危重病人的优化抗菌治疗进展.ppt

Click to edit Master title style,Click to edit Master text styles,Second Level,Third Level,Fourth Level,Fifth Level,抗感染药物发展简史,1929 Alexander Fleming,发现青霉素,Howard,Florey,和,Ernst Chain,分离获得青霉素，,用于动物试验。,青霉素首次用于救治战伤,患者，拯救了 许多人,的生命。,1950s,大量抗生素用于临床。,Discovery of Antibacterial Agents,Cycloserine,Erythromycin,Ethionamide,Isoniazid,Metronidazole,Pyrazinamide,Rifamycin,Trimethoprim,Vancomycin,Virginiamycin,Imipenem,1930,1940,1950,1960,1970,1980,1990,2000,Penicillin,Prontosil,Cephalosporin C,Ethambutol,Fusidic acid,Mupirocin,Nalidixic acid,Oxazolidinones,Cecropin,Fluoroquinolones,Newer aminoglycosides,Semi-synthetic penicillins&cephalosporins,Newer carbapenems,Trinems,Synthetic approaches,Empiric,screening,Newer macrolides&ketolides,Rifampicin,Rifapentine,Semi-synthetic glycopeptides,Semi-synthetic streptogramins,Neomycin,Polymixin,Streptomycin,Thiacetazone,Chlortetracycline,Glycylcyclines,Minocycline,Chloramphenicol,A poster from World War II,dramatically showing the virtues of the new miracle drug,and representing the high level of motivation in the country to aid the health of the soldiers at war.,抗生素时代感染仍是人类健康的主要“杀手”,IIIIIIII,新出现或“再出现”的感染性疾病,emerging and re-emerging infectious diseases,HIV/AIDS,、,Ebola,、,Hantavirus,新型肝炎、新型克雅病（疯牛病）,大肠杆菌,O157,、霍乱,O139,环孢子菌病、隐孢子菌病、人类,Ehrlichosis,肺结核、,疟疾、鼠疫、霍乱、黄热病、登革热,和登革出血热,免疫抑制患者机会性真菌和呼吸道病毒性肺炎,细菌耐药愈演愈烈,PRSP,、,MRSP,、,MRSA/MRSE,、,VRE,、,VISA/VERA,ESBL,、,ampC,、,SSBL,、金属酶,.,MDR,结核菌,美国因细菌耐药增加医疗费用超过,40,亿美元,!,临床关注的耐药问题,Resistances of Clinical Concerns,革兰阳性细菌,金匍菌,MRSA,VISA,VRSA,VRE,(,地理上差别,),肺炎链球菌,青霉素和喹诺酮耐药,革兰阴性细菌,肠杆菌科,ESBLs,喹诺酮,头孢菌素,青霉素类,氨基糖苷类,碳青霉烯类,非发酵菌,(,假单孢菌,+/-,不动杆菌,),喹诺酮,头孢菌素,青霉素类,氨基糖苷类,碳青霉烯类,Resistant bacteria,Mutations,XX,Antibiotic resistance:genetic events,Susceptible bacteria,Resistant bacteria,Gene transfer,Resistant StrainsRare,x,x,Resistant Strains,Dominant,Antimicrobial,Exposure,x,x,x,x,x,x,x,x,x,x,Selection for Antimicrobial-Resistant Strains,寻找新的抗感染药物,-,新药越来越少,限制人以外(畜牧业)使用,-,减少对人类的影响,加强抗感染药物的临床管理,-,分级和分线,合理使用抗感染药物,-,优化抗菌治疗,优化抗感染药物使用策略,-,减少抗生素选择性压力,加强医院感染的控制,-,减少耐药菌株院内传播,细菌耐药的临床对策,-,Measures to Resistance,Infectious