感染病患者多重耐藥菌感染風(fēng)險(xiǎn)診斷培訓(xùn)課件

1、抗感染藥物發(fā)展簡史1929 Alexander Fleming 發(fā)現(xiàn)青霉素 Howard Florey 和 Ernst Chain分離獲得青霉素，用于動(dòng)物試驗(yàn)。 青霉素首次用于救治戰(zhàn)傷患者，拯救了 許多人的生命1950s 大量抗生素用于臨床。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.抗感染藥物發(fā)展簡史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臨床關(guān)注的耐藥問題Resistances of Clinical Concerns革蘭陽性細(xì)菌金匍菌 MRSA, VISA, VRSAVRE (地理上差別)肺炎鏈球菌 青霉素和大環(huán)內(nèi)酯耐藥 革蘭陰性細(xì)菌腸桿菌科ESBLs-喹諾酮,頭孢菌素,青霉素類,氨基糖苷類碳青霉烯酶（KPC, NDM-1?）-碳青酶烯耐藥在中國出現(xiàn)和蔓延非發(fā)酵菌(假單孢菌/不動(dòng)桿菌)喹諾酮, 頭孢菌素,青霉素類,氨基糖苷,碳青霉烯類臨

5、床關(guān)注的耐藥問題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經(jīng)驗(yàn)性抗感染治療的基本原則耐藥背景下的個(gè)體化治療理性回歸/責(zé)任所在經(jīng)驗(yàn)性抗感染治療的基本原則理性回歸/責(zé)任所在慢性咳嗽和黃痰-原因哮喘 后鼻腔鼻漏病毒感染后氣道高反應(yīng)性胃酸返流吸煙相關(guān)的慢性支氣管炎支氣管擴(kuò)張癥彌漫性泛細(xì)支氣管炎肺泡蛋白沉積癥急性發(fā)熱 -WBC不高/淋巴增高（無感染灶）病毒！ -WBC增高/中性粒增高/核左移 可能細(xì)菌！ 部位/病原體？ 原發(fā)性菌血癥？慢性發(fā)熱 IE、布病、慢性感染灶？結(jié)核??？ 非感染性發(fā)熱 藥物熱、風(fēng)濕病、惡性腫瘤正確診斷是正確治療的前提發(fā)熱的診斷與鑒別診斷慢性咳嗽和黃痰-原因哮喘 急性發(fā)熱正

7、確診斷是正確治療的前提發(fā)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) 合格標(biāo)本進(jìn)行微生物學(xué)檢查 開始經(jīng)驗(yàn)性抗感染治療 目標(biāo)治療經(jīng)驗(yàn)性治療和目標(biāo)治療的統(tǒng)一Rapi

9、d testsStart adequate anti選擇哪種抗菌藥物 感染部位的常見病原學(xué) 選擇能夠覆蓋病原體的抗感染藥物 -抗菌譜/組織穿透性/耐藥性/安全性/費(fèi)用考慮藥代動(dòng)力學(xué)/藥效動(dòng)力學(xué)考慮病人生理和病理生理狀態(tài) 高齡/兒童/孕婦/哺乳 腎功不全/肝功不全/肝腎功能聯(lián)合不全其它因素 殺菌和抑菌/單藥和聯(lián)合/靜脈和口服/ 療程 經(jīng)驗(yàn)性抗感染治療合理選擇藥物-considerations in choosing antibiotic for empiric therapy 評估病原體 -有的而放矢！評估耐藥性 -到位不越位！病情嚴(yán)重性評估+選擇哪種抗菌藥物經(jīng)驗(yàn)性抗感染治療合理選擇藥物-con

