模板-感染病患者多重耐药菌感染风险的分层-陈佰义终稿

陈 佰 义,感染病患者多重耐药菌感染风险的分层,谈耐药背景下的个体化抗感染治疗,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 soldiers at war.,Discovery of Antibacterial Agents,CycloserineErythromycinEthionamideIsoniazidMetronidazolePyrazinamideRifamycinTrimethoprimVancomycinVirginiamycin,Imipenem,1930,1940,1950,1960,1970,1980,1990,2000,PenicillinProntosil,Cephalosporin C,EthambutolFusidic 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 streptogramins,NeomycinPolymixinStreptomycinThiacetazone,Chlortetracycline,Glycylcyclines,Minocycline,Chloramphenicol,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 青霉素和大环内酯耐药 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酶（KPC, NDM-1?）-碳青酶烯耐药在中国出现和蔓延非发酵菌(假单孢菌/不动杆菌)喹诺酮, 头孢菌素,青霉素类,氨基糖苷,碳青霉烯类,Antibiotic Control and Infection Control:The Two Sides of the Resistance “Coin”,Rekha Murthy. Implementation of Strategies to Control Antimicrobial Resistance Chest 2001;119;405-411,Control of Antibiotic Resistance,No simplistic policy,Homogenous protocol,Mixing,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,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 -指南VS 临床实践,内 容 安 排,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,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 for chronic lymphocytic leukemia.,COP,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),合格标本进行微生物学检查 开始经验性抗感染治疗 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,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 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,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),2002,Vancomycin-resistantS. aureus,CDC, MMWR 2002;51(26):565-567,1960,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,中国大陆ESBL的发生率,%,year,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,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 -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）,aExcept nonfermenters/non-Pseudomonas species.Adapted from Carmeli 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. Clin 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,PCP,LD,对于选择抗菌药物-耐药性 VS 严重性哪个更重要？,PCP,LD,耐药菌感染 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合理使用碳青霉烯类药物 -指南 VS 临床实践,内 容 安 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,所有抗感染指南都推荐碳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？,Effectiveness- role of carbapenem？-Why？When？Which？Empiric therapycovers close to 100% of suspected pathogensDirected therapyClinical successSafety profile Adverse eventsCost/effectivenessMinimizing resistanceSelf resistance/Resistance to other agents,Considerations in Choosing Antibiotic for Optimal Therapy,Change of paradigm,We are living in an era of high resistanceG- ves resistant to - penicillins/cephalosporins - quinolones - aminoglycosides - TMP/SMX Think MDR rather than resistance,Increasing proportion of MDR GNR,DAgata E. ICHE 2004,%MDR,Susceptibilities ESBL vs non-ESBL,Schwaber M. AAC 2005,ESBL contribute most to MDR pathogens,Failure ESBL vs non-ESBL,0%,20%,40%,60%,80%,100,%,Schwaber, 2005*,Kim, 2002*,Patterson DL, 2001,Arrifin H, 2000*,non-ESBL,ESBL,Failure,* failure = mortality,Susceptibilities of 1030 ESBL producing E. coli & Klebsiella spp.,Colodner R. ICAAC 2005,Mortality among 60 patients with ESBL producing Klebsiella Bacteremia,Paterson DL. Ann Intern Med,Whether we like it or not,Accumulation of ESBLs & quinolone resistance will drive carbapenem use,When 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 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MDROs感染的高风险人群,老年人 误吸(对于肺炎而言)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、三代头孢菌素过期一年内多次(2次)住院先期手术住LCTF长期血液透析实体脏器移植,Risk factors for infection with ESBL producers outside hospital,Colodner et al EJCMID 2004 23, 163.,What patients can benefit most from ertapenem treatment,G negatives -Including ESBL+,CAP in advanced age,CAPwith aspiration,CAP Severe,How to predict? -bacteria -resistance,医院获得性肺炎细菌学演变-抗生素选择性压力的体现,早期(Early),中期(Middle),晚期(Late),1 3 5 10 15 20,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,1 3 5 10 15 20,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/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？,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 CAP,Risk factors for Pseudomonas -severe structural lung disease (eg, bronchiectasis) -recent antibiotic therapy or stay 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,135 次VAP ICU变量 OR PMV7 days 6.0 .009先期ABs 13.5 7 days / prior ABs,Trouillet, et al. Am J Respir Crit Care Med. 1998;157:531,Effectiveness- role of carbapenem？-Why？When？Which？Empiric therapycovers close to 100% of suspected pathogensDirected therapyClinical successSafety profile Adverse eventsCost/effectivenessMinimizing resistanceSelf resistance/Resistance to other agents,Considerations in Choosing Antibiotic for Optimal Therapy,Ertapenem Pharmacokinetics: Minimal Selectivity for Resistant P aeruginosa Under Clinical Conditions,Minimal resistance selection among P aeruginosa (MIC90:16 mg/L)Minimal resistance selection among Enterobacteriaceae (MIC90:0.03 mg/L),N=68 healthy volunteers,MRSA=methicillin-resistant S aureus; MSSA=methicillin-susceptible S aureus.Adapted from Nix 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/L,TotalFree,0.01,0.1,1000,1,10,100,0,4,8,12,16,20,24,MIC90,mg/L Organism16P aeruginosa, enterococci, MRSA1.0 Anaerobes0.25 MSSA, pneumococci0.12Group A streptococci0.03Enterobacteriaceae,Hours After 1 g Intravenous Dose of Ertapenem,Summary 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 Antimicrob 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 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 of 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 a