Diseases Expert Resources,Infectious Diseases,Specialists,Optimal,Patient Care,Infection Control,Professionals,Healthcare,Epidemiologists,ClinicalPharmacists,Clinical,Pharmacologists,Surgical Infection,Experts,Clinical,Microbiologists,感染性疾病及抗感染治疗,感染病和传染病,infectious diseases,contagious or communicable diseases,感染病科是否一门专业？,ID specialist,ID division,额外的话,感染病科超越了传统意义的学科,感染性疾病的诊断、治疗与预防控制,感染病,临床微生物,感控,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,感染控制减少医感染,医院感染诊治,配合,整合,共同提高,慢性咳嗽和黄痰,-,原因,哮喘,后鼻腔鼻漏,病毒感染后气道高反应性,胃酸返流,慢性支气管炎,支气管扩张症,弥漫性泛细支气管炎,肺泡蛋白沉积症,C,ryptogenic Organizing,P,neumonia,咳嗽、气短、肺部浸润影,抗菌药物管理策略,(Antibiotic Management Strategies),指南（,Guidelines,）,限制处方（,formulary restriction,）,抗生素轮换,(Antibiotic Cycling),抗生素替换,/,干预策略,(substitution/intervention,）,抗菌治疗策略,(Antibiotic Therapy Strategies),降阶梯治疗策略（,De-Escalation Therapy,短程治疗策略,(short-course therapy),联合治疗（,combination therapy,）,优化药动学,/,药效学原则（,Optimizing PK/PD principles,）,消除定植策略（,Antimicrobial Decolonization Strategies,）,危重病人优化抗感染治疗策略,Optimizing antimicrobial therapy in critically ill patients,指南是优化治疗的有效手段,改善抗菌药物疗效,避免不必要使用抗菌药物,自动化抗菌药物管理系统,-,应用计算机平台成功识别抗菌药物不良反应,-,使不良反应发生率降至最低,危重病人优化抗感染治疗策略,Optimizing antimicrobial therapy in critically ill patients,1,、,Classen DC,Pestotnik SL,Evans RS,et al:Adverse drug events in hospitalized patients.Excess length of stay,extra costs,and attributable mortality.,JAMA,1997;277:301-3064.,2,、,Evans RS,Classen DC,Pestotnik SL,et al:Improving empiric antibiotic selection us ing computer decision support.,Arch Intern Med,1994;154:878-88493,限制处方（,formulary restriction,）,限制使用某种或某类抗菌药物做为一种策略有助于减少细菌耐药,性、不良反应以及费用,1,尤其在耐药菌感染爆发流行时有效，如同时加强感染控制措施和,对医生进行教育则效果更为明显,限制使用的抗菌药物常为广谱抗生素、快速出现耐药和容易出现,毒性者,(,如氨基糖苷类,),方法学问题,-,很难证明限制处方能从整体上控制细菌的耐药，限制,使用某种或某类抗菌药物使其耐药性减低,，,但非限制使用药物,则耐药性可能增加,危重病人优化抗感染治疗策略,Optimizing antimicrobial therapy in critically ill patients,Kollef MH,Fraser VJ:Antibiotic resistance in the intensive care unit.,Ann Intern Med,2001:134:298-314,在某一预定时间段对于某一用药指征病人采用某一方案，之后,的某一预定时间段对于同一用药指征病人换用另一种方案。