10、si-個(gè)體化評估-特殊修正因子 先期抗菌藥物對細(xì)菌學(xué)及其耐藥性影響 不同部位感染-病原體的流行病學(xué) 從病原學(xué)認(rèn)識(shí)感染性疾病SSSSPCP-個(gè)體化評估-特殊修正因子 不同部位感染-病原體的流行病學(xué) 抗菌譜(coverage)組織穿透性(tissue penetration)耐藥性(resistance, specifically local resistance) 參考代表性資料/依靠當(dāng)?shù)刭Y料安全性(safety profile) 藥物本身/制劑/工藝/雜質(zhì)費(fèi)用/效益(cost/effectiveness) 失敗或副作用致再治療費(fèi)用更高經(jīng)驗(yàn)性抗感染治療藥物選擇的基本原則抗菌譜(coverage)

11、經(jīng)驗(yàn)性抗感染治療藥物選擇的基本原評價(jià)病原體耐藥可能？是否耐藥菌？ -了解耐藥病原體流行狀況 參考代表性治療/依靠當(dāng)?shù)刭Y料 -個(gè)體化用藥-合理用藥的精髓 病人來源：社區(qū)、養(yǎng)老院、醫(yī)院 高齡、基礎(chǔ)疾病、近期抗菌藥物、近期住院、侵襲性操作、晚發(fā)醫(yī)院感染 評價(jià)病原體耐藥可能？是否耐藥菌？S. aureusPenicillin1944Penicillin-resistantS. aureus金黃色葡萄球菌耐藥的發(fā)生發(fā)展過程Methicillin1962Methicillin-resistantS. aureus (MRSA)Vancomycin-resistantenterococci (VRE)Van

12、comycin1990s1997VancomycinintermediateS. aureus(VISA)2002Vancomycin-resistantS. aureusCDC, MMWR 2002;51(26):565-5671960S. aureusPenicillin1944Penic評價(jià)病原體耐藥可能？是否耐藥菌？ -了解耐藥病原體流行狀況 參考代表性治療/依靠當(dāng)?shù)刭Y料 -個(gè)體化用藥-合理用藥的精髓 病人來源：社區(qū)、養(yǎng)老院、醫(yī)院 高齡、基礎(chǔ)疾病、近期抗菌藥物、近期住院、侵襲性操作、晚發(fā)醫(yī)院感染 評價(jià)病原體耐藥可能？是否耐藥菌？中國大陸ESBL的發(fā)生率% Wang H, Chen M.

13、 Diagnos Microbiol Infect Dis, 2005, 51, 201-208CMSS/SEANIR/CARES. year細(xì)菌耐藥監(jiān)測結(jié)果如何解讀？中國大陸ESBL的發(fā)生率% Wang H, Chen M. 實(shí)驗(yàn)室藥物敏感性監(jiān)測的解讀意義 -反映了耐藥趨勢/告誡要謹(jǐn)慎使用抗菌藥物 -影響選擇藥物/考慮耐藥性對療效的影響不足 -實(shí)驗(yàn)室收集菌株/大型教學(xué)醫(yī)院/ICU 抗生素選擇壓力導(dǎo)致耐藥性高估！ -沒有臨床背景資料/不能用于指導(dǎo)個(gè)體化用藥 (年齡、基礎(chǔ)疾病、社區(qū)/醫(yī)院感染、前期抗菌藥物使用情況) 實(shí)驗(yàn)室藥物敏感性監(jiān)測的解讀意義 -反映了耐藥趨勢/告誡要謹(jǐn)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) 對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重癥感染 耐藥菌感染！重癥感染 革蘭陰性腸桿菌科細(xì)菌感染！肺炎鏈球菌、化膿性鏈球菌、軍團(tuán) 菌、肺孢子菌等均可致重癥感染PCPLD對于選擇抗菌藥物-耐藥性 VS 嚴(yán)重性哪個(gè)更重要？重癥感染PCPLD對于選擇抗菌藥物-耐藥性 VS 嚴(yán)重性哪PCPLD耐藥菌感染 VS 嚴(yán)重感染-PCP和LD告訴我們

19、什么？觀點(diǎn): -耐藥性判斷 對于合理選擇抗菌藥物更重要！ 包括重癥感染 -即使重癥感染,抗感染治療方案 仍需根據(jù)病原體及其耐藥性評估 來制定PCPLD耐藥菌感染 VS 嚴(yán)重感染觀點(diǎn):經(jīng)驗(yàn)性抗感染治療的基本原則耐藥背景下的個(gè)體化治療以CAP/HAP為例經(jīng)驗(yàn)性抗感染治療的基本原則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*病原體社區(qū)治療入院治療

