感染病患者多重耐药菌感染风险诊断培训课件

1、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 soldier

2、s at war.抗感染药物发展简史1929 Alexander FDiscovery of Antibacterial AgentsCycloserineErythromycinEthionamideIsoniazidMetronidazolePyrazinamideRifamycinTrimethoprimVancomycinVirginiamycinImipenem19301940 195019601970198019902000PenicillinProntosilCephalosporin CEthambutolFusidic acidMupirocinNalidixic acidO

3、xazolidinonesCecropinFluoroquinolonesNewer aminoglycosidesSemi-synthetic penicillins & cephalosporinsNewer carbapenemsTrinemsSynthetic approachesEmpiric screeningNewer macrolides & ketolidesRifampicinRifapentineSemi-synthetic glycopeptidesSemi-synthetic streptograminsNeomycinPolymixinStreptomycinThi

4、acetazoneChlortetracyclineGlycylcyclinesMinocyclineChloramphenicolDiscovery of Antibacterial Age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,碳青霉烯类临

5、床关注的耐药问题Resistances of CliniInfectionControlAntibioticstewardshipVREMRSAABESBL K. pneumoniaeAntibiotic 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 Resist

6、anceInfectionAntibioticVREMRSAESBL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 -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慢性咳嗽和黄痰-原因哮喘 急性发热正

7、确诊断是正确治疗的前提发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 lymph

8、ocytic leukemia.COP27-year-old man with acute lymRapid 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 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Rapi

9、d testsStart adequate anti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+选择哪种抗菌药物经验性抗感染治疗合理选择药物-con

10、si-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SSSSPCP-个体化评估-特殊修正因子 不同部位感染-病原体的流行病学 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抗菌谱(coverage)

11、经验性抗感染治疗药物选择的基本原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 评价病原体耐药可能？是否耐药菌？S. aureusPenicillin1944Penicillin-resistantS. aureus金黄色葡萄球菌耐药的发生发展过程Methicillin1962Methicillin-resistantS. aureus (MRSA)Vancomycin-resistantenterococci (VRE)Van

12、comycin1990s1997VancomycinintermediateS. aureus(VISA)2002Vancomycin-resistantS. aureusCDC, MMWR 2002;51(26):565-5671960S. aureusPenicillin1944Penic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 评价病原体耐药可能？是否耐药菌？中国大陆ESBL的发生率% Wang H, Chen M.

13、 Diagnos Microbiol Infect Dis, 2005, 51, 201-208CMSS/SEANIR/CARES. year细菌耐药监测结果如何解读？中国大陆ESBL的发生率% Wang H, Chen M. 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) 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No Risk Fa

14、ctors 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, Long hospitalization and/or infection following invasive procedures (5 days) Recent Abx No Yes! (

15、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, advanced AIDS, neutropenia, or other severe immunodeficiency Drugs of choiceAmoxi/calv

16、Ampicillin/sulb2nd or 3rd GFQsPip/tazoCefaperazone/sulbactamertapenemCeftazidine cefepimePip/tazoCefperazone/sulbactamImipenem meropenemaExcept nonfermenters/non-Pseudomonas species.Adapted from Carmeli Y. Predictive factors for multidrug-resistant organisms. In: Role of Ertapenem in the Era of Anti

17、microbial 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(1

18、2):17921798; Shah PM. Clin Microbiol Infect. 2008;14(suppl 1):175180.Stratification for Risk for MDR Gram-Negative PathogensNo Risk Factors for MDROsRisk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？重症感染PCPLD对于选择抗菌药物-耐药性 VS 严重性哪PCPLD耐药菌感染 VS 严重感染-PCP和LD告诉我们

19、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PCPLD耐药菌感染 VS 严重感染观点: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为例经验性抗感染治疗的基本原则21Craven DE. Curr Opin Infect Dis. 2006;19:153-160.The Changing Spectrum of PneumoniaCAP, HCAP, HAPHealthcare-associated pneumonia is a relatively new clinical en

20、tity that includes 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 pneumonia

21、b. HCAP=healthcare-associated pneumoniac. HAP=hospital-acquired pneumoniad. VAP=ventilator-associated pneumoniaCraven DE. Curr Opin Infect DiH. influenzaeK. pneumoniaeS. pneumoniaeM. pneumoniaeL. pneumophilaC. pneumoniaeH. influenzaeK. pneumoniaeS. pCommunity-acquired pneumonia in Europe*病原体社区治疗入院治疗

22、ICU发表的研究数量92313肺炎链球菌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流感流行后/坏死性肺炎

