1、 陈 佰 义 中国医科大学附属第一医院感染病科 辽宁省医院感染管理质控中心 C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1939 Howard Florey 和 Ernst Chain分离获得青霉素，用于动物试验。1942 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 hig
2、h level of motivation in the country to aid the health of the soldiers at war.Discovery of Antibacterial AgentsCycloserineErythromycinEthionamideIsoniazidMetronidazolePyrazinamideRifamycinTrimethoprimVancomycinVirginiamycinImipenem19301940195019601970198019902000PenicillinProntosilCephalosporin CEth
3、ambutolFusidic acidMupirocinNalidixic acidOxazolidinonesCecropinFluoroquinolonesNewer aminoglycosidesSemi-synthetic penicillins&cephalosporinsNewer carbapenemsTrinemsSynthetic approachesEmpiric screeningNewer macrolides&ketolidesRifampicinRifapentineSemi-synthetic glycopeptidesSemi-synthetic strepto
4、graminsNeomycinPolymixinStreptomycinThiacetazoneChlortetracyclineGlycylcyclinesMinocyclineChloramphenicol“Close the book on infectious disease”“Infectious disease will be with us for the foreseeable future”US Surgeon General William Stewart,1969Harvard Medical School Mary Wilson,1998IIIIIIII新出现或“再出现
5、”的感染性疾病 emerging and re-emerging infectious diseasesn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Ehrlichosisn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n免疫缺陷人群不断增加-机会性真菌和呼吸道病毒性肺炎n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
6、药问题临床关注的耐药问题Resistances of Clinical Concerns革兰阳性细菌n金匍菌 MRSA,VISA,VRSAnVRE(地理上差别)n肺炎链球菌 青霉素和喹诺酮耐药 革兰阴性细菌n肠杆菌科ESBLsu喹诺酮,头孢菌素,青霉素类,氨基糖苷类u碳青霉烯类n非发酵菌(假单孢菌+/-不动杆菌)u喹诺酮,头孢菌素,青霉素类,氨基糖苷类,碳青霉烯类 Resistant bacteriaMutationsXXAntibiotic resistance:genetic events Susceptible bacteriaResistant bacteriaGene transfe
7、r Resistant StrainsRarexxResistant Strains DominantAntimicrobial Exposure xxxxxxxxxxSelection for Antimicrobial-Resistant Strains抗生素选择压力抗生素选择压力耐药菌的播散寻找新的抗感染药物寻找新的抗感染药物 -新药越来越少新药越来越少限制人以外限制人以外(畜牧业畜牧业)使用使用 -减少对人类的影响减少对人类的影响加强抗感染药物的临床管理加强抗感染药物的临床管理 -分级和分线分级和分线合理使用抗感染药物合理使用抗感染药物 加强医院感染的控制加强医院感染的控制 -减少耐药
8、菌株院内传播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：Rapid testsWhen available.Gram stain!Start adequate antibiotic coverage(within 1 hour?)Drain purulent collectionSampling
9、Including 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 Independently Related to MortalityVariableRelative O.R.p ValueUnderlying disease(UF+RF)3.09.0007Shock2.850.016Bacteremia2.630.019Ineffective Initial Therapy4.71.0001Leroy O I
10、ntensive Care Med 1995;21:24-31Importance of Adequate and Appropriate Antimicrobial TreatmentAdequate antimicrobial treatmentMortalityIncreasedDecreasedInadequate antimicrobial treatmentOngoing bacterial proliferation and inflammationselection of drug-resistant microorganismsEwig et al,Thorax 2002;5
11、7:366Effect of Early Administration of Antibiotics on OutcomesHouck PM et al.Arch Intern Med 2004;164:637-44VariableAll patientsAntibiotics within 4 hoursAntibiotics after 4 hoursAdjusted Odds Ratiop Value30-day mortality12.011.612.70.85.005In-hospital mortality7.06.87.40.85.03%of patients with LOS5
12、 d43.342.145.10.90.00330-day readm rate13.413.113.90.95.34Early Administration of Abx significantly decrease mortality and LOSStart empirical antibiotic therapy as soon as possible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
13、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Infectious Diseases Expert ResourcesInfectious Diseases SpecialistsOptimal Patient CareInfection Control ProfessionalsHealthcare EpidemiologistsClinicalPharmacistsClinical PharmacologistsSurgical InfectionExpertsClinicalMicrobiologis
14、ts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/he
15、ptic 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-considerations in choosing antibiotic for empiric therapy l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 si
16、te of infectionGram染色结果-与上述病原体是否符合？Gram stain-in accordance with suspected pathogen?l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 infectionM o u th P e p to c o c