,出发点：轮换使用的药物可能有助于降低微生物对以前所用,药物的耐药性，使之在将来的治疗中更有效，减少某一,抗生,素的选择压力,抗生素轮换策略,(Antibiotics Rotation or Cycling）,1、,Lavin BS:Antibiotic cycling and marketing in the 21,st,century:A perspective from the pharmaceutical industry.Infect Control Hosp Epidemiol 2000;21(Suppl):S32-S35,2、Gruson D,Hilber G,Vargas F,et al.Rotation and restricted use of antibiotics in a medical intensive care unit:impact on the incidence of ventilator-associated pneumonia,caused by antibiotic-resistant gram-negative bacteria.Am J Respir Crit Care Med 2000;162:837-843,3、Raymond DP,Pelletieetie,Crabtree TD,et al.Impact of a rotating empiric antibiotic schedule on infectious mortality in an intensive care unit.Crit Care Med 2001;29:,1101-1108,危重病人优化抗感染治疗策略,Optimizing antimicrobial therapy in critically ill patients,抗生素干预策略,(,Antibiotics intervention),针对一定范围内出现的耐药细菌的爆发流行，以治疗耐药菌感染、控制耐药菌流行为目的，策略性选择抗感染用药方案。,针对,ESBL,S,的发生和,VRE,采取的措施主要包括减少三代头孢菌素的使用,两个目的治疗感染,/,不诱导细菌耐药,用于进行抗生素干预药物选择：,对主要（被干预）耐药细菌有效,目的不同，选用药物不同。如针对不同目的选择对应药物。,不应诱导出其他耐药菌,危重病人优化抗感染治疗策略,Optimizing antimicrobial therapy in critically ill patients,.,Time course,No simplistic policy(homogenous protocoles),Homogenous protocol,Rotation/Cycling,Mixing,抗菌药物管理策略,(Antibiotic Management Strategies),指南（,Guidelines,）,限制处方（,formulary restriction,）,抗生素轮换,(Antibiotic Cycling),抗生素替换,/,干预策略,(substitution/intervention,）,抗菌治疗策略,(Antibiotic Therapy Strategies),降阶梯治疗策略（,De-Escalation Therapy,短程治疗策略,(short-course therapy),联合治疗（,combination therapy,）,优化药动学,/,药效学原则（,Optimizing PK/PD principles,）,消除定植策略（,Antimicrobial Decolonization Strategies,）,危重病人优化抗感染治疗策略,Optimizing antimicrobial therapy in critically ill patients,Gain in mortality in Patients With Sepsis,Without,%,Mortality,Activated C protein,Bernard GR et al.,N Engl J.Med,2001;344:699-709.,31%,25%,0,10,20,30,40,50,60,70,31%,25%,-6%,Hydrocortisone,Annane et al.,JAMA,2002;,288:862-871,63%,53%,63%,53%,-10%,Adequate ATB therapy,Valles J et al.,Chest,2003;123:1615-1624.,63%,31%,-32%,With,Early goal,47%,30%,-17%,Rivers E et al.NEJM,2001;,345:1368-73,抗菌药物管理策略,(Antibiotic Management Strategies),指南（,Guidelines,）,限制处方（,formulary restriction,）,抗生素轮换,(Antibiotic Cycling),抗生素替换,/,干预策略,(substitution/intervention,）,抗菌治疗策略,(Antibiotic