1、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 high level of motivation in the country to aid the health of the s
2、oldiers at war.Discovery of Antibacterial AgentsCycloserineErythromycinEthionamideIsoniazidMetronidazolePyrazinamideRifamycinTrimethoprimVancomycinVirginiamycinImipenem19301940195019601970198019902000PenicillinProntosilCephalosporin CEthambutolFusidic acidMupirocinNalidixic acidOxazolidinonesCecropi
3、nFluoroquinolonesNewer aminoglycosidesSemi-synthetic penicillins&cephalosporinsNewer carbapenemsTrinemsSynthetic approachesEmpiric screeningNewer macrolides&ketolidesRifampicinRifapentineSemi-synthetic glycopeptidesSemi-synthetic streptograminsNeomycinPolymixinStreptomycinThiacetazoneChlortetracycli
4、neGlycylcyclinesMinocyclineChloramphenicol临床关注的耐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 青霉素和大环内酯耐药 革兰阴性细菌n肠杆菌科uESBLs-喹诺酮,头孢菌素,青霉素类,氨基糖苷类u碳青霉烯酶（KPC,NDM-1?）-碳青酶烯耐药在中国出现和蔓延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,碳青霉烯类VREMRSAABESBL K.pneumoniaeAntibiotic Contro
5、l and Infection Control:The Two Sides of the Resistance“Coin”Rekha Murthy.Implementation of Strategies to Control Antimicrobial Resistance Chest 2001;119;405-411Control of Antibiotic Resistance经验性抗感染治疗的基本原则耐药背景下的个体化治疗理性回归/责任所在慢性咳嗽和黄痰-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 -WB
6、C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及鉴别诊断27-year-old man with acute lymphocytic leukemia.51-year-old man with chronic myelogenous leukemia.22-year-old woman with adult T-cell leukemia.67-year-old woman with adult T-cell leukem
7、ia.61-year-old man with interstitial fibrosis;patient was receiving chlorambucil for chronic lymphocytic leukemia.COPRapid testsWhen available.Gram stain!Start adequate antibiotic coverage(within 1 hour?)Drain purulent collectionSamplingIncluding invasive procedureswhen needed(BAL)合格标本进行微生物学检查 开始经验性
8、抗感染治疗 目标治疗经验性治疗和目标治疗的统一选择哪种抗菌药物 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/组织穿透性/耐药性/安全性/费用考虑药代动力学/药效动力学考虑病人生理和病理生理状态 高龄/儿童/孕妇/哺乳 肾功不全/肝功不全/肝肾功能联合不全其它因素 杀菌和抑菌/单药和联合/静脉和口服/疗程 经验性抗感染治疗合理选择药物-considerations in choosing antibiotic for empiric therapy 评估病原体 -有的而放矢！评估耐药性 -到位不越位！病情严重性评估+-个体化评估-特殊修正因子 先期抗菌药物对细菌学及其耐药性影
9、响 不同部位感染-病原体的流行病学 从病原学认识感染性疾病SSSSPCP抗菌谱(coverage)组织穿透性(tissue penetration)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的基本原则评价病原体耐药可能？是否耐药菌？-了解耐药病原体流行状况了解耐药病原体流行状况 参考代表性治疗/依靠当地资料 -个体化用药个体化用药-合理用药的精髓合理用药的
10、精髓 病人来源：社区、养老院、医院 高龄、基础疾病、近期抗菌药物、近期住院、侵袭性操作、晚发医院感染 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(MRSA)Vancomycin-resistantenterococci(VRE)Vancomycin1990s1997VancomycinintermediateS.aureus(VISA)2002Vancomycin-resistantS.
