1、陈 佰 义 中国医科大学附属第一医院,经验性抗感染治疗-药物选择的基本原则与临床实践,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。,A poster from World War II,dramatically showing the virtues of the new miracle drug,and representing the high level of motivation in
2、the country to aid the health of the soldiers at war.,Discovery of Antibacterial Agents,CycloserineErythromycinEthionamideIsoniazidMetronidazolePyrazinamideRifamycinTrimethoprimVancomycinVirginiamycin,Imipenem,1930,1940,1950,1960,1970,1980,1990,2000,PenicillinProntosil,Cephalosporin C,EthambutolFusi
3、dic acidMupirocinNalidixic acid,OxazolidinonesCecropin,Fluoroquinolones,Newer aminoglycosides,Semi-synthetic penicillins&cephalosporins,Newer carbapenems,Trinems,Synthetic approaches,Empiric screening,Newer macrolides&ketolides,Rifampicin,Rifapentine,Semi-synthetic glycopeptidesSemi-synthetic strept
4、ogramins,NeomycinPolymixinStreptomycinThiacetazone,Chlortetracycline,Glycylcyclines,Minocycline,Chloramphenicol,“Close the book on infectious disease”,“Infectious disease will be with us for the foreseeable future”,US Surgeon General William Stewart,1969,Harvard Medical School Mary Wilson,1998,抗生素时代
5、感染仍是人类健康的重要威胁,IIIIIIII,新出现或“再出现”的感染性疾病 emerging and re-emerging infectious diseases,新病原体不断出现-HIV/AIDS、Ebola、Hantavirus 新型肝炎、新型克雅病（疯牛病）肠杆菌O157、霍乱O139 环孢子菌病、隐孢子菌病、人类Ehrlichosis老病卷土重来-肺结核、疟疾、鼠疫、霍乱、黄热病、登革热 和登革出血热免疫缺陷人群不断增加-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
6、 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,VRSAVRE(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,Antibiotic resistance:genetic events,Susceptible bacteria,Selection for Antimicrobial-Resistant Strains
7、,抗生素选择压力,耐药菌的播散,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 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,减少抗生素选择性压力,抗感染药物的临床应用,治疗性应用经验治疗：因无法确定感染的微生物，推断可能的病原体，参考本地区药敏监测结果，故抗生素必须覆盖所有可能的微生物，常选用联合治疗或单一广谱抗生素,治疗性应用目标治疗：确定了病原体，选用窄谱、低毒性的抗生素,预防性应用：,Fighting infection in the firs
8、t hours,Rapid testsWhen available.Gram stain!,Start adequate antibiotic coverage(within 1 hour?)Tillou A et al.Am Surg 2004;70:841-4,Drain purulent collection,SamplingIncluding invasive procedureswhen needed(BAL),经验性治疗和目标治疗的统一留取标本进行微生物学检查开始经验性抗感染治疗目标治疗,Factors Selected by Multivariate Analysis Indep
9、endently Related to Mortality,Leroy O Intensive Care Med 1995;21:24-31,Importance of Adequate and Appropriate Antimicrobial Treatment,Adequate antimicrobial treatment,Mortality,Increased,Decreased,Inadequate antimicrobial treatment,Ongoing bacterial proliferation and inflammationselection of drug-re
10、sistant microorganisms,Ewig et al,Thorax 2002;57:366,Effect of Early Administration of Antibiotics on Outcomes,Houck PM et al.Arch Intern Med 2004;164:637-44,Early Administration of Abx significantly decrease mortality and LOS,Start empirical antibiotic therapy as soon as possible,慢性咳嗽和黄痰-原因,哮喘 后鼻腔鼻