Therapy Strategies),降阶梯治疗策略（,De-Escalation Therapy,短程治疗策略,(short-course therapy),联合治疗（,combination therapy,）,优化药动学,/,药效学原则（,Optimizing PK/PD principles,）,消除定植策略（,Antimicrobial Decolonization Strategies,）,危重病人优化抗感染治疗策略,Optimizing antimicrobial therapy in critically ill patients,Avoiding the adverse outcomes of resistanceindividual patient perspective,应用耐药可能性低的药物到位！,治疗决定个体化,耐药的可能性？,病人的致病微生物？,病人来源,?,选择压力,用当地的监测资料不越位！,耐药,交叉耐药资料,De-escalating strategy-what?,充分治疗？,vs,抗感染药物滥用？,开始 选用能够覆盖可能病原体药物,联合治疗,细菌学结果阳性后改用窄谱抗菌药物,对象？重症感染！,选择药物？,经验性治疗的药物选择原则,特别关注耐药病原体,关注特殊病原体,如何实施？,De-escalating strategy-how?,重症感染,宿主因素,Host factor,免疫缺陷,高龄,疾病,治疗,临床疾病感染所致临床综合征,中枢神经系统,CNS,医院获得性肺炎,HAP,呼吸机相关肺炎,ventilator associated pneumonnia,菌血症,Bacteremia,肺炎,pneumonia,原发性或不明原因,Primary or unknown,严重软组织感染,Severe soft tissue,重症感染病原体和背景,高致病性病原体,High virulence pathogens,金黄色葡萄球菌,S.aureus,铜绿假单孢菌,P.aeruginosa,化脓性链球菌,S.pyogenes,医院获得性感染,Nosocomial infections,病人因素,Patient factors,免疫缺陷,Immunocompromized,病情危重,Critically ill,病原体因素,Pathogen factors,高致病性和/或难治性微生物,Virulent and/or difficult to treat organisms,Sepsis,SIRS plus Documented,Infection,重症感染？,Severe Sepsis,Sepsis plus,organ failure,Septic shock,Severe sepsis and,Hypotension,despite,adequate ressucitation,SIRS,at least 2 of the following,T38C or 90 beats/min,RR 20 breaths/min,WBC 12,000 cells/ml,10%immature forms,ACCP/SCCM consensus conference 1992,Mortality in sepsis,Mortality(%),0,10,20,30,40,50,60,70,SIRS,Sepsis,Severe,sepsis,Sepsis,shock,Main determinant of mortality:Organ failure,对象？重症感染！,选择药物？,经验性治疗的药物选择原则,责任病原体的估计,特别关注耐药病原体,关注特殊病原体,如何实施？,De-escalating strategy-how?,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,(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,(,cidal vs static/mono vs combination/IV vs PO/duration),经验性抗感染治疗药物选择,-considerations in choosing antibiotic for empiric therapy,培养结果前依据基本信息选择抗感染药物,choosing Abx before culture result,感染部位和可能病原体的关系,association of pathogen with site of infection,Gram,染色结果,-,与上述病原体是否符合？