11、aureusCDC,MMWR 2002;51(26):565-5671960评价病原体耐药可能？是否耐药菌？-了解耐药病原体流行状况 参考代表性治疗/依靠当地资料 -个体化用药-合理用药的精髓 病人来源：社区、养老院、医院 高龄、基础疾病、近期抗菌药物、近期住院、侵袭性操作、晚发医院感染%Wang H,Chen M.Diagnos Microbiol Infect Dis,2005,51,201-208CMSS/SEANIR/CARES.year细菌耐药监测结果如何解读？细菌耐药监测结果如何解读？实验室药物敏感性监测的解读实验室药物敏感性监测的解读意义-反映了耐药趋势/告诫要谨慎使用抗菌药物
12、-影响选择药物/考虑耐药性对疗效的影响不足 -实验室收集菌株/大型教学医院/ICU 抗生素选择压力导致耐药性高估！-没有临床背景资料/不能用于指导个体化用药 (年龄、基础疾病、社区/医院感染、前期抗菌药物使用情况)No Risk Factors for MDROsRisk Factors for MDR EnterobacteriaceaeaRisk Factors for MDR PseudomonasHealth care contact No Yes!(eg,recent hospital admission,nursing home,dialysis)without invasive
13、procedure Yes,Long hospitalization and/or infection following invasive procedures(5 days)Recent Abx No Yes!(14 days in past 90 days)Yes!(14 days in past 90 days)对Patient characteristics Young few comorbidities 65 yrs comorbidities such as TPN or renal insufficiency co-morbidities such as CF,structur
14、al lung disease,advanced AIDS,neutropenia,or other severe immunodeficiency Drugs of choiceAmoxi/calvAmpicillin/sulb2nd or 3rd GFQsPip/tazoCefaperazone/sulbactamertapenemCeftazidine cefepimePip/tazoCefperazone/sulbactamImipenem meropenemaExcept nonfermenters/non-Pseudomonas species.Adapted from Carme
15、li Y.Predictive factors for multidrug-resistant organisms.In:Role of Ertapenem in the Era of Antimicrobial Resistance newsletter.Available at:www.invanz.co.il/secure/downloads/IVZ_Carmeli_NL_2006_W-226364-NL.pdf.Accessed 7 April 2008;Dimopoulos G,Falagas ME.Eur Infect Dis.2007;4951;Ben-Ami R,et al.C
16、lin Infect Dis.2006;42(7):925934;Pop-Vicas AE,DAgata EMC.Clin Infect Dis.2005;40(12):17921798;Shah PM.Clin Microbiol Infect.2008;14(suppl 1):175180.Stratification for Risk for MDR Gram-Negative Pathogens重症感染 耐药菌感染！重症感染 革兰阴性肠杆菌科细菌感染！肺炎链球菌、化脓性链球菌、军团 菌、肺孢子菌等均可致重症感染PCPLD对于选择抗菌药物-耐药性 VS 严重性哪个更重要？PCPLD耐药菌
17、感染 VS 严重感染-PCP和LD告诉我们什么？观点:-耐药性判断 对于合理选择抗菌药物更重要！包括重症感染 -即使重症感染,抗感染治疗方案 仍需根据病原体及其耐药性评估 来制定经验性抗感染治疗的基本原则耐药背景下的个体化治疗以CAP/HAP为例22Craven DE.Curr Opin Infect Dis.2006;19:153-160.The Changing Spectrum of PneumoniaCAP,HCAP,HAPHealthcare-associated pneumonia is a relatively new clinical entity that includes
18、a spectrum of adult pts who have a close association with acute-care hospitals or reside in chronic-care settings that increase their risk for pneumonia caused by MDR pathogens.PneumoniaCAPaHCAPbHAPc/VAPdMorbidity&MortalityRisk of MDR Pathogensa.CAP=community-acquired pneumoniab.HCAP=healthcare-asso
19、ciated pneumoniac.HAP=hospital-acquired pneumoniad.VAP=ventilator-associated pneumoniaH.influenzaeK.pneumoniaeS.pneumoniaeM.pneumoniaeL.pneumophilaC.pneumoniaeCommunity-acquired pneumonia in Europe*病原体社区治疗入院治疗ICU发表的研究数量92313肺炎链球菌肺炎链球菌19,319,325,925,921,721,7流感嗜血杆菌3,34,05,1军团菌1,94,97,9金匍菌金匍菌0,20,21,4
