根据PKPD理论合理使用抗菌药南京.ppt

根据PK/PD理论合理使用抗菌药,2019年CHINET监测网细菌检出率,G-,G+,2019年CHINET监测网各医院MRS检出率（%）,近年CHINET监测网ESBL检出率（%）,近年CHINET监测网泛耐药G-杆菌检出率（%）,中国CHINET（2019）,MSSA与MRSA的耐药率（%）,不发酵革兰阴性菌对所测抗菌药物的耐药率（%）,societaldrugssocietalconsequences,医疗机构的责任,明确有无适应症选择哪种抗菌药物感染部位的常见病原学选择能够覆盖病原体的抗感染药物-抗菌谱/耐药性/杀菌和抑菌/组织穿透性/安全性/费用考虑病人生理和病理生理状态高龄/儿童/孕妇/哺乳肾功能不全/肝功能不全/肝肾功能联合不全怎么给药单药和联合/静脉和口服/疗程优化药代动力学/药效动力学(PK/PD),如何合理使用抗菌药物,病原菌,体外药效：MIC,0,Concentration,Time(hours),AUC=AreaundertheconcentrationtimecurveCmax=Maximumplasmaconcentration,PK/PD参数,浓度依赖性抗菌药物的评价指标,时间依赖性抗菌药物的评价指标,17,9.5,9.5,9.5,8.5,8.5,8.5,7.5,7.5,7.5,6.5,6.5,6.5,Control1/4MICMIC4MIC16MIC64MIC,5.5,5.5,5.5,4.5,4.5,4.5,3.5,3.5,3.5,2.5,2.5,2.5,1.5,0246,1.5,0246,1.5,02468,Tobramycin,Ciprofloxacin,Ticarcillin,Time(h),Log10cfu/ml,不同MIC妥布霉素、环丙沙星及替卡西林对铜绿假单胞菌的杀菌曲线,ZhanelGG,etal.Drugs,2019,62(1)13-59,PK/PD体外研究,W.A.Craing.DiagMicrobiolInfect2019,抗菌药物的PK/PD分类,0,Concentration,Time(hours),Cmax=Maximumplasmaconcentration,一、氨基糖苷类：Cmax/MIC,Kashubaetal.AntimicrobAgentsChemother2019;43:623629,Probabilityofresolution(%),FirstCmax:MIC10gives90%probabilityofWBCandtemperatureresolution,ProbabilityoftemperatureresolutionbyDay7,Probabilityofwhitebloodcell(WBC)countresolutionbyDay7,0,0,20,40,60,80,100,5,10,25,30,15,20,FirstCmax:MIC,氨基糖苷:Cmax/MIC与HAP治疗反应,Nicolauetal.AntimicrobAgentsChemother2019;39:650655,氨基糖苷:QD与TID给药,氨基糖苷类给药方案优化,一日一次给药优点：Cmax:MIC8-10，有效率90%耐药突变下降减少耳、肾毒性,0,Concentration,Time(hours),AUC=Areaundertheconcentrationtimecurve,二、喹诺酮类：AUC/MIC,氟喹诺酮最佳AUIC（AUC/MIC）,30,125,G+,G-,AntimicrobAgentsChemother,2019Oct;45(10):2793-7,Forrestetal.AntimicrobAgentsChemother1993;37:10731081,AUIC与严重感染病人治疗反应,StreptococcuspneumoniaeCAPAUIC33.7,Forrestetal.AntimicrobAgentsChemother1993;37:10731081MoutonJWetal.DrugResistanceUpdates.2019;14:107117ThomasKLetal.AntimicrobAgentsChemother.2019;42:521527,107例急性CAP，使用5种方案（头孢甲肟、头孢他啶、环丙沙星、头孢他啶+妥布霉素，环丙沙星+哌拉西林）,提高AUIC可以减少耐药,Baquero67:27-33Cantnetal.InterJAntimicrobChemother2019,氟喹诺酮给药方案优化,提高疗效：推荐每日一次给药Cmax/MIC8-1024-hAUC/MIC(AUIC)G-:AUIC100-125G+:AUIC30-40防止耐药CmaxMPC争取较高的AUIC,三、-内酰胺类：TMIC,0,Concentration,Time(hours),Required%TMICforcidal:40%forcarbapenems50%forpenicillins70%forcephalosporins,DrusanoGL.ClinInfectDis.2019;36(suppl1):S42-S50.,Required%TMICforstatic20%forcarbapenems30%forpenicillins40%forcephalosporins,-lactam:optimalTMIC?,AryunKimetal.,Pharmacotherapy.201927(11):1490-7,美国康涅狄格州Hartford医院的研究结果,背景：针对470株铜绿假单胞菌，比较哌拉西林他唑巴坦各种给药方式的效果目的：计算达到50%TMIC*的可能性，研究最佳给药方式,RobertsJA,etal.,InternationalJournalofAntimicrobialAgents.2010.35:156-163,RobertsJA,etal.,InternationalJournalofAntimicrobialAgents.2010.35:156-163,P=0.04,间断输注组：特治星3.375gq4h或q6h30分钟输注N=41延长输注组：特治星3.375gq8h4h输注N=38,ThomasP,etal.,ClinicalInfectiousDiseases2019;44:357-63,美国纽约Albany医学中心的研究结果-降低死亡率,192例铜绿假单胞菌感染患者,criticallyillpatientswithanAPACHEIIscore17,一日多次给药，争取TMIC40-50%注意：多数半衰期仅1h左右的-内酰胺类，对重症患者或耐药菌感染，Q12h/Q8h的给药方式不能获得40-50%的TMIC优化-内酰胺类的给药方式加大剂量：受肾功能限制可能需要调整剂量增加给药次数：Q8h转为Q6h采用持续静脉滴注/延长滴注时间,-内酰胺类给药方案优化,S.aureus,MIC,0.1,10,100,1000,1,Concentration(g/mL),0,12,24,20,4,8,16,Time(hours),头孢他啶：1g/2gtid的比较,增加给药剂量,增加给药频率,TMIC比较,MoutonJW,etal.,DrugResistanceUpdates,2011;14:107-17,DandekarPKetal.Pharmacotherapy.2019;23:988-991.,Meropenem500mgAdministeredasa0.5hor3hInfusion,MIC,0,2,4,6,8,0.1,1.0,10.0,100.0,Concentration(mcg/mL),Time(h),RapidInfusion(30min),延长输注时间,美罗培南不同给药方式PTA,JournalofAntimicrobialChemotherapy.2009;64:142-150,3G/D,6G/D,美罗培南：延长滴注时间治疗多耐洋葱伯克霍尔德菌,Meropenem2ginfusedover3hoursq8h,Time(h),Concentration(mcg/mL),0,8,16,24,32,40,0.1,1,10,100,MIC=16mcg/mL,TMICexposurewas40%ofthedosingintervalattheMICof16mcg/mL,KutiJLetal.Pharmacotherapy.2019;24:1641-1645,JournalofAntimicrobialChemotherapy.2009;64:142-150,延长输注提高敏感折点,对不敏感菌株更有意义,持续输注的问题,药品常温下稳定性长期占据一条输液管路导管相关感染的发生,延长给药问题,药师多次调剂护师多次配药,指南推荐用法(2019ATSHAP/VAP/HCAP),HAP,指南推荐用法(2019加拿大指南HAP/VAP),VAP,四、大环内酯类,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。,五、万古霉素,(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。,Figure2Relationshipbetweenpharmacokinetic/pharmacodynamicindicesforvancomycinandbacteriologicefficacyagainstmethicillin-susceptibleStaphylococcusaureus.Thisplot,whichdelineatesthechangeincolony-formingunits(cfu)inanexperimentalmouseinfectionmodel3differentways,suggeststhattheareaunderthecurvedividedbytheMIC(AUC/MIC)isthemostvaluablepharmacokinetic/pharmacodynamicparameterforpredictingtheactivityofvancomycinagainstmethicillin-susceptibleS.aureus.,RybakMJ.Thepharmacokineticandpharmacodynamicpropertiesofvancomycin.ClinInfectDis2019;42(Suppl.1):S359.,Moise-BroderPA,etal.ClinPharmacokinet.2019;43(13):925-42,万古霉素在金葡菌引起的LRTI的药效学,图：LINEZOLID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LINEZOLIDTMIC与细菌学疗效相关系数最高为84，当TMIC为40即可达到良好的细菌学疗效。,六、利奈唑胺,严重感染病人：GroupI:600mg/q12hGroupC:D1300mgloading+900C,D21200mg/d,AdembriC,etal.InternationalJournalofAntimicrobialAgents.2019;31:1229.,AdembriC,etal.InternationalJournalofAntimicrobialAgents.2019;31:1229.,CurrentOpinioninPharmacology2019,11:470476,延长输注内酰胺类药物未解决问题,适用于人体的最佳值(fTMIC)，要比临床前值更高吗？需要进行血药浓度监测进行个体化用药吗？缺乏资料哪种细菌多少MICs最适合延长给药时间需要临床试验证实群体药动学和MonteCarlo模拟何种病人会最大受益需要在严重败血症病人和具多种并发症病人中进行临床试验持续给药对靶细菌耐药的影响如何目前缺乏临床资料,Theopeninglineoftheint