23、MRSA?Community-acquired pneumonia iHistory of MRSA in U.S.59青霉素上市第一个MRSA菌株出现Healthcare associated MRSACA-MRSACA-MRSA 爆发于不同人群儿童中出现没有“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 History of MRSA in U.S.59青霉素上CommunityAcquired MRSAIn contrast to the rise in nosoc

24、omial MRSA from 1990 to the present, growing awareness of community-acquired MRSA has occurred through published reports of MRSA outbreaks for which traditional risk factors were not identified.Necrotizing pneumonia,United States and Europe1980Outbreak in Detroit, Mich2/3 of patients were IVDUMid 19

25、90sChildrenw/o identifiable risk factorsLate 1990s 1998 - Athletes/sports teams 1999 - Native Americans 2000 Prison and jail populations2003IVDU=intravenous drug users.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

26、 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.Gillet Y et al. Lancet. 2002;359:753-759. CDC. Morb Mortal Wkly Rep. 1999;48:707-710.CommunityAcquired MRSAIn contRemains

27、 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 CAPBut has emerged as a cause of severe CAP Compared to non-MRSA CAP, patients were2:More ill (more likely to be comatose, req

28、uire intubation, pressors and die in the ER)More CXR abnormalities (multiple infiltrates, cavitation)Mortality rate 14% (up to 50% in some studies)Epidemiology of MRSA Community-Acquired Pneumonia (CAP)1Klevens JAMA 2007; 298: 1763-1771; 2Moran CID 2012; 54:1126-33 Remains an uncommon cause of CAppr

29、oach to Empiric Therapy: CAPEmpiric treatment for MRSA is recommended for severe CAP defined by:ICU admissionNecrotizing or cavitary infiltratesEmpyemaDiscontinue 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 Clin Micro 2008Approach to Empiric Th

30、erapy: CCharacterization 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%); celluliti

31、s (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Characterization of CA-MRSA AsEpidemiology of MRSAH-MRSAReservoires -hosp

32、itals -LTCFs5 genetic backgroudsH-MRSA in community -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

33、管）合理使用抗MRSA药物糖肽类/利奈唑胺Epidemiology of MRSAH-MRSAH-MRPrediction of MRSA in Patients 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 hospita

34、lIdentified risk factors associated with MRSA pneumonia.Prediction of MRSABMC InfectioCommunity-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

35、 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?Community-acquired pneumonia iCAP due to GNBANSORP, 2002-2004, 912 CAP93 (10.1%) were caused by GNB肠杆菌科-K. pneumoniae (59), Enterobacter spp. (7), S. marcescens (1)非发酵菌-P. aer

36、uginosa (25), A. baumannii (1), Higher morbidity and co-morbid diseasesSeptic shock, malignancy, CV disease, smoking, hypoNa, dyspneaHigher mortality 18.3% 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病原体HAP初始经验性抗菌药物选择的流程图ATS. Am J Respir Crit Care Med 2005;171:388-416既往90天内曾经使用过抗菌药物住院时间为5天或

37、更长在社区或其他医疗机构抗生素耐药出现的频率高存在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怀疑HAP、VAP或HCAP晚发(5 days)HAP否是Stratification of HAP Patients at Risk for MDR OrganismsThe differences not firmly settled Available data indicate in spontaneously breathing pts -potent

38、ially drug resistant microorganisms may play a minor role -GNEB(abx susceptible), S aureus (MSSA) and S pneumoniae as leading pathogens-spontaneously breathing VS ventilatedEwig S, Torres A, et al.(1999) Bacterial colonization patterns in mechanically ventilated patients with traumatic and medical h

39、ead injury. Incidence, risk factors, and association with VAP. Am J Respir Crit Care Med 159:188198Rello J, Torres A (1996) Microbial causes of VAP. Semin Respir Infect 11:2431Stratification of HAP PatientsMechanical Ventilation Is Associated With a Significantly Increased Incidence of Respiratory T

40、ract 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 Mechanical Ventilation Is AssoTime from Hospitalization (day

41、s)Time from Intubation (days)Late-onset HAPEarly-onset VAPLate-onset VAP Early-onset HAP0123456701234567(American Thoracic Society. Am J Respir Crit Care Med 2005;171:388-416)Stratification of Patients at Risk for MDR Organisms-early onset VS late-onsetTime from Hospitalization (dayEarly-onsetLate-o

42、nsetpneumoniapneumoniaOthers 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. pneumoniae RSVS. marcescens Fungi E. coli Other GNB S. aureus (MRSA) GN

43、B, 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-onsetEarly-onsetLate-onsetGNB, Gr-Recent Antibiotic Therapy and Pseudomonal ResistanceTrouillet JL et al

44、. 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 rotationaP=.0009 bP

45、=.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 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 (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)