20、1,47,67,6GNB0,42,77,5肺炎支原体11,17,52鹦鹉热衣原体1,51,91,3病毒11,710,95,1病原学不明49,843,841,5*Woodhead M.Eur Resp J 2002;20:Suppl.36,20-27病原体排序肺链 S pneumoniae非典型病原体 atypicals 流感嗜血杆菌 H infuenzae卡他莫拉菌 M catarrhalis金葡菌 S aureus革兰阴性肠杆菌 GNB流感流行后/坏死性肺炎 MRSA?History of MRSA in U.S.59青霉素上市第一个MRSA菌株出现CA-MRSA 爆发于不同人群儿童中出现没
21、有“经典”危险因素的MRS感染98MMWR 报告4例健康儿童死于 MRSA感染99CA-MRSA 成为 SSTI的主要原因0405在美国侵袭性MRSA导致18,650 死亡 Community Acquired MRSAIn contrast to the rise in nosocomial MRSA from 1990 to the present,growing awareness of community-acquired MRSA has occurred through published reports of MRSA outbreaks for which traditiona
22、l risk factors were not identified.Necrotizing pneumonia,United States and Europe1980Outbreak in Detroit,Mich2/3 of patients were IVDUMid 1990sChildrenw/o identifiable risk factorsLate 1990s 1998-Athletes/sports teams 1999-Native Americans 2000 Prison and jail populations2003IVDU=intravenous drug us
23、ers.Groom AV et al.JAMA.2001;286:1201-1205.Herold BC et al.JAMA.1998;279:593-598.CDC.Morb Mortal Wkly Rep.2001;50:919-922.Naimi TS et al.JAMA.2003;290:2976-2984.Zetola N et al.Lancet Infect Dis.2005;5:275-286.Levine DP et al.Ann Intern Med.1982;97:330-338.CDC.Morb Mortal Wkly Rep.2003;52:793-795.Gil
24、let Y et al.Lancet.2002;359:753-759.CDC.Morb Mortal Wkly Rep.1999;48:707-710.uRemains an uncommon cause of CAP -CDC surveillance study of invasive MRSA1-0.74/100,000 -EMERGEncy ID NET Study Group(12 U.S.ERs)2 MRSA accounted for 2.4%of all CAP;5%of ICU CAPuBut has emerged as a cause of severe CAP Com
25、pared to non-MRSA CAP,patients were2:More ill(more likely to be comatose,require intubation,pressors and die in the ER)More CXR abnormalities(multiple infiltrates,cavitation)uMortality rate 14%(up to 50%in some studies)Epidemiology of MRSA Community-Acquired Pneumonia(CAP)1Klevens JAMA 2007;298:1763
26、-1771;2Moran CID 2012;54:1126-33 Approach to Empiric Therapy:CAPEmpiric treatment for MRSA is recommended for severe CAP defined by:nICU admissionnNecrotizing or cavitary infiltratesnEmpyemaDiscontinue empiric Rx if cultures do not grow MRSALiu CID 2011;52;285-322中国社区MRSA流行病学？我们怎么办？Valentini Ann of
27、Clin Micro 2008Characterization of CA-MRSA Associated with Skin and Soft Tissue Infection in Beijing:High Prevalence of PVL+ST398A prospective cohort of adults with SSTI between 2009.01 2010.08 at 4 hospitals in Beijing501 SSTI patients were enrolled -Cutaneous abscess(40.7%);impetigo(6.8%);cellulit
28、is(4.8%)S.aureus accounted for 32.7%(164/501)-5 isolates(5/164,3.0%)were CA-MRSA -most dominant ST was ST398(17.6%)-prevalence of PVL gene was 41.5%(66/159)in MSSA.王辉 PLoS ONE,2012;7(6):e38577.到目前为止CA-MRSA所致CAP尚无报告Epidemiology of MRSAH-MRSAReservoires -hospitals -LTCFs5 genetic backgroudsH-MRSA in c
