抗生素合理使用

抗生素合理使用主要内容流行病学感染有关概念PK/PD理论细菌耐药与抗菌药物使用急诊常见感染病处置流行病学-严重感染非心脏ICU患者的首要死亡原因年死亡率与心肌梗塞相同在美国人口的全部死因中居第11位每年约750,000例严重感染发病率：3/1000每年死亡患者超出225,000例死亡率：约30%

常见的致死率高的临床综合症严重感染-发展趋势人口老龄化医疗水平提升，生命支持治疗发展免疫功能低下（肿瘤治疗、器官移植）介入性技术和装置推广应用细菌耐药性与院内感染增多严重感染与其他疾病比较发病率死亡率NationalCenterofHealthStatistics.2023.AmericanCancersociety，2023感染的有关概念ACCP/SCCM联席会议定义BoneRC,BalkRA,CerraFB,etal.Chest.1992Jun;101(6):1644-55.Review.BoneRC,BalkRA,CerraFB,etal.Chest.1992Jun;101(6):1644-55.Review.SIRSBoneRC,BalkRA,CerraFB,etal.Chest.1992Jun;101(6):1644-55.Review.SEPSISBoneRC,BalkRA,CerraFB,etal.Chest.1992Jun;101(6):1644-55.Review.SEVERESEPSIS感染的演变过程Infection/TraumaSIRSSEPSISSEVEREsepsisMODS具有两项一下临床体现:1.体温>38℃或<36℃2.心率>90次/分3.呼吸频率>20次/分4.白细胞计数>12,000/mm3或<4,000/mm3或幼粒细胞>10%感染引起的SIRSMODS的体现SevereSepsis治疗感染源的处置抗菌药物使用循环支持机械通气肾脏替代镇定/止痛营养WheelerAP,BernardGR.Treatingpatientswithseveresepsis.NEnglJMed.1999Jan21;340(3):207-14.Review.

抗生素使用目的控制感染较少副作用合理剂量疗程正常菌群稳定合理药物，途径，方式PharmacologyofAntimicrobialTherapyDosingregimenConcentrationsinserumConcentrations

intissuesand

bodyfluidsConcentrations

atsiteofinfectionPharmacologic

andtoxicologic

effectAntimicrobial

effectAbsorption

Distribution

EliminationPharmacokinetics(PK)Pharmacodynamics(PD)MIC、MBC抗菌药物起效过程剂量药动学药效学起效溶解吸收分布代谢排泄时间依赖杀菌浓度依赖杀菌抗生素后效应细菌数量死亡率症状体征辨认药代动力学和MICDifferentpatternoftime-killingof3AbxVSPseudomonasKillingandrateofkillingdependsonconcentrationRateofkillingincreasesnomoreasconcentrationincreases,killingdependsonexposuretimePK/PDPredictorsofEfficacy-acombinationofPKandPDTimeMIC90LogConcentration24h-AUCT>MICCmax,Cmax/MIC24h-AUC/MIC(AUIC)DoseDoseCmaxT>MICParametersofinterestPK/PDPredictorsofEfficacy根据PK/PD抗菌药物分类时间依赖性与时间有关，但抗菌活性连续时间较长对致病菌的杀菌作用取决于峰浓度抗菌作用与同细菌接触时间亲密有关时间依赖且PAE或T1/2较长氨基糖苷类、氟喹诺酮类、酮内酯类、两性霉素B、daptomycin、甲硝唑多数β-内酰胺类、林可霉素类恶唑烷酮类、氟胞嘧啶

链阳霉素、四环素、碳青霉烯类、糖肽类、大环内酯类、唑类抗真菌药主要参数AUC0-24/MIC(AUIC)Cmax/MIC主要参数

T>MIC和AUC>MIC主要参数

T>MIC,PAE，T1/2AUC/MIC

浓度依赖性Required%T>MICforcidal:~40%forcarbapenems~50%forpenicillins~70%forephalosporinsDrusanoGL.ClinInfectDis.2023;36(suppl1):S42-S50.

Required%T>MICforstatic

－20%forcarbapenems－30%forpenicillins

－40%forcephalosporins

-lactam:optimalT>MIC?Drusano.ClinInfectDis2023;36(Suppl.1):S42–S50MaximizingT>MIC提升剂量－安全性前提增长给药频率延长输注时间-内酰胺类－优化暴露时间

-Lactam:OptimizingExposureDandekarPKetal.Pharmacotherapy.2023;23:988-991.Meropenem500mgAdministered

asa0.5hor3hInfusionMIC024680.11.010.0100.0Concentration

(mcg/mL)Time(h)RapidInfusion(30min)ExtendedInfusion(3h)TreatmentofMultidrug-resistantBurkholderiacepaciaWithProlongedInfusionMeropenemMeropenem2ginfusedover3hoursq8hTime(h)Concentration(mcg/mL)08162432400.1110100MIC=16mcg/mLT>MICexposurewas40%ofthedosingintervalattheMICof

16mcg/mLKutiJLetal.Pharmacotherapy.2023;24:1641-1645Mooreetal.JInfectDis1987;155:93–99Aminoglycoside:optimalCmax:MIC

-RelationshipBetweenCmax:MICandClinicalResponseClinicalresponse(%)Cmax:MIC02040608010024681012556570838992WhatistheOptimalAUICforFluoroquinolones?30125ForG+ForG-Forrestetal.AntimicrobAgentsChemother1993;37:1073–1081FluoroquinoloneTherapyforNosocomialPneumonia