11、漏病毒感染后气道高反应性胃酸返流吸烟相关的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,急性发热 WBC不高/淋巴增高（无感染灶）病毒！WBC增高/中性粒增高/核左移 可能细菌！部位/病原体？原发性菌血症？慢性发热 IE、布病、慢性感染灶？结核病？非感染性发热 药物热、风湿病、恶性肿瘤,正确诊断是正确治疗的前提,发热的诊断与鉴别诊断,Cryptogenic Organizing Pneumonia,Infectious Diseases Expert Resources,Infectious Diseases Specialists,Optimal Patient Care,Inf
12、ection Control Professionals,Healthcare Epidemiologists,ClinicalPharmacists,Clinical Pharmacologists,Surgical InfectionExperts,ClinicalMicrobiologists,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)选择能够覆盖病原体的抗感染药物(antibiotics requirement)-抗菌谱/组织穿透性/耐药性/安全性/费用考虑药代动力学/药效
13、动力学(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),经验性抗感染治疗合理选择药物-consider
14、ations 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 infectionGram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
15、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,注意特殊修正因子/特别是先期抗菌药物对细菌学的影响,不同感染部位的常见感染性病原体Possible pathogens on site of infection,关注特殊病原体,肺孢子菌肺炎-免疫缺陷-相对特异临床-积极病原学检查,重症军团菌肺炎发热、少痰多肺叶、多肺段受累肺外表现,抗菌谱(coverage)通读药物说明书和相关资料组织穿透性(ti
16、ssue 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)-血脑屏障、血胰屏障、胎盘屏障等耐药性(resistance,specifically local resistance)参考代表
17、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能够覆盖可能病原体的抗菌药物（Abx requirements）,血脑屏障：多数抗菌药物脑脊液浓度很低脂溶性溶性较高、非极性、蛋白结合率低者易通过血脑屏障炎症时血脑屏障通透性可增加,体内特殊生理屏障,胎盘屏障：几乎所有抗菌药物都能穿透胎盘屏障进入胚胎循环在妊娠期应避免使用对胎儿发育有影响的抗菌药物 氯霉素、氨基糖苷类、四环素类、磺胺类、氟喹诺酮类、利福平等,抗菌药物在脑脊液中分布,骨组织分布：氟喹诺酮类、磷霉
18、素类、林可霉素/克林霉素 等少数药物可在骨组织中达到有效浓度 前列腺分布：氟喹酮类、大环内酯类、SMZ/TMP、四环素类在前列腺液或 组织中可达有效浓度 浆膜腔和关节腔：抗菌药物全身用药后大多可分布至各体腔和关节腔中，但 若有包裹性积液或脓腔壁厚者，有时需腔内局部注入药物,体内特殊生理屏障,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 inflam
19、mation)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)-血脑屏障、血胰屏障、胎盘屏障等耐药性(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能够覆盖可能病原体的抗菌药物（Abx requirem
20、ents）,评价评价耐药病原体,重症感染耐药菌感染！重症感染革兰阴性杆菌感染！军团菌、肺炎链球菌都可致重症感染,是否耐药菌？依据宿主相关因素-高龄、基础疾病、近期使用抗菌药物、住院-病人来源：社区、养老院、医院-耐药病原体流行状况是否重症?-依据临床表现-氧和、血液动力学、肾功能 肠功能,Risk factors for infection with ESBL producers outside hospital,Colodner et al EJCMID 2004 23,163.,Prevalence of rectal carriage of Extended-Spectrum-lacta
21、mase-producing Escherichia Coli among elderly people in a community setting in Shenyang,横断面研究/整群抽样-276名社区老人、直肠拭子/大肠杆菌ESBL检测、分子分型和PEGF结果:直肠拭子ESBL+大肠杆菌携带率7.0%（19/270）.19株ESBL+菌株ESBL基因型均为CTX-M 型 12株为CTX-M-14 型（63.2%),3株 CTX-M-22型,1株 CTX-M-24型，2株 CTX-M-57-like型，1株同时产CTX-M-24和CTX-M-57-like型.序列分析表明CTX-M-5
22、7-like基因序列中第865位点发生GA替换,导致 氨基酸序列中第289位点发生DN替换,该基因序列不同于 GenBank数 据库已发表序列，提示新型ESBLs基因型(GenBank 序列号 EF426798),Tian SF,Chen BY.Prevalence of rectal carriage of Extended-Spectrum-lactamase-producing Escherichia Coli among elderly people in a community setting in Shenyang,China.Canadian Journal of microbi
23、ology 2008;54:15,19株产ESBLs的大肠埃希菌的PFGE图谱左起依次为：Marker，菌株编号T2-S28.,产ESBLs菌株PFGE图谱呈多样性，提示社区产ESBLs的大肠埃希菌为多克隆起源,Univariate analysis of risk factors for carriage of ESBL-producing Escherichia coli in the community(n=270),Potential Risk factors No(%)ESBLs Total No Odds ratio(95%CI)P value Age(years)74 16(7.