17、 c u s P e p to stre p to c o c c u s A c tin o m y c e s S k in/S o ft T issu e S.a u re u s S.p y o g e n e s S.e p id e rm id is P a ste u re lla B o n e a n d Jo in t S.a u re u s S.e p id e rm id is S tre p to co c c i N.g o n o rrh o e a e G ra m-n e g a tiv e ro d s A b d o m e n E.c o li,P r
18、o teu s K le b sie lla E n te ro c o c c u s B a c te ro id e s sp.U rin ary T ra ct E.c o li,P ro teu s K le b sie lla E n te ro c o c c u s S ta p h sa p ro p h y tic u s U p p e r R esp irato ry S.p n e u m o n ia e H.in flu e n za e M.c a ta rrh a lis S.p y o g e n e s L o w e r R e sp ira to ry
19、 C o m m u n ity S.p n e u m o n ia e H.in flu e n za e K.p n e u m o n ia e L e g io n e lla p n e u m o p h ila M y c o p la sm a,C h la m yd ia L o w e r R e sp ira to ry H o sp ita l K.p n e u m o n ia e P.a e ru g in o sa E n te ro b a c te r sp.S e rra tia sp.S.a u re u s M e n in g itis S.p n
20、 e u m o n ia e N.m e n in g itid is H.in flu e n za G ro u p B S tre p E.c o li L iste ria 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(tissue penetration)抗菌药物的特性（antibioti
21、c 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)参考代表性资料/依靠当地资料安全性(safety profile)-药物本身
22、/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 氯霉素氯霉素青霉素青霉素万古霉素万古霉素链霉素链霉素两性霉素两性霉素B B磺胺药磺胺药氨苄西林氨苄西林阿
23、米卡星阿米卡星庆大霉素庆大霉素林可霉素林可霉素吡嗪酰胺吡嗪酰胺羧苄西林羧苄西林奈替米星奈替米星妥布霉素妥布霉素多粘菌素多粘菌素B B异烟肼异烟肼哌拉西林哌拉西林头孢孟多头孢孟多红霉素红霉素克林霉素克林霉素利福平利福平头孢噻肟头孢噻肟头孢哌酮头孢哌酮苯唑西林苯唑西林乙胺丁醇乙胺丁醇头孢他啶头孢他啶甲硝唑甲硝唑头孢呋新头孢呋新美洛西林美洛西林环丙沙星环丙沙星拉氧头孢拉氧头孢磷霉素磷霉素阿昔洛韦阿昔洛韦亚胺培能亚胺培能阿糖腺苷阿糖腺苷脑膜炎症或无炎症时脑膜炎症或无炎症时csfcsf浓度均可达到抑菌浓度均可达到抑菌水平（水平（MIC)MIC)仅在脑膜炎症时仅在脑膜炎症时csfcsf浓浓度均可达到抑菌水
24、平度均可达到抑菌水平（MICMIC）脑膜炎症时脑膜炎症时csfcsf可达可达一定浓度一定浓度脑膜炎症时脑膜炎症时csfcsf浓度仍浓度仍呈微量者（呈微量者（60 years2.65Diabetes2.57Colodner et al EJCMID 2004 23,163.Prevalence of rectal carriage of Extended-Spectrum-lactamase-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、
25、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-57-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)Ti
26、an 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 microbiology 2008;54:1519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 Univa
27、riate 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(7.4)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
28、(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 antibiotic 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 o
29、f 455 episodes of K.pneumoniae bacteremia(253 nosocomial)in 12 hospitalsn30.8%为医院获得,ICU中43.5%产ESBLsnESBLs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).n其它危险因素 TPN,肾功衰竭,烧伤n非ESBL危险:碳青霉烯、头孢吡肟、喹诺酮、氨基糖苷类 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
30、 7 days/prior ABsTrouillet,et al.Am J Respir Crit Care Med.1998;157:531Trouillet 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n发生VAP15天内使用抗菌药（亚胺培南,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=.05Resistance of P aeruginosa Strains To Imipenem,Ceftazidime,or Ciprofloxacin,
31、According to Previous Therapy With Imipenem,a 3rd-generation Cephalosporin,or a FluoroquinoloneNo.(%)of patients,by previous drug therapy receivedImipenemThird-generation cephalosporinFluoroquinoloneStrain resistanceNo(n=114)Yes(n=21)No(n=73)Yes(n=62)No(n=100)Yes(n=35)To imipenem19(16.7)11(52.4)a12(
32、16.4)18(29.0)18(18)12(34.3)dTo ceftazidime17(14.9)7(33.3)6(8.2)18(29.0)b14(14)10(28.6)To ciprofloxacin35(30.7)11(52.4)25(34.2)21(33.9)26(26)20(57.1)c关注耐药病原体-近期应用抗菌药物与铜绿耐药S.aureusPenicillin1944Penicillin-resistantS.aureus金黄色葡萄球菌耐药的发生发展过程金黄色葡萄球菌耐药的发生发展过程Methicillin1962Methicillin-resistantS.aureus(MRS
33、A)Vancomycin-resistantenterococci(VRE)Vancomycin1990s1997VancomycinintermediateS.aureus(VISA)2002Vancomycin-resistantS.aureusCDC,MMWR 2002;51(26):565-5671960Macrolide 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%