,Gram stain-in accordance with suspected pathogen?,某些病原体易于造成某些部位的感染,Some pathogen easily cause some site of infection,经验性抗感染治疗药物选择,-considerations in choosing antibiotic for empiric therapy,不同感染部位的常见感染性病原体,Possible pathogens on site of infection,经验性抗感染治疗药物选择,Bacteria by Site of Infection,感染的病原学,抗菌谱,(coverage),通读药物说明书和相关资料,组织穿透性,(tissue penetration),抗菌药物的特性,（,antibiotic itself,）,脂溶性,(lipid solubility)/,分子量,(MW),组织特性（血运/炎症）,(tissue itself-blood supply and inflammation),急性感染/慢性感染,(acute vs chronic infection),细胞内病原体,(intra vs extracellullar pathogen),体内特殊生理屏障,(physiologic barriers),耐药性,(resistance,specifically local resistance),参考代表性资料/依靠当地资料,安全性,(safety profile)-,药物本身/制剂/工艺/杂质,费用/效益,(cost/effectiveness),失败或副作用致再治疗费用更高,经验性抗感染治疗药物选择,能够覆盖可能病原体的抗菌药物,（,Abx requirements,）,对象？重症感染！,选择药物？,经验性治疗的药物选择原则,责任病原体的估计（医院感染为例）,特别关注耐药病原体,关注特殊病原体,如何实施？,De-escalating strategy-how?,美国医院感染常见菌群构成的变化,经验性抗感染治疗药物选择,Bacteria by Site of Infection,Microbiology of sepsis,Martin GS et al.New Engl J Med 2003;348:1546-54,经验性抗感染治疗药物选择,Bacteria by Site of Infection,22.9%,66.4%,绿脓杆菌,13.3%,肺炎克雷伯杆菌,12.2%,大肠杆菌,8.9%,不动杆菌,7.7%,肠杆菌属,7.7%,其他,内感染致病菌分布比例,院,张永信，顾建传等，医院内感染的两年前瞻性调查，,中华医学杂志,1991,年第,71,卷第,5,期,院内感染革兰阴性菌分布,*汪复，朱德妹等，2003,3,*王辉，陈民钧等，2003,3,NOSOCOMIAL PATHOGENS,ICU:U.S.,1992-1999,BSI,blood stream infection;CNS,coagulase negative staphylococci,HAP,hospital acquired pneumonia;UTI,urinary tract infection,ICU Patients,Non-ICU Patients,Source:NNIS data.,Clin Chest Med,.20:303-315.,医院感染耐药变迁：革兰阳性球菌,ICU Patients,Non-ICU Patients,医院感染耐药变迁：革兰阴性杆菌,Source:NNIS data.,Clin Chest Med,.20:303-315.,结构分类 功能分类 名称 来源 水解底物,CA,抑制 代表酶,(,Ambler)(Bush),丝氨酸-,Lam,C,1,头孢菌素酶 染色体 头孢菌素 ,AmpC,A 2a,青霉素酶 质粒 青霉素类 ,G+,菌中青霉素酶（,PC1）,2b,广谱酶 质粒 青霉素类 ,TEM-1，2、SHV-1,头孢菌素,SHV-1,ROB-1,2be,超广谱酶 质粒 青霉素类 ,TEM-329,SHV-29,I/II/III/,单环,2,br,耐酶抑制剂广谱酶 质粒 青霉素 ,TEM30-61,TRC-1，SHV10,2c,羧苄青霉素酶 质粒 青霉素 ,PSE-1/3/4、CARB-3,羟苄西林,BRO-1,-2,2e,头孢菌素酶 染色体 头孢菌素 ,头孢菌素诱导酶,Cxase,2f,非金属碳青霉烯酶 染色体,PC/,头孢菌素 ,IMI-1,NMC-A、Sme-1,/,碳青霉烯,D 2d,氯唑西林酶 质粒 青霉素/林氯西林 /,OXA-1OXA15,PSE-2,4,青霉素酶 染色体 青霉素 ,Zinc-Lam,B,3,金属酶 染色体 全部,B,内酰胺类 ,IMP-1,CcrA,L-1,内酰胺酶分类及其特性,AmpC,治疗原则,对严重感染,首选碳青酶烯类,也可以应用四代头孢菌素,对一般感染或严重感染病情稳定后改药，,根据药敏结果选用氨基糖甙类(阿米卡星、,庆大霉素）、喹诺酮类(环丙沙星）,及磺胺类(,TMP/SMZ）,抗生素,Extended