22、ICU發(fā)表的研究數(shù)量92313肺炎鏈球菌19,325,921,7流感嗜血桿菌3,34,05,1軍團(tuán)菌1,94,97,9金匍菌0,21,47,6GNB0,42,77,5肺炎支原體11,17,52鸚鵡熱衣原體1,51,91,3病毒11,710,95,1病原學(xué)不明49,843,841,5*Woodhead M. Eur Resp J 2002; 20: Suppl. 36, 20-27病原體排序肺鏈 S pneumoniae非典型病原體 atypicals 流感嗜血桿菌 H infuenzae卡他莫拉菌 M catarrhalis金葡菌 S aureus革蘭陰性腸桿菌 GNB流感流行后/壞死性肺炎

23、MRSA?Community-acquired pneumonia iHistory of MRSA in U.S.59青霉素上市第一個(gè)MRSA菌株出現(xiàn)Healthcare associated MRSACA-MRSACA-MRSA 爆發(fā)于不同人群兒童中出現(xiàn)沒有“經(jīng)典”危險(xiǎn)因素的MRS感染98MMWR 報(bào)告4例健康兒童死于 MRSA感染99CA-MRSA 成為 SSTI的主要原因0405在美國侵襲性MRSA導(dǎo)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中國社區(qū)MRSA流行病學(xué)？我們怎么辦？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. 王輝 PLoS ONE,2012; 7(6): e38577.到目前為止CA-MRSA所致CAP尚無報(bào)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 感染危險(xiǎn)因素: 年齡65歲， 嚴(yán)重基礎(chǔ)疾病， 傷口 廣譜抗生素使用， 住院時(shí)間延長， 多次住院 侵襲性操作（氣管插管、切開/植入血管導(dǎo)

33、管）合理使用抗MRSA藥物糖肽類/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*病原體社區(qū)治療入院治療ICU發(fā)表的研究數(shù)量92313肺炎鏈球菌19,325,921,7流感嗜血桿菌3,34,05,1軍團(tuán)菌1,94,97,9金匍菌0,21,47,6GNB0,42,77,5肺炎支原體11,17,52鸚鵡熱衣原體1,51,91,3病毒11,710,95,1病原學(xué)不明49,843,841,5*Woodhead M. Eur Resp J

35、 2002; 20: Suppl. 36, 20-27病原體排序肺鏈 S pneumoniae非典型病原體 atypicals 流感嗜血桿菌 H infuenzae卡他莫拉菌 M catarrhalis金葡菌 S aureus革蘭陰性腸桿菌 GNB?Community-acquired pneumonia iCAP due to GNBANSORP, 2002-2004, 912 CAP93 (10.1%) were caused by GNB腸桿菌科-K. pneumoniae (59), Enterobacter spp. (7), S. marcescens (1)非發(fā)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病原體的危險(xiǎn)因素否是窄譜抗菌藥物廣譜抗菌藥物-針對MDR病原體HAP初始經(jīng)驗(yàn)性抗菌藥物選擇的流程圖ATS. Am J Respir Crit Care Med 2005;171:388-416既往90天內(nèi)曾經(jīng)使用過抗菌藥物住院時(shí)間為5天或

37、更長在社區(qū)或其他醫(yī)療機(jī)構(gòu)抗生素耐藥出現(xiàn)的頻率高存在HCAP相關(guān)危險(xiǎn)因素90天內(nèi)住急性病院兩天及以上家庭內(nèi)輸液治療（含抗生素）30天內(nèi)有過持續(xù)透析家庭外傷治療家庭成員有耐多藥病原體感染免疫抑制性疾病和/或免疫抑制劑治療陰性預(yù)計(jì)值的價(jià)值更大懷疑HAP、VAP或HCAP晚發(fā)(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)