嚴重感染的抗感染策略

1、邱海波東南大學醫(yī)學院附屬中大醫(yī)院東南大學急診與危重病醫(yī)學研究所,重癥感染的重要性 細菌耐藥機制及ICU細菌流行情況 重癥感染的治療策略－感染灶的充分引流－早期經驗性治療－正確的目標性治療,,內 容 提 要,Sepsis = Infection+SIRS,細菌侵入,臨床體征,infection損傷 SIRS sepsis severe s

2、epsis septic shock MODS/ MOF,感染過程,,,,,,,Impact of adequate empirical antibiotic therapy on the outcome of pats admitted to ICU with sepsis,CCM, 2003, 31: 2742,Annual incidence of severe sepsis: 3 cases/ 1,

3、000 Kill: 1,400 people worldwide /d 25 people /hMoreover, No. of sepsis pats is projected to increase by 1.5% per annum 嚴重感染的病死人數(shù)超過乳腺癌、直腸癌、結腸癌、胰腺癌和前列腺癌的總和嚴重感染 vs AMI:發(fā)病率相同，病死率明顯高,Sepsis in worldwide,Surviving Sep

4、sis Compaign拯救Sepsis運動,,巴塞羅那宣言,ESICM SCCM ISF 2002年10月2日, 西班牙,全球Sepsis的發(fā)病率和死亡率均很高，耗費大量的人力物力呼吁全球 醫(yī)務專業(yè)人員和組織、政府、衛(wèi)生機構甚至公眾支持該行動Improve survival in severe sepsisAIM: 5年內Sepsis死亡率減少25%,第一階段/Phase I,Develop guidelines

5、Bedside clinician could use to improve outcome in severe sepsis ans septic shock,第二階段/Phase II,ESICM SCCM ISFAACCN/ACCP/ACEP/ATS/ANZICS/ESCMID/ERS/SIF,Guidelines for sepsis. Intensive Care Med 2004, 30: 536-555,Guide

6、lines for management of severe sepsis/ septic shockInitial resuscitation: early goal-directed therapyDiagnosis: appropriate cultureAntibiotic therapy: Early broad-spectrum, reassessed 2-3d Source control: Fluid the

7、rapy: colloids=crystalloids,VLTVasopressors: After VLS, NE vs Dopa, Low-dose dopa is not , cath for vaso Inotropic therapy: low CO-dobu, high CO is notSteroid: low dose rhAPC: APACHE II >25, sepsis-induced ARDS/M

8、OF and no bleeding risk,第二階段/Phase II,Guidelines for management of severe sepsis/septic shockBlood product administration: target Hb 7-9g/dl, EPO only in renal failureMechanical ventilation: Ppla<30, Hypercapnia,

9、optimal PEEP, Prone positionSedation, analgesia and NBMs: ProtocolGlucose control: <150mg%Renal replacement: Bicarbonate: pH < 7.15DVT: UH/LMWHStress ulcer prophylaxis: H2blocker,第二階段/Phase II,To use the mana

10、gement guidelinesTo evalute the impact on clinical outcome of severe sepsis,第三階段/Phase III,ESICM SCCM ISFAACCN/ACCP/ACEP/ATS/ANZICS/ESCMID/ERS/SIF,,Guidelines for the Management of Adults with Hospital-acquired, Ven

11、tilator-associated, and Healthcare-associated Pneumonia,This official statement American Thoracic Society (ATS) And Infectious Diseases Society of America (ISDA)Approved by the ATS Board of Directors, December 2004 a

12、nd the IDSA Guideline Committee, October 2004,Am J Respir Crit Care Med 2005, 171. 388–416,Epidemiology,2nd most common nosocomial infection 5-10 cases/ 1000 admissions6- to 20-fold higher in those mechanically ventila

13、ted25% of all ICU infections>50% of all antibiotics prescribed for this indicationHigh morbidity and mortality 33-50% attributable mortalityFrequently polymicrobialGram-negative bacilli frequently predominate

14、Antibiotic resistance complicates management,Chastre J, Fagon JY. Am J Respir Crit Care 2002;165:867Tablan OC, et al. MMWR Recomm Rep 2004;53(RR-3):1-36,重癥感染的重要性 細菌耐藥機制及ICU細菌流行情況 重癥感染的治療策略 －感染灶的充分引流 －早期經驗性治療

15、 －正確的目標性治療,內 容 提 要,MRS 耐苯唑西林，對Vaco敏感性降低VRSAPRP 耐青霉素和多重耐藥的肺炎鏈球菌VRE 耐萬古霉素的腸球菌ESBL 產生超廣譜β-Lac酶的KPN和EcoAmpC 持續(xù)高產AmpC酶的陰溝、腸桿菌和弗 勞地枸櫞酸桿菌等Multi-res 多重耐藥銅綠、嗜麥芽和不動桿菌,細菌耐藥--全球性難題,細菌的抗