Spectrum,b-,Lactamases(ESBLs),质粒介导,被酶抑制剂所抑制,克雷伯菌属和大肠杆菌常见,所有肠杆菌科,以及其它,GNR,100,种以上,底物亲和性不同,TEM,SHV,CTX,产,ESBL,菌对所有青霉素,头孢菌素和氨曲南耐药,常规检测时可表现为敏感,ESBLs in China,SENTRY data,1,:,大肠杆菌,ESBLs 13-35%,肺炎克雷伯菌,20%,CTX-M-3,和,CTX-M-14,最常见,2、3,华山医院,1000,菌细菌,4,:,51%,肺炎克雷伯菌,24%,大肠杆菌,多为,CTX-M,和,TEM,1 Bell JM,Diag Microbiol Infect Dis 2002;193,2 Li CR,Int J Antimicrob agent 2003;521,3 Munday CJ,Int J Antimicrob Agent 2004;175,4 Xiong Z.Diag Microbiol Inf Dis 2002;195,E,SBL,治疗原则,针对,ESBL,特性及耐药特点，推荐使用：,碳青酶烯类抗生素,b,-,内酰胺类/酶抑制剂？,三、四代头孢菌素？,2003年,NCCLS,规定明确指出：凡是实验室分离到的产,ESBLs,的细菌，即使体外试验对头孢菌素或氨曲南敏感，临床上必须报告耐药。,体外敏感的头孢菌素能否治疗产,ESBLs,细菌感染？,？,Why should producers be considered resistant to,all,penicillins and cephalosporins?,接种效应,Inoculum effect,高接种量时，,MIC,明显增加,动物试验研究,Animal studies,失败,:,头孢菌素,b-,内酰胺酶抑制剂复合制剂,卡巴配能,病人资料,接种效应（,Inoculum effect）,多种因素会影响药物敏感性测试的结果接种细菌量的多少,实验室中检测,MIC,时常用浓度为10,5,CFU/ml,的接种量,临床中菌血症患者体内的病菌浓度一般为10,3,10,4,CFU/ml,组织感染的病菌浓度为10,5,10,7,CFU/ml,脑膜炎的病菌浓度为10,7,10,8,CFU/ml。,接种细菌数量多时，细菌受到药物抑制的速度和程度降低。因此，接种量大时出现耐药的可能性也较大,当接种细菌数量增多时，抗菌药物的,MIC,会有改变,抗菌药物对某一细菌的,MIC,随细菌的接种数量增加而明显升高的现象称为,接种效应,标准接种物（10,5,）和大接种物（10,7,）时抗菌药对产,ESBLs,大肠埃希菌的,MIC（ug/ml）,Thomson KS,et al.Cefepime,piperacillin-tazobactam,and the inoculum effect in tests with extended-spectrum beta-lactamase-producing Enterobacteriaceae.AAC,2001;45(12):3548-54,2,2,1024,256,128,4,64,4,TEM-10,PAB-C10,4,2,256,32,128,4,1024,16,TEM-3,PAB-C3,4,2,128,32,128,4,1024,32,TEM-4,PAB-C4,256,4,32,16,128,8,512,32,SHV-2,PAB-C14,8,2,512,32,128,4,8,0.25,TEM-12,PAB-C12,4,2,1024,64,32,1,32,1,TEM-43,PAB-C43,64,2,1024,256,128,8,1024,64,SHV-7,PAB-CS7,10,7,10,5,10,7,10,5,10,7,10,5,10,7,10,5,哌拉西林/他唑巴坦,头孢他啶,头孢吡肟,头孢曲松,酶,菌株,在细菌不同接种物情况下的药物,MIC,值（,ug/ml）,美罗培南,10,5,10,7,0.03 0.03,0.03 0.03,0.03 0.06,0.03 0.06,0.03 0.03,0.03 0.03,0.03 0.06,接种效应启示,严重感染时体内的菌量较多，,接种物效应,明显的抗生素临床疗效可能受到影响，所以三、四代头孢对产,ESBL,细菌即使体外敏感，体内疗效可能不太可靠；而碳青霉烯和酶抑制剂复合制剂（哌拉西林/他唑巴坦）对产,ESBSLs,细菌的体内疗效更加可靠,这是为什么,NCCLS,规定：“凡是产,ESBLs,的细菌无论体外对头孢菌素是否敏感，临床均应报告耐药”的原因,每个药物都有“接种效应”！,中国,ESBL,以,CTX-M,型为主！