34、)Vietnam88.3%RHong Kong 76.5%RTaiwan87.2%RChina75.6%RKorea85.1%R-ermB more common(50%)China,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.赵铁梅，刘又宁.中华内科杂志.2004;43(5):329-3
35、32/AAC,2004;48（10）:4040-4041耐药表型耐药表型基因型基因型N=148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(physio
36、logic 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 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
37、低的药物到位！治疗决定个体化u耐药的可能性？l病人的致病微生物？病人来源?l选择压力用当地的监测资料不越位！u耐药u交叉耐药资料选择哪种抗菌药物(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
38、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 therapyPharmacology of Antim
39、icrobial TherapyDosingregimenConcentrationsin serumConcentrationsin tissues and body fluidsConcentrationsat site of infectionPharmacologic and toxicologic effectAntimicrobialeffectPharmacokinetics(PK)MIC、MBCDifferent pattern of time-killing of 3 Abx VS PseudomonasKilling and rate of killing depends
40、on concentrationRate of killing increases no more as concentration increases,killing depends on exposure timePK/PD Predictors of Efficacy-a combination of PK and PDTimeMIC90Log Concentration24h-AUCT MICCmax,Cmax/MIC24h-AUC/MIC(AUIC)DoseDoseCmaxTMICParameters of interestPK/PD Predictors of Efficacy时间
41、依赖性时间依赖性与时间有关，但抗菌活性持续时与时间有关，但抗菌活性持续时间较长间较长对致病菌的杀菌作用对致病菌的杀菌作用取决于峰浓度取决于峰浓度抗菌作用与抗菌作用与同细菌接触时间密切相关同细菌接触时间密切相关时间依赖且时间依赖且PAEPAE或或T1/2T1/2较长较长 氨基糖苷类、氟喹诺酮类、氨基糖苷类、氟喹诺酮类、酮内酯类、两性霉素酮内酯类、两性霉素B B、daptomycindaptomycin、甲硝唑甲硝唑多数多数-内酰胺类、内酰胺类、林可霉素类林可霉素类恶唑烷酮类、氟胞嘧啶恶唑烷酮类、氟胞嘧啶 链阳霉素、四环素、链阳霉素、四环素、碳青霉烯类、糖肽类、碳青霉烯类、糖肽类、大环内酯类、唑类
42、抗真菌药大环内酯类、唑类抗真菌药 主要参数主要参数AUC0-24/MIC(AUIC)Cmax/MIC 主要参数主要参数 TMIC和和AUCMIC主要参数主要参数 TMIC,PAE，T1/2 AUC/MIC 浓度依赖性浓度依赖性Required%TMIC for cidal:n 40%for carbapenemsn 50%for penicillinsn 70%for cephalosporinsDrusano GL.Clin Infect Dis.2003;36(suppl 1):S42-S50.Required%TMIC for static 20%for carbapenems 30%f
43、or penicillins 40%for cephalosporins -lactam:optimal TMIC?Drusano.Clin Infect Dis 2003;36(Suppl.1):S42S50Maximizing TMIC提高剂量安全性前体增加给药频率延长输注时间-内酰胺类优化暴露时间-Lactam:Optimizing ExposureDandekar PK et al.Pharmacotherapy.2003;23:988-991.Meropenem 500 mg Administered as a 0.5 h or 3 h InfusionMIC024680.11.01
44、0.0100.0Rapid Infusion(30 min)Extended Infusion(3 h)Treatment of Multidrug-resistant Burkholderia cepacia With Prolonged Infusion Meropenem08162432400.1110100MIC=16 mcg/mLTMIC exposure was 40%of the dosing interval at the MIC of16 mcg/mLKuti JL et al.Pharmacotherapy.2004;24:1641-1645Moore et al.J In
45、fect Dis 1987;155:9399Aminoglycoside:optimal Cmax:MIC -Relationship Between Cmax:MIC and Clinical ResponseClinical response(%)Cmax:MIC02040608010024681012556570838992What is the Optimal AUIC for Fluoroquinolones?30125For G+For G-Forrest et al.Antimicrob Agents Chemother 1993;37:10731081Fluoroquinolo
46、ne Therapy for Nosocomial Pneumonia Correlation Between Drug Exposure(AUC/MIC)&OutcomePatients cured(%)020406080100062.562.5125125250250500500AUC:MICClinicalMicrobiologicalAUC:MIC125 lead to appropriate clinical and microbiological outcomeGram-Negative Bacterial Eradication and Fluoroquinolone AUICD
47、ays 0 2 4 6 8 10 12 140100755025AUIC 125-250AUIC 250AUIC 125%Patients remaining culture positiveForrest et al.Antimicrob Agents Chemother.1993;37:1073-1081Higher AUC:MIClead to letter bacterial eradicationProbability of Developing ResistanceThomas KL et al.Antimicrob Agents Chemother.1998;42:521527A
48、UC024h:MIC 100AUC024h:MIC 100 Free AUIC 30-40Resistance preventionnCmax MPCnHigher AUICBaquero&Negri.BioEssays 1997;19:731-6 Drlica K.ASM News 2001;67:27-33Cantn et al.Inter J Antimicrob Chemother 2006(in press)Concentration (g/ml)Time post administration(h)CmaxMPCTmax MICWindow of selectionMICMPC(M
49、IC of mutants)Resistant mutantSusceptible bacteria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(physio
50、logic 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老人感染特点o易发生细菌感染o常见肺炎、尿感、胆道感染、败血症o常见菌
