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1、主要内容,流行病学感染相关概念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所有死因中居第11位 每年约750,000例严重感染 发病率：3/1000 每年死亡患者超过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高，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,National Center of Health Statistics.2001.Amer
2、ican Cancer society，2001,感染的相关概念,ACCP/SCCM联席会议定义,Bone RC,Balk RA,Cerra FB,et al.Chest.1992 Jun;101(6):1644-55.Review.,Bone RC,Balk RA,Cerra FB,et al.Chest.1992 Jun;101(6):1644-55.Review.,SIRS,Bone RC,Balk RA,Cerra FB,et al.Chest.1992 Jun;101(6):1644-55.Review.,SEPSIS,Bone RC,Balk RA,Cerra FB,et al.C
3、hest.1992 Jun;101(6):1644-55.Review.,SEVERE SEPSIS,感染的演变过程,具有两项一下临床表现:1.体温38 或90次/分3.呼吸频率20次/分4.白细胞计数12,000/mm3或10%,感染引起的SIRS,MODS的表现,Severe Sepsis 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静/止痛营养,Wheeler AP,Bernard GR.Treating patients with severe sepsis.N Engl J Med.1999 Jan 21;340(3):207-14.Review.,抗生素使用目标,Pha
4、rmacology of Antimicrobial Therapy,Dosingregimen,Concentrationsin serum,Concentrationsin tissues and body fluids,Concentrationsat site of infection,Pharmacologic and toxicologic effect,Antimicrobialeffect,AbsorptionDistributionElimination,Pharmacokinetics(PK),Pharmacodynamics(PD),MIC、MBC,抗菌药物起效过程,剂量
5、,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识别,药代动力学和MIC,Different pattern of time-killing of 3 Abx VS Pseudomonas,Killing and rate of killing depends on concentration,Rate of killing increases no more as concentration increases,killing depends on exposure time,PK/PD Predictors of Efficacy,
6、-a combination of PK and PD,Time,MIC90,Log Concentration,24h-AUC,T MICCmax,Cmax/MIC24h-AUC/MIC(AUIC),Dose,Dose,Cmax,TMIC,Parameters of interest,PK/PD Predictors of Efficacy,依据PK/PD抗菌药物分类,时间依赖性,与时间有关，但抗菌活性持续时间较长,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密切相关,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
7、-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 TMIC和AUCMIC,主要参数 TMIC,PAE，T1/2 AUC/MIC,浓度依赖性,Required%TMIC for cidal:40%for carbapenems 50%for penicillins 70%for ephalosporins,Drusano GL.Clin Infect Dis.2003;36(suppl 1):S42-S50.,Required%TMIC for static 20%fo
8、r carbapenems 30%for penicillins 40%for cephalosporins,-lactam:optimal TMIC?,Drusano.Clin Infect Dis 2003;36(Suppl.1):S42S50,Maximizing TMIC提高剂量安全性前提增加给药频率延长输注时间,-内酰胺类优化暴露时间-Lactam:Optimizing Exposure,Dandekar PK et al.Pharmacotherapy.2003;23:988-991.,Meropenem 500 mg Administered as a 0.5 h or 3 h
9、Infusion,MIC,0,2,4,6,8,0.1,1.0,10.0,100.0,Concentration(mcg/mL),Time(h),Rapid Infusion(30 min),Treatment of Multidrug-resistant Burkholderia cepacia With Prolonged Infusion Meropenem,Meropenem 2 g infused over 3 hours q 8 h,Time(h),Concentration(mcg/mL),0,8,16,24,32,40,0.1,1,10,100,MIC=16 mcg/mL,TMI
10、C exposure was 40%of the dosing interval at the MIC of16 mcg/mL,Kuti JL et al.Pharmacotherapy.2004;24:1641-1645,Moore et al.J Infect Dis 1987;155:9399,Aminoglycoside:optimal Cmax:MIC-Relationship Between Cmax:MIC and Clinical Response,Clinical response(%),Cmax:MIC,0,20,40,60,80,100,2,4,6,8,10,12,Wha
11、t is the Optimal AUIC for Fluoroquinolones?,30,125,For G+,For G-,Forrest et al.Antimicrob Agents Chemother 1993;37:10731081,Fluoroquinolone Therapy for Nosocomial Pneumonia Correlation Between Drug Exposure(AUC/MIC)&Outcome,Patients cured(%),0,20,40,60,80,100,062.5,62.5125,125250,250500,500,AUC:MIC,
12、Clinical,Microbiological,AUC:MIC125 lead to appropriate clinical and microbiological outcome,Gram-Negative Bacterial Eradication and Fluoroquinolone AUIC,Days,0 2 4 6 8 10 12 14,0,100,75,50,25,AUIC 125-250,AUIC 250,AUIC 125,%Patients remaining culture positive,Forrest et al.Antimicrob Agents Chemoth