,产,ESBL,细菌抗菌药物疗效,Antibiotic Therapy in the Presence of an ESBL-producing Organism,碳青霉烯显著降低产,ESBL,肺克菌血症的,14,天病死率,碳青霉烯单药优于喹诺酮或菲碳青霉烯的,-,内酰胺类,产,ESBL,细菌菌血症在,5 d,内应用碳青霉烯显著降低病死率,Paterson DL et al.,Clin Infect Dis,.2004;39:31-37.,BLIC=,-lactam/,-lactamase inhibitor combination,AMG=aminoglycoside,No Abx=no antibiotics,De-Escalation:A Multi-center Experience,398 VAP ,20,研究中心,降阶梯指之一或两者,:,用药数量减少,抗菌谱缩窄,碳青霉烯,头孢吡肟,pip/taz,喹诺酮,22.1%,降阶梯,15.3%,升阶梯,57,铜绿,:13,降阶梯,14,升阶梯,检出病原体降阶梯达,26.8%,，否则,6.5%,恰当治疗降阶梯达,27.1%,，否则,16.6%(p=0.01,),Kollef MH,Morrow LE,Niederman MS,et al.Chest 2006;129:1210-1218,De-escalation Reduces Mortality,Escalation Increases Mortality,IMP,及,MEP,为相似药,均对青霉素结合蛋白(,PBPs),高亲和力,均对大部分,超广谱,-,内酰胺酶稳定,ESBLs,AmpC,OXA,均有超广谱抗菌活性，覆盖多数临床常见的需氧、厌氧菌,均为治疗,革兰阴性菌,严重感染,最有效,的一线经验用药之一,均为抗绿脓杆菌药争论的焦点！,绿脓杆菌的耐药机制,外排泵,亢,进,MEPIMP,泵,A,MexA-MexB,OprM,过度表达+/-,泵,B,MexE-MexF,OprN,过度表达+-,外膜,通,透性下,降,（,OprD,缺损,）,+,酶,天然来源碳青霉烯酶,（,L1,）（,嗜麦芽）,获得性碳青霉烯酶,B,类（,金属酶）：,IMP、VIM,类及,SPM-1+,A,类：,NMC-A,、KPC-1、GES-2,等 +,D,类：,OXA 23-27、40、48、54+,C,类：,AmpC,PBPs,的变异,美罗培南与,PBP,2,及,PBP,3,亲和力更强；亚胺培南对临床分离,的铜绿假单孢菌,PBP,4,亲和力下降（意义,？）,这些差别引起了“争论”,亚胺培南：,选择出,OprD,缺失株，但损害的只是自己，不影响别类药,美罗培南还选出非特异性的泵出系统，可伤及喹诺酮类及,-,内酰胺类,美罗培南：,我获得耐药要难得多，因为要两个突变因子：,OprD、,泵出系统,同时出现两个突变的频率是,10,-14,，,而非,2 d)(OR=3.9).,没有,ESBL,危险：碳青霉烯、头孢吡肟、喹诺酮、氨基糖苷类,其它危险因素,:,TPN,肾功衰竭,烧伤,Paterson et al:Ann Intern Med 2004;140:26-32.,VAP,细菌学,:,抗菌药物使用与耐药菌感染的关系,135,次,VAP,57%,由于潜在耐药革兰阳性或阴性菌所致,55%,年感染,31%,只有革兰阳性菌,42%,只有革兰阴性菌,分为,4,组,:MV,时间,(7 days),先期抗菌药物,如,MV 7 d,+,先期应用抗菌药物,(n=84),59%,细菌为,MDR.,抗假单孢菌治疗万古霉素有效率,80%,Trouillet et al:AJRCCM 1998;157:531,Recent Antibiotic Therapy and Pseudomonal Resistance,Trouillet JL et al.,Clin Infect Dis,.2002;34:1047-1054.,铜绿,VAP:34,株派拉西林耐药,;101,株派拉西林敏感,发生,VAP15,天内使用抗菌药物,（亚胺培南,3,代头孢和喹诺酮,),增加铜绿假单孢菌对同种药物的耐药性,a,P,=.0009,b,P,=.003,c,P,=.001,d,P,=.05,影响,细菌学的修正因子,革兰,阴性肠杆菌,住,护理院、,基础,心肺疾病、,多种,内科合并症,近期,抗感染药物治疗,铜绿,假单孢菌,结构性,肺病,(支扩),糖皮质激素(10mg强的松/天),过去,的一个月使用广谱抗生素,7天,营养,不良,厌氧菌误吸因素,易患因素：老年、脑血管病,临床综合征：,吸入性肺炎、坏死性肺炎、肺脓肿、脓胸、支气管扩张,、,肺孢子菌,免疫缺陷宿主,相对特异的临床表现,结核分枝杆菌,影响,细菌学的修正因子,肺孢子菌肺炎,江永林,对象？重症感染！,选择药物？,经验性治疗的药物选择原则,责任病原体的估计,特别关注耐药病原体,关注特殊病原体,如何实施？,De-escalating strategy-how?,怀疑,HAP,VAP,或,HCAP,取得,LRT,标本培养,(,定量或者半定量,)&,显微镜检查,48-72 Hs,临床改善,降阶梯治疗，,如果可能,.,治疗,7-8,天和再评估,寻找其它病原体,并发症,其它诊断或者感染部位,2&3,天:,培养结果