－CorrelationBetweenDrugExposure(AUC/MIC)&OutcomePatientscured(%)0204060801000–62.562.5–125125–250250–500>500AUC:MICClinicalMicrobiologicalAUC:MIC>125leadtoappropriateclinicalandmicrobiologicaloutcomeGram-NegativeBacterialEradication

andFluoroquinoloneAUIC

Days02

46

81012140100755025AUIC125-250AUIC>250AUIC<125%Patientsremaining

culturepositiveForrestetal.AntimicrobAgentsChemother.1993;37:1073-1081HigherAUC:MICleadtoletterbacterialeradicationProbabilityofDevelopingResistanceThomasKLetal.AntimicrobAgentsChemother.1998;42:521–527AUC0–24h:MIC

100AUC0–24h:MIC<100Daysfrominitiationoftherapy05101520020406080100Probabilityofremainingsusceptible(%)Datafrom107acutelyillpatientswithnosocomialRTIstreatedwith5differentantibioticregimens(ciprofloxacin,cefmenoxime,ceftazidime,ciprofloxacinpluspiperacillin,ceftazidimeplustobramycin)OptimizingFQstherapyforS.pneumoniae

fromPK/PDpointofviewEfficacyCmax/MICratio8-1024-hAUC/MIC(AUIC)TotalAUIC>100FreeAUIC>30-40ResistancepreventionCmax>MPCHigherAUICBaquero&Negri.BioEssays1997;19:731-6DrlicaK.ASMNews2023;67:27-33Cantónetal.InterJAntimicrobChemother2023(inpress)Concentration(µg/ml)Timepostadministration(h)CmaxMPCTmaxMICWindowofselectionMICMPC(MICofmutants)ResistantmutantSusceptiblebacteria重症患者抗菌药物使用重症患者，利用PK/PD理论合理的使用抗菌药物，同步还要关注重症患者的全身情况选择抗菌药物时应考虑的其他原因OtherconsiderationsinchoosingAbx－杀菌vs抑菌(Cidalvsstatic)

严重/复杂感染选杀菌剂cidalforseriousandcompicatedinfections－单药vs联合(monotherapyvscombination)：－静脉vs口服(IVvsoral)－疗程(duration)Bioavailability－以活性状态到达目的细菌的能力口服吸收率－决定多少药物发挥活性作用多少胃肠道副作用对细菌耐药产生影响的大小药物穿透力药物对水解酶的稳定性药物对微生物的杀菌能力－感染部位（MIC/MBC,T>MIC）选择口服抗菌药物应该考虑TheDurationofAntimicrobialTherapyBacterialoadClinicalcourseRecurrence急性感染Acuteinfection慢性感染，疗程不足Chronicinfection,durationnotenough慢性感染，足疗程Chronicinfection,durationenough8vs.15DaysofAntibioticTherapy

Ventilator-AssociatedPneumonia(cont’d)ChastreJ,etal.JAMA.2023;290:2588-2598.前瞻,随机,双盲临床研究51法国ICUs至少进行机械通气48hs药物由治疗医生选择方案遵从ATS指南主要观察指标病死率微生物学证明的感染复发VAP发生后28天不用抗菌药物的时间CAP指南推荐疗程同种药物短程和长程疗效比较PinzoneMR,

etal.Duration

ofantimicrobialtherapyin

community

acquired

pneumonia:lessismore.ScientificWorldJournal.

2023Jan21;2023:759138.不同药物短程和长程疗效比较在确保初始抗菌药物正确，给药方式，途径合理的情况下，VAP患者与CAP患者推荐短程抗生素治疗降阶梯治疗ICU住院时间抗菌药物疗程机械通气院感率MDR发生率P>0.05GonzalezL,etal.Factorsinfluencingtheimplementationofantibioticde-escalationandimpactofthisstrategyincriticallyillpatients.CritCare.2023Jul12;17(4):R140.外科ICU感染的降阶梯治疗Morel,etal.Deescalation

as

part

of

global

strategy

of

empiric

antibiotherapy

management.A

retrospective

study

inamedico-surgical

intensive

care

unit.Crit

Care.2023;14(6):R225.推荐在重症感染或感染休克患者进行降阶梯治疗，而且是安全可行的靶位变化膜通透性↓泵出机制↑替代途径灭活酶细菌耐药模式图细菌耐药示意图抗菌药物的附加损害51MRSAVRE产ESBLs菌株MDR铜绿假单胞菌MDR不动杆菌难辨梭状芽孢杆菌四代头孢菌素(头孢吡肟)碳青霉烯类(亚胺培南/美罗培南)三代头孢菌素氟喹诺酮Pena,etal,AntimocrobAgentsChemother1998;42:53-8西班牙巴塞罗那Bellvitge医院

抗生素干预策略的成效93年1~8月ESBLs日益严重93年9月降低三代头孢菌素使用增长亚胺培南的使用94年1月特治星加入干预，与亚胺培南同步使用94年5月开始增长特治星用量，同步降低亚胺培南和三代头孢使用后，ESBLs发生率才开始明显下降克里夫兰退伍老兵医院抗生素干预RiceLetal.ClinInfectDis1996;23:118-24RiceL.Pharmacotherapy1999;19(8Pt2):120S-128S耐药率(%)抗生素用量(g)中国抗菌药物干预情况BaoL,.PLoSOne.

2023,13;10(3):e0118868.InfectionControlAntibioticControlVREMRSAESBLK.pneumoniaeAntibioticControlandInfectionControl:TheTwoSidesoftheResistance“Coin”RekhaMurthy.ImplementationofStrategiestoControlAntimicrobialResistanceChest2023;119;405-411ControlofAntibioticResistance控制抗菌药物使用量对降低抗菌药物的附加损害，降低耐药率具有主要作用感染病诊疗、治疗与预防、控制的学科体系感染病