感染病患者多重耐药菌感染风险的分层课件.ppt

1、抗感染药物发展简史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 the country to aid the health of the sol

2、diers at war.Discovery of Antibacterial AgentsCycloserineErythromycinEthionamideIsoniazidMetronidazolePyrazinamideRifamycinTrimethoprimVancomycinVirginiamycinImipenem19301940195019601970198019902000PenicillinProntosilCephalosporin CEthambutolFusidic acidMupirocinNalidixic acidOxazolidinonesCecropinF

3、luoroquinolonesNewer aminoglycosidesSemi-synthetic penicillins&cephalosporinsNewer carbapenemsTrinemsSynthetic approachesEmpiric screeningNewer macrolides&ketolidesRifampicinRifapentineSemi-synthetic glycopeptidesSemi-synthetic streptograminsNeomycinPolymixinStreptomycinThiacetazoneChlortetracycline

4、GlycylcyclinesMinocyclineChloramphenicol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.pneumoniaeAntibio

5、tic Control 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 ResistanceNo simplistic policyHomogenous protocolMixing经验性抗感染治疗的基本原则经验性抗感染治疗的基本原则耐药背景下的个体化治疗耐药背景下的个体化治疗理性回归

6、理性回归/责任所在责任所在经验性抗感染治疗的基本原则经验性抗感染治疗的基本原则 -耐药背景下的个体化治疗合理使用碳青霉烯类药物合理使用碳青霉烯类药物 -指南VS 临床实践内内 容容 安安 排排慢性咳嗽和黄痰慢性咳嗽和黄痰-原因原因哮喘 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吸烟相关的慢性支气管炎支气管扩张症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

7、前提正确诊断是正确治疗的前提发热的诊断与鉴别诊断发热的诊断与鉴别诊断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 leukemia.61-year-old man with interstitial fibrosis;patient was receiving chlorambucil

8、for chronic lymphocytic leukemia.COPRapid testsWhen available.Gram stain!Start adequate antibiotic coverage(within 1 hour?)Tillou A et al.Am Surg 2004;70:841-4Drain purulent collectionSamplingIncluding invasive procedureswhen needed(BAL)合格标本进行微生物学检查合格标本进行微生物学检查 开始经验性抗感染治疗开始经验性抗感染治疗 目标治疗目标治疗经验性治疗和目标治

9、疗的统一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+-个体化评估个体化评估-特殊修正因子特殊修正

10、因子 先期抗菌药物对细菌学及其耐药性影响先期抗菌药物对细菌学及其耐药性影响 不同部位感染不同部位感染-病原体的流行病学病原体的流行病学 从病原学认识感染性疾病MouthPeptococcusPeptostreptococcusActinomycesSkin/Soft TissueS.aureusS.pyogenesS.epidermidisPasteurellaBone and JointS.aureusS.epidermidisStreptococciN.gonorrhoeaeGram-negative rodsAbdomenE.coli,ProteusKlebsiellaEnterococ

11、cusBacteroides sp.Urinary TractE.coli,ProteusKlebsiellaEnterococcusStaph saprophyticusUpper RespiratoryS.pneumoniaeH.influenzaeM.catarrhalisS.pyogenesLower Respiratory CommunityS.pneumoniaeH.influenzaeK.pneumoniaeLegionella pneumophilaMycoplasma,ChlamydiaLower RespiratoryHospitalK.pneumoniaeP.aerugi

12、nosaEnterobacter sp.Serratia sp.S.aureusMeningitisS.pneumoniaeN.meningitidisH.influenzaGroup B StrepE.coliListeria抗菌谱(coverage)组织穿透性(tissue penetration)耐药性耐药性(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

13、原则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？评价病原体耐药可能？是否耐药菌？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)Van

14、comycin-resistantenterococci(VRE)Vancomycin1990s1997VancomycinintermediateS.aureus(VISA)2002Vancomycin-resistantS.aureusCDC,MMWR 2002;51(26):565-5671960评价病原体耐药可能？评价病原体耐药可能？是否耐药菌？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 -个体化用药个体化用药-合理用药的精髓合理用药的精髓 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 0102030405060

15、702001200220032004200520062007200828.645.75954.657.86060.260.225.734.947.736.640.451.53845.7E.coliK.pneumoniae%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？Wang H,Chen M.Diagnos Microbiol Infect Dis,2005,51,201-208CMSS/SEANIR/CARES.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意义-反映了耐药趋势/告诫要谨慎使用抗菌药物 -影响选择药物/考虑耐药性对疗效的影响不足不足 -实验室收集菌株

16、/大型教学医院/ICU 抗生素选择压力导致耐药性高估！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 procedure Yes,L

17、ong 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,structural lung disease

18、,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 Carmeli Y.Predictive

19、 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.Clin Infect Dis.

