTA结果.

50and100mgq12hoftigecyclineprovidedPTA(AUC24/MIC>18)valuesof100%forMICs≤0.25mg/Lgoingdownto65%and0foranMICof0.5mg/L,with100and50mgq12hrespectively,A.Canut.EurJClinMicrobiolInfectDis(2012)31:2227多粘菌素PK/PD特性PhillipJ.Pharmacokinetic/PharmacodynamicInvestigationofColistinagainstPseudomonasaeruginosaUsinganInVitroModelAACSept.2010,p.3783多粘菌素E硫酸盐：口服给药、局部给药多粘菌素E甲磺酸盐（CMS）：静脉注射、肌内注射，雾化吸入或鞘内注射多粘菌素B硫酸盐：静脉注射，肌内注射，雾化吸入浓度依赖性：ƒAUC/MICPK/PD靶值：肺部感染中细菌数减少1个lgcfuƒAUC/MIC铜绿假单胞菌：；鲍曼不动杆菌：大环内酯类PK/PD研究4种大环内酯类药物对肺炎链球菌的杀菌曲线结果表明2种酮内酯类药物Telithromycin和ABT-773呈浓度依赖性大环内酯类为时间依赖性，但其中的酮内酯类属浓度依赖性。糖肽类抗生素

PK/PD研究(a)在万古霉素2,

4,

8,

16,

和64倍MIC对S.

aureusATCC29213

的KCs.(b)在万古霉素2,

4,

8,

16和64倍MIC对S.

epidermidisATCC29886

的KCs结果提示万古霉素属于时间依赖性抗菌药物。Non-concentrationdependentkillingof

teicoplaninagainstS.aureus1234567891003691215182124hlog10cfu/ml2xMIC4xMIC8xMIC16xMIC64xMICControl210-1-2-3-43010030010001030100300100020406080100∆log10CFU/gover24h24-hAUC/MICPeak/MICT>MICEbertS.etal.27thICAAC1987.CraigWA&AndesDR.46thICAAC2006.RelationshipofPK/PDforVancomycinBacteriologicEfficacyvs.MSSAinThighsofNeutropenicMiceLINEZOLID治疗大鼠股部肺炎链球菌感染PK/PD参数与细菌学疗效关系可见LINEZOLID

T>MIC％与细菌学疗效相关系数最高为84％，当T>MIC％为40％即可达到良好的细菌学疗效。AndesD,etal.AntimicrobAgentsChemother2002;46:3484-9.斯沃AUC24/MIC>100临床疗效卓越WhitehouseT,etal.JAntimicrobChemother.2005r;55:333-40斯沃AUC24/MIC>100时，细菌清除率高达75％以上一项随机、双盲、安慰剂对照性研究，比较利奈唑胺与替考拉宁治疗ICU患者的药代动力学，用法用量：斯沃600mgivq12h；替考拉宁安慰剂400mgivq12h，给药3次后400mgq24h；替考拉宁400mgivq12h，给药3次后400mgq24h清除率(%)76％95.8％75.4％**CoNS：凝固酶阴性葡萄球菌利奈唑胺PTA结果

PTA(AUC24/MIC>100)higherthan90%forMICs≤2mg/LForanMICof4mg/L,thePTAreachedavalueofabout40%A.Canut.EurJClinMicrobiolInfectDis(2012)31:2227Concentration-dependentagentsAntibioticconcentrationMIC

Time24-hrAUC/MICiscorrelatedwithoutcomeofinfection,themagnituderequiredforsuccessandMICatwhichthisoccursbecomesthePDbreakpoint24-hrAUC/MICandPeak/MICRatios

CorrelationofserumpharmacokineticswithMICofanorganismAreaunderthecurvetoMICratioPeaktoMICratioLevofloxacinPK/PDParametersAgainstS.pneumoniaeinNeutropenicMouseThighInfectionModel%T>MICPeak/MIC24-HrAUC/MICHandbookofExperimentalPharmacology.Vol127:QuinoloneAntibacterials.1998Relationshipbetween24HrAUC/MICandmortalityforfluoroquinolonesagainstS.pneumoniaeinimmunocompetentanimalsMortality(%)24-hrAUC/MIC1251052.502040608010010050Relationshipbetween24HrAUC/MICandmortality

forfluoroquinolonesagainstGram-negative

bacilliinimmunocompromisedanimalsMortality(%)24-hrAUC/MIC310003001003010020406080100Clinicalfailurerate 43% 11.5% 1%LevofloxacinPK/PDcorrelations

134hospitalizedpatientswithRTI,SSTIorUTItreatedwith500mgqdfor5–14daysJacobs.ClinMicrobiolInfect2001;7:589–96[AdaptedfromPrestonetal.JAMA1998;279:125–9]4323310010102030405060708090100No.ofpatientsAUC:MIC<25Peak:MIC<3AUC:MIC25–100Peak:MIC3–12AUC:MIC>100Peak:MIC>12SuccessFailureClinicaloutcomeRelationshipBetween24-HrAUC/MICandEfficacyofCiprofloxacinin64PatientswithSeriousBacterialInfections24-hrAUC/MICRelationshipbetweenmax.Peak/MICratioandtherateofclinicalresponseforaminoglycosides

Mooreet.al.JInfectDis,1987,155:93

MaximumPeak/MICratioResponserate,%Kashubaetal.AntimicrobAgentsChemother1999;43:623–629Probabilityofresolution(%)FirstCmax:MIC10gives90%probabilityofWBCandtemperatureresolutionProbabilityoftemperatureresolutionbyDay7Probabilityofwhitebloodcell(WBC)countresolution

byDay7002040608010051025301520FirstCmax:MICOptimisingaminoglycosidetherapyfornosocomialpneumonia氨基糖苷类日剂量单次给药

1、提高抗菌活性氨基糖苷类属于浓度依赖型抗生素，氨基糖苷类Cmax/MIC与临床疗效呈正相关。在日剂量不变的情况下，单次给药可以获得较多次给药更高的Cmax，使Cmax/MIC比值增大，从而明显提高抗菌活性和临床疗效。但应注意Cmax不得超过最低毒性剂量。2、降低耐药性发生

GouldIM,MilneKandJasonC.DrugExpClinRes.1990;16:621~8.3、降低肾毒性

VerpootenGA,GiulianoRA,VerbistL,etal.ClinPharmacolTher1989;45:22-274、降低耳毒性

FishmanDN,KayeKM.InfectDisClinNirthAm,2000，14(2):475DaptomycinPharmacodynamicsBactericidalinvitroaRapidConcentration-dependentkillingKeypredictorsofefficacybasedonanimalmodelsPeakexposure:Cmax/MICTotalexposure:AUC/MIC5-10hpostantibioticeffectCmax=maximumplasmaconcentration;MIC=minimuminhibitoryconcentration;AUC=areaundertheconcentration-timecurve.aTheclinicalsignificanceofin