24、4)216 75 3(5.6)54 0.74(0.21-2.62)0.77 Gender Female 12(7.8)153 Male 7(6.0)117 0.81(0.31-2.13)0.81 Diabetes No 11(6.3)174 Yes 8(8.3)96 1.35(0.52-3.47)0.62 Hospitalization in past one year No 18(6.8)264 Yes 1(16.7)6 2.73(0.30-24.66)0.34 Surgery in past one year No 19(7.1)268 Yes 0(0)2 0.0 0.8 Use of a
25、ntibiotic in past three months No 12(5.3)227 Yes 7(16.3)43 3.48(1.29-9.44).018,产ESBL细菌感染的危险因素,Prospective study of 455 episodes of K.pneumoniae bacteremia(253 nosocomial)in 12 hospitals30.8%为医院获得,ICU中43.5%产ESBLsESBLs危险因素 先期使用氧亚氨基-内酰胺类抗菌药物 过去14天内使用2 d(OR=3.9).其它危险因素 TPN,肾功衰竭,烧伤非ESBL危险:碳青霉烯、头孢吡肟、喹诺酮、氨
26、基糖苷类 Paterson et al:Ann Intern Med 2004;140:26-32.,VAP耐药菌感染的危险因素,135 次VAP ICU变量 OR PMV7 days 6.0.009先期ABs 13.5.001广谱ABs 4.1.025,MV 7 days/prior ABs,Trouillet,et al.Am J Respir Crit Care Med.1998;157:531,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（亚胺
27、培南,3代头孢和喹诺酮)增加铜绿对同种药物的耐药性,aP=.0009 bP=.003 cP=.001 dP=.05,关注耐药病原体-近期应用抗菌药物与铜绿耐药,S.aureus,Penicillin,1944,Penicillin-resistantS.aureus,金黄色葡萄球菌耐药的发生发展过程,Methicillin,1962,Methicillin-resistantS.aureus(MRSA),Vancomycin-resistantenterococci(VRE),Vancomycin,1990s,1997,VancomycinintermediateS.aureus(VISA),
28、2002,Vancomycin-resistantS.aureus,CDC,MMWR 2002;51(26):565-567,1960,Macrolide resistant S.pneumoniae in Asian Countries:ANSORP 1998-2001,-555 isolates-macrolide susceptibility-216 S(38.9%)-10 I(1.8%)-329 R(59.3%)Vietnam88.3%RHong Kong 76.5%RTaiwan87.2%RChina75.6%RKorea85.1%R-ermB more common(50%)Chi
29、na,Taiwan,Sri Lanka,Korea.-mefA more common Hong Kong,Singapore,Thailand,Malaysia.-most countries MIC90 12 mg/L.,Song et al,Journal of Antimicrobial Chemotherapy 2004;53(3):457-463.,红霉素耐药肺炎链球菌表型和基因型,赵铁梅，刘又宁.中华内科杂志.2004;43(5):329-332/AAC,2004;48（10）:4040-4041,耐药表型,基因型,N=148,抗菌谱(coverage)通读药物说明书和相关资料组
30、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)-血脑屏障、血胰屏障、胎盘屏障等耐药性(resistance,specifically local resistan
31、ce)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能够覆盖可能病原体的抗菌药物（Abx requirements）,评估责任病原体评估病原体耐药性,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,选择哪种抗菌药物(
32、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
33、/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,Pharmacology of Antimicrobial Therapy,Dosingregimen,Concentrationsin serum,Concentrationsin tissues and body fluids,Concentrationsat site of infection,Pharmacologic and toxicologic effect,Antim