20、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对于选择抗菌药物对于选择抗菌药物-耐药性耐药性 VS 严重性哪个更重要？严重性哪个更重要？PCP

21、LD耐药菌感染耐药菌感染 VS 严重感染严重感染-PCP和LD告诉我们什么？观点观点:-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经验性抗感染治疗的基本原则 -耐药背景下的个体化治疗合理使用碳青霉烯类药物合理使用碳青霉烯类药物 -指南 VS 临床实践内内 容容 安安 排排CAP 碳青霉烯HAP 碳青霉烯CNS感染 碳青霉烯中性粒细胞减少性发热 碳青霉烯外科感染 碳青霉烯抗感染指南中碳青霉烯的地位抗感染指南中碳青霉烯的地位 所有抗感染指南都推荐碳青霉烯作为治疗选择之一！所有抗感染指南都推荐碳

22、青霉烯作为治疗选择之一！如何恰到好处地个体化应用碳青霉烯？如何恰到好处地个体化应用碳青霉烯？Effectiveness-role of carbapenem？-Why？When？Which？nEmpiric therapyucovers close to 100%of suspected pathogensnDirected therapyuClinical successSafety profile nAdverse eventsCost/effectivenessMinimizing resistancenSelf resistance/Resistance to other agents

23、 Considerations in Choosing Antibiotic for Optimal TherapyChange of paradigmWe are living in an era of high resistanceG-ves resistant to -penicillins/cephalosporins -quinolones -aminoglycosides -TMP/SMX Think MDR rather than resistanceIncreasing proportion of MDR GNRDAgata E.ICHE 2004%MDRSppESBLcipr

24、ogentamicinTMP/sulPip/tzKlebsiellaN=90+49%16%30%40%KlebsiellaN=158-97%97%91%99%E.coliN=70+16%14%11%71%E.coliN=535-93%96%71%99%Susceptibilities ESBL vs non-ESBL Schwaber M.AAC 2005ESBL contribute most to MDR pathogensFailure ESBL vs non-ESBL0%20%40%60%80%100%Schwaber,2005*Kim,2002*Patterson DL,2001Ar

25、rifin H,2000*non-ESBLESBLFailure*failure=mortalitySusceptibilities of 1030 ESBL producing E.coli&Klebsiella spp.Colodner R.ICAAC 2005Mortality among 60 patients with ESBL producing Klebsiella BacteremiaPaterson DL.Ann Intern MedWhether we like it or notAccumulation of ESBLs&quinolone resistance will

26、 drive carbapenem useWhen and which?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 fee

27、ding)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)经验性抗感染治疗怎样选择碳青霉烯？经验性抗感染治疗怎样选择碳青霉烯？评估病原体 有的而放矢！评估耐药性 到位不越位！MDR Enterobacteriaceae（ESBL-producer)？MDR P.aeruginosa/A.acinetobacter？入院即可能有入院即

28、可能有MDROs感染的高风险人群感染的高风险人群u老年人 u误吸(对于肺炎而言)u基础内科疾病 -结构性肺病/粒缺/严重免疫缺陷除外-铜绿风险u过期三个月使用任何静脉抗生素 -特别是FQ和二、三代头孢菌素u过期一年内多次(2次)住院u先期手术u住LCTFu长期血液透析u实体脏器移植Risk factors for infection with ESBL producers outside hospitalFactorOdds ratioRx 3 gen ceph15.8Rx 2 gen ceph10.1Hospital in last 3 months8.95Rx quinolone4.1Rx

29、 penicillins4.0Antibiotic Rx in last 3 months3.23Age 60 years2.65Diabetes2.57Colodner et al EJCMID 2004 23,163.What patients can benefit most from ertapenem treatment G negatives -Including ESBL+CAP in advanced ageCAPwith aspirationCAP Severe How to predict?-bacteria -resistance医院获得性肺炎细菌学演变医院获得性肺炎细菌

30、学演变-抗生素选择性压力的体现抗生素选择性压力的体现早期(Early)中期(Middle)晚期(Late)肺链流感嗜血杆菌MSSA MRSA肠杆菌科细菌(抗生素敏感)肠杆菌科细菌(抗生素不敏感)肺克,大肠 肺克,大肠铜绿假单胞菌 MDR XDR PDR不动杆菌 MDR XDR PDR嗜麦芽窄食单胞菌抗生素选择性压力 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 re

31、quirement)-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/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/

32、IV vs PO/duration)经验性抗感染治疗怎样选择碳青霉烯？经验性抗感染治疗怎样选择碳青霉烯？评估病原体 有的而放矢！评估耐药性 到位不越位！MDR Enterobacteriaceae（ESBL-producer)？MDR P.aeruginosa/A.acinetobacter？IDSA Guidelines on Empiric Therapy for CAPRisk factors for Pseudomonas -severe structural lung disease(eg,bronchiectasis)-recent antibiotic therapy or st