13、er.1993;37:1073-1081,Higher AUC:MIClead to letter bacterial eradication,Probability of Developing Resistance,Thomas KL et al.Antimicrob Agents Chemother.1998;42:521527,AUC024h:MIC 100,AUC024h:MIC 100,Days from initiation of therapy,0,5,10,15,20,0,20,40,60,80,100,Probability of remaining susceptible(
14、%),Data from 107 acutely ill patients with nosocomial RTIs treated with 5 different antibiotic regimens(ciprofloxacin,cefmenoxime,ceftazidime,ciprofloxacin plus piperacillin,ceftazidime plus tobramycin),Optimizing FQs therapy for S.pneumoniae from PK/PD point of view,EfficacyCmax/MIC ratio 8-1024-h
15、AUC/MIC(AUIC)Total AUIC 100 Free AUIC 30-40Resistance preventionCmax MPCHigher AUIC,Baquero 67:27-33Cantn et al.Inter J Antimicrob Chemother 2006(in press),重症患者抗菌药物使用,重症患者，运用PK/PD理论合理的使用抗菌药物，同时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它因素 Other considerations in choosing Abx,杀菌 vs 抑菌(Cidal vs static)严重/复杂感染选杀菌剂cida
16、l for serious and compicated infections单药 vs 联合(monotherapy vs combination)：静脉 vs 口服(IV vs oral)疗程(duration),Bioavailability以活性状态到达目标细菌的能力,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,TMIC）,选择口服抗菌药物应该考虑,The Duration of Antimicrobial Therapy,Bacteria load,Clinical co
17、urse,Recurrence,急性感染Acute infection,慢性感染，疗程不足Chronic infection,duration not enough,慢性感染，足疗程Chronic infection,duration enough,8 vs.15 Days of Antibiotic TherapyVentilator-Associated Pneumonia(contd),Chastre J,et al.JAMA.2003;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48 hs药物由治疗医生选择 方案遵从ATS 指南主要观察指标
18、 病死率 微生物学证实的感染复发 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,Pinzone MR,et al.Durationof antimicrobial therapy incommunityacquiredpneumonia:less is more.Scientific World Journal.2014 Jan 21;2014:759138.,不同药物短程和长程疗效比较,在保证初始抗菌药物正确，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,P0.0
19、5,Gonzalez L,et al.Factors influencing the implementation of antibiotic de-escalation and impact of this strategy in critically ill patients.Crit Care.2013 Jul 12;17(4):R140.,外科ICU感染的降阶梯治疗,Morel,etal.Deescalationaspartof globalstrategyofempiricantibiotherapymanagement.Aretrospectivestudyin amedico-s
20、urgicalintensivecareunit.CritCare.2010;14(6):R225.,推荐在重症感染或感染休克患者进行降阶梯治疗，并且是安全可行的,靶位改变,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,50,Pena,et al,Antimocrob Agents Chemother 1998;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18月ESBLs日益严重,93年9月减少三代头孢菌素使用增加亚胺培南的使用,94年1月特治星加入干预，与亚胺培南同时使用,94年5月开始增加特治星用量，同时减少亚
21、胺培南和三代头孢使用后，ESBLs发生率才开始明显下降,克里夫兰退役老兵医院抗生素干预,Rice L et al.Clin Infect Dis 1996;23:118-24Rice L.Pharmacotherapy 1999;19(8 Pt 2):120S-128S,耐药率(%),抗生素用量(g),中国抗菌药物干预情况,Bao L,.PLoS One.2015,13;10(3):e0118868.,Antibiotic Control and Infection Control:The Two Sides of the Resistance“Coin”,Rekha Murthy.Imple
22、mentation of Strategies to Control Antimicrobial Resistance Chest 2001;119;405-411,Control of Antibiotic Resistance,控制抗菌药物使用量对减少抗菌药物的附加损害，减少耐药率具有重要作用,感染病诊断、治疗与预防、控制的学科体系,感染病,临床微生物,感染控制,发热病人的诊治微生物致感染病 免疫缺陷人群感染 器官移植等医院感染诊治,感染控制减少医感染,配合整合共同提高,急诊抗生素使用特点,潜在威胁生命的细菌感染,抗生素选择无把握时,厌氧菌感染,G-菌败血症,假单胞菌感染,严重肠杆菌属感染
23、,耐药G+球菌感染,细菌性脑膜炎,中性粒系减少患者,中性粒系减少伴有发热患者,急诊外伤的处理,急诊外伤后预防抗菌药物,伤口感染治疗,足背刺伤,破伤风,狂犬病,猫抓伤,猫抓病,狗咬伤,人咬伤,暴露后处理,HIV暴露,HBV、HCV暴露,防范措施,甲型流感,脑膜炎双球菌预防,PPD阳性,选择哪种抗菌药物(which antibiotic?)感染部位的常见病原学(possible pathogens on site of infection)能够覆盖病原体的抗感染药物(antibiotics requirement)抗菌谱coverage)/组织穿透性(tissue penetration)/耐药性
24、(resistance pattern)/安全性(safety)/费用(cost)优化药代动力学/药效动力学(optimizing PK/PD)考虑病人生理和病理生理状态(physiologic and pathophysiology)高龄/儿童/孕妇/哺乳(advanced age/children/pregnant women/breast feeding)肾功能不全/肝功能不全/肝肾功能联合不全(renal/heptic dysfunction/combined)其它因素(other considerations)杀菌和抑菌/单药和联合/静脉和口服/疗程,合理的经验性抗感染治疗药物选择 considerations in choosing antibiotic for empiric therapy,谢谢！,