29、ommunity-patients with risk factors-contact with patients with risk factorsTrue community-MRSA-no healthcare-associated risk factors-with PVL geneshealthcarecommunityAcquiredOnsetH-MRSA 感染危险因素:年龄65岁，严重基础疾病，伤口 广谱抗生素使用，住院时间延长，多次住院 侵袭性操作（气管插管、切开/植入血管导管）合理使用抗MRSA药物糖肽类/利奈唑胺Prediction of MRSA in Patients
30、with Non-Nosocomial pneumoniaBMC Infectious Diseases 2013,13:370 doi:10.1186/1471-2334-13-370Retrospective study from January 2008 to December 2011.943 culture-positive MRSA and non-MRSA pneumonia outside the hospitalIdentified risk factors associated with MRSA pneumonia.病原体社区治疗入院治疗ICU发表的研究数量92313肺炎
31、链球菌19,325,921,7流感嗜血杆菌3,34,05,1军团菌1,94,97,9金匍菌0,21,47,6GNB0,42,77,5肺炎支原体11,17,52鹦鹉热衣原体1,51,91,3病毒11,710,95,1病原学不明49,843,841,5*Woodhead M.Eur Resp J 2002;20:Suppl.36,20-27病原体排序肺链 S pneumoniae非典型病原体 atypicals 流感嗜血杆菌 H infuenzae卡他莫拉菌 M catarrhalis金葡菌 S aureus革兰阴性肠杆菌 GNB?CAP due to GNBANSORP,2002-2004,91
32、2 CAP93(10.1%)were caused by GNBn肠杆菌科-K.pneumoniae(59),Enterobacter spp.(7),S.marcescens(1)n非发酵菌-P.aeruginosa(25),A.baumannii(1),Higher morbidity and co-morbid diseasesSeptic shock,malignancy,CV disease,smoking,hypoNa,dyspneaHigher mortality n18.3%vs 6.1%(p5 days)HAP或 MDR病原体的危险因素否是窄谱抗菌药物广谱抗菌药物-针对MDR
33、病原体HAP初始初始经验性经验性抗菌药物抗菌药物选择选择的流程图的流程图ATS.Am J Respir Crit Care Med 2005;171:388-416n既往90天内曾经使用过抗菌药物n住院时间为5天或更长n在社区或其他医疗机构抗生素耐药出现的频率高n存在HCAP相关危险因素90天内住急性病院两天及以上家庭内输液治疗（含抗生素）30天内有过持续透析家庭外伤治疗家庭成员有耐多药病原体感染n免疫抑制性疾病和/或免疫抑制剂治疗阴性预计值的价值更大Stratification of HAP Patients at Risk for MDR OrganismsThe differences
34、not firmly settled Available data indicate in spontaneously breathing pts -potentially drug resistant microorganisms may play a minor role -GNEB(abx susceptible),S aureus(MSSA)and S pneumoniae as leading pathogens-spontaneously breathing VS ventilated1.Ewig S,Torres A,et al.(1999)Bacterial colonizat
35、ion patterns in mechanically ventilated patients with traumatic and medical head injury.Incidence,risk factors,and association with VAP.Am J Respir Crit Care Med 159:1881982.Rello J,Torres A(1996)Microbial causes of VAP.Semin Respir Infect 11:2431Mechanical Ventilation Is Associated With a Significa
36、ntly Increased Incidence of Respiratory Tract MRSA Infection Pujol M et al.Eur J Clin Microbiol Infect Dis.1998;17:622-628.A prospective cohort study conducted to define the clinical and epidemiological characteristics of MRSA VAP acquired during a large-scale outbreak of MRSA Stratification of Pati
37、ents at Risk for MDR Organisms-early onset VS late-onsetEarly-onsetLate-onsetpneumoniapneumoniaOthers based on(5 days)specific risksS.pneumoniae P.aeruginosa Anaerobic bacteria H.influenzaeEnterobacter spp.Legionella pneumophilaS.aureus Acinetobacter spp.Influenza A and B Enterobacteriaceae K.pneumo