33、ay in hospital(especially in the ICU).Adapted from Mandell LA,et al.Clin Infect Dis.2003;37:14051433.VAPMDR细菌感染的危险因素细菌感染的危险因素 135 次次VAP ICU变量 OR PMV7 days 6.0 .009先期ABs 13.5 7 days/prior ABsTrouillet,et al.Am J Respir Crit Care Med.1998;157:531Effectiveness-role of carbapenem？-Why？When？Which？nEmpiri

34、c therapyucovers close to 100%of suspected pathogensnDirected therapyuClinical successSafety profile nAdverse eventsCost/effectivenessMinimizing resistancenSelf resistance/Resistance to other agents Considerations in Choosing Antibiotic for Optimal TherapyErtapenem Pharmacokinetics:Minimal Selectivi

35、ty for Resistant P aeruginosa Under Clinical ConditionsMinimal resistance selection among P aeruginosa(MIC90:16 mg/L)Minimal resistance selection among Enterobacteriaceae(MIC90:0.03 mg/L)N=68 healthy volunteersMRSA=methicillin-resistant S aureus;MSSA=methicillin-susceptible S aureus.Adapted from Nix

36、 DE,et al.J Antimicrob Chemother.2004;53(suppl S2):ii23ii28;Friedland I,et al.J Chemother.2002;14(5):483491.Plasma Ertapenem Concentration,mg/LTotalFree0.010.1100011010004812162024MIC90,mg/L Organism16P aeruginosa,enterococci,MRSA1.0 Anaerobes0.25 MSSA,pneumococci0.12Group A streptococci0.03Enteroba

37、cteriaceaeHours After 1 g Intravenous Dose of ErtapenemSummary Effect of Ertapenem on P aeruginosa,Enterobacteriaceae,and Other G-ve Pathogens Use of ertapenem not decrease susceptibilities of P aeruginosa,Enterobacteriaceae,or other G-ve pathogens to carbapenems Adapted from Livermore DM,et al.J An

38、timicrob Chemother.2005;55(3):306311;DiNubile MJ,et al.Eur J Clin Microbiol Infect Dis.2005;24:443449;DiNubile MJ,et al.Diagn Microbiol Infect Dis.2007;58:491494;DiNubile MJ,et al.Antimicrob Agents Chemother.2005;49(8):32173221;Crank C,et al.Poster presented at:44th Annual Meeting of the Infectious

39、Diseases Society of America(IDSA);1215 October 2006.Toronto,Ontario,Canada;Goff DA,Mangino JE.Poster presented at:47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy(ICAAC);1720 September 2007;Chicago,Illinois,USA;Goldstein EJC,et al.Poster presented at:44th Annual Meeting o

40、f the Infectious Diseases Society of America(IDSA);1215 October 2006;Toronto,Ontario,Canada;Carmeli Y,et al.Poster presented at:47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy(ICAAC);1720 September 2007;Chicago,Illinois,USA.Clinical StudiesOASIS I and OASIS II STITCH Cra

41、nk Goff Goldstein CarmeliBasic Science StudyLivermoreNo Risk Factors for MDR PathogensRisk Factors for MDR EnterobacteriaceaeaRisk Factors for MDR PseudomonasHealth care contact No Yes!(eg,recent hospital admission,nursing home,dialysis)without invasive procedure Yes,Long hospitalization and/or infe

42、ction following invasive procedures(5 days)Recent Abx No Yes!(14 days in past 90 days)Yes!(14 days in past 90 days)Patient characteristics Young few comorbidities 65 yrs comorbidities such as TPN or renal insufficiency co-morbidities such as CF,structural lung disease,advanced AIDS,neutropenia,or ot

43、her severe immunodeficiency Carbapenem?Limited use of carbapenems Ertapenem(group 1 carbapenem)Imipenem,meropenem,doripenem(group 2 carbapenems)Appropriate Carbapenems Based on Risk for MDR Gram-Negative PathogensaExcept nonfermenters/non-Pseudomonas species.Adapted from Carmeli Y.Predictive factors

44、 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.Clin Infect Dis.2006;42(

45、7):925934;Pop-Vicas AE,DAgata EMC.Clin Infect Dis.2005;40(12):17921798;Shah PM.Clin Microbiol Infect.2008;14(suppl 1):175180.耐药背景下的个体化抗感染治疗耐药背景下的个体化抗感染治疗-小结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 Conclusions MDR革兰阴性杆菌在逐渐增加 -碳青霉烯具有重要地位 碳青霉烯耐药问题值得关注 -铜绿假单胞菌/鲍曼不动杆菌 需要合理使用碳青霉烯 -MDR肠杆菌科细菌 VS 非发酵铜绿/鲍曼感染？Suggested use of Carbapenems 怀疑MDR肠杆菌科细菌感染 用I类碳青霉烯(Ertapenem)怀疑铜绿或鲍曼 用II类碳青霉烯(imipenem or meropenem)不怀疑耐药(MDR)菌感染 限制使用碳青霉烯No simplistic policyHomogenous protocolMixing.