16、生素耐藥機制,改變細胞膜的通透性 使抗生素滲透障礙產生滅活酶和鈍化酶改變抗生素作用靶位,ESBLs Plasmid-Mediated Extended Spectrum Beta-Lactamase,對三代頭孢菌素如頭孢他啶、頭孢曲松、頭孢噻肟或氨曲南的抑菌圈減小(R、I、S)加克拉維酸可使抑菌圈擴大(≥5 mm)如為ESBL，應報告所有青霉素類，頭孢菌素類，氨曲南耐藥，即使體外敏感，也應視為耐藥,ESBLs產生/增

17、加的原因3年北京30家醫(yī)院他啶和噻肟消耗量,年,kg,肺克和大腸對他啶和噻肟的耐藥率,年(初代分離株數(shù)),R%,大腸桿菌,肺炎克雷伯菌和產酸克雷伯菌,32個醫(yī)院1994-2001年大腸桿菌及肺炎克雷伯菌產生ESBLs百分率,101 66,319 263,260 229,356 270,300 150,158 164,數(shù)字為株數(shù),%,年,ESBLs對重癥感染患者的預后有明顯影響,臨床研究證明：ESBL組死亡率(40%)明顯高于無ES

18、BL組(18%）,（P=0.06),,抗生素治療過程中誘導產生 并可選擇出持續(xù)高產AmpC突變體第三代頭孢菌素是弱誘導劑，但具有選擇去阻遏突變株作用β-內酰胺酶抑制劑均不能抑制AmpC酶 相反，克拉維酸是強誘導劑突變株不僅對第三代頭孢菌素耐藥，對β-內酰胺類抗生素/酶抑制劑復合物也耐藥碳青霉烯對AmpC酶高度穩(wěn)定，沒有選擇去阻遏突變株作用,I型β-內酰胺酶(AmpC酶),抗生素應用與AmpC突變,抗生素種類

19、治療后耐藥的發(fā)生率三代頭孢菌素 19%(6/13)氨基糖苷類 1%(1/89)亞胺配南 0%(0/17)其他 0%(0/33)最初敏感的菌株，經治療后出現(xiàn)耐藥,Joseph W. Chow, et al. Ann Int Med, 1991, 115(8):585-590,三代頭孢不僅可誘導ESBLs，也可選擇出AmpC,三代頭孢選擇出

20、高產AmpC耐藥菌的速度,使用的出現(xiàn)耐藥的MIC(治療前)MIC(治療后)抗菌藥物抗菌藥物抗菌藥物mg/mlmg/ml使用天數(shù)頭孢唑肟頭孢唑肟8324頭孢他啶，慶大霉素頭孢他啶≤2>165頭孢噻肟，阿米卡星頭孢噻肟≤4>326頭孢噻肟，慶大霉素頭孢噻肟8327頭孢噻肟頭孢噻肟≤4>3216頭孢他啶，妥布霉素頭孢他啶≤2>1618

21、,高產AmpC腸桿菌耐藥與三代頭孢使用的關系,三代頭孢使用4-18天后就可選擇出高產AmpC霉腸桿菌耐藥菌,Joseph W. Chow, MD, et al. Annals of Internal Medicine. 1991; 115:585-590,AmpC酶流行情況,約30-50%腸桿菌屬 (弗勞地枸櫞酸菌,沙雷氏菌)高產AmpC酶131株三代頭孢耐藥的E coli的耐藥分析 ESBL’s

22、 13.7% 高產AmpC34.0% 其他酶機制6.5%,JAMA 2000,產AmpC酶耐藥菌引發(fā)的臨床后果更加嚴重,產AmpC霉腸桿菌屬感染患者死亡率是非耐藥菌感染患者的2倍,產AmpC酶細菌感染的患者死亡率更高,Joseph W. Chow, MD, et al. Annals of Internal Medicine. 1991; 115:585-590,持續(xù)高產AmpC酶的對策,中重度感染應選擇的抗生素：

23、碳青霉烯類、四代頭孢、氟喹喏酮類、氨基糖苷類避免使用第三代頭孢、酶抑制劑復合藥,AmpC 酶,Inoue K, et al. Chemotherapy 1995, 41(4): 257-266,ESBLs與高產AmpC的差異,ESBLs 高產AmpC耐藥譜多重多重三代頭孢耐藥耐藥四代頭孢部分敏感敏感棒酸敏感不敏感哌酮/舒巴坦多敏感耐藥 PIP/三唑多敏感耐

24、藥頭霉素敏感耐藥碳青霉烯類敏感敏感,,,,,,,SSBL--24株陰溝腸桿菌的耐藥情況,酶型株數(shù)三嗪 他啶吡肟 