38、niae RSVS.marcescens Fungi E.coli Other GNB S.aureus(MRSA)GNB,Gram-negative bacilli;MRSA,methicillin-resistant S.aureusAdapted from Am J Respir Crit Care Med.2005;171:388416.Stratification of HAP Patients at Risk for MDR Organisms-early onset VS late-onset-Recent Antibiotic Therapy and Pseudomonal R
39、esistanceTrouillet JL et al.Clin Infect Dis.2002;34:1047-1054.P.aeruginosa VAP:34 isolates piperacillin and multi-drug resistant;101 sensitiveUse of antibiotics(imipenem,third generation cephalosporin and quinolone)within 15 days of VAP increased PA resistance to the same agent-patient-specific abx
40、rotationaP=.0009 bP=.003 cP=.001 dP=.05Resistance of P aeruginosa Strains To Imipenem,Ceftazidime,or Ciprofloxacin,According to Previous Therapy With Imipenem,a 3rd-generation Cephalosporin,or a FluoroquinoloneNo.(%)of patients,by previous drug therapy receivedImipenemThird-generation cephalosporinF
41、luoroquinoloneStrain 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(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)cStratification of Patients at Risk f
42、or MDR Organisms既往应用抗生素发生CRAB的风险比(OR)Kim YJ,et al.J Korean Med Sci.2012 May;27(5):471-5.碳青霉烯使用是IR-MDRAB出现的唯一独立危险因素Ye JJ,et al.PLoS One.2010 Apr 1;5(4):e9947Stratification of Patients at Risk for MDR Organisms-Recent Antibiotic Therapy and Acinetobacter ResistanceRisk Factors for Infections With Mult
43、idrug-Resistant Stenotrophomonas maltophilia in Patients With Cancer.CANCER。2007；109（12）：2615-22Stratification of Patients at Risk for MDR Organisms-Recent Antibiotic Therapy and S maltophilia医院获得性肺炎细菌学演变-抗生素选择性压力的体现抗生素选择性压力 二代头孢菌素 三代头孢菌素/酶抑制剂复合制剂 碳青霉烯+抗MRSA hospital/ICU admmissionLOS 7dLOS 7dAB0AB+
44、ABAB0Wide-spectrum PCs+inhibitorOr 3rd G antipseudomonal cephalosporins Aminoglycosides or FQsaminoglycoside or FQs +carbapenem Or Wide-spectrum PCs+inhibitor制剂(+vancomycin)S pneumoniae,H influenzae,S aureus,and anaerobesPseudomonas,MRSA,Acinetobacter,S maltophiliaChristian B,Seminars in respiratory
45、 and Critical care medicine 2002,23:457-469European HAP guideline-2002 GNEB,S.aureus,S.pneumoniae Drug-resistant microorganisms may play minor role in non-ventilated patientsS.aureus,S.pneumoniae,H.influenzae,nondrug-resistant GNEBMRSA,drug-resistant GNEB,P.aeruginosa,A.baumanniiERS,European Respira
46、tory Society;ESCMID,European Society of Clinical Microbiology and Infectious Diseases;ESICM,European Society of Intensive Care Medicine;GNEB,Gram-negative Enterobacteriaceae.Torres A et al.Intensive Care Med.2009;35(1):9-29.HAP SuspectedVentilation50Leading PathogensSlide LibraryTime of Onset医院获得性肺炎细菌学演变-抗生素治疗的方向二代头孢菌素 三代头孢菌素/酶抑制剂复合制剂 碳青霉烯+抗MRSA 酶抑制剂复合制剂 耐药背景下的个体化抗感染治疗-小结正确诊断是正确治疗的前提努力实现经验性治疗和目标治疗之统一经验性抗感染治疗的两种能力 -评估病原体 流行病学/个体化评估/从病原学识别感染性疾病 -评估耐药性 流行病学基础上的个体化评估 耐药菌感染:高龄/基础疾病/近期住院(ICU)/晚发医院感染/抗生素暴露 Homogenous protocolMixingThank You谢谢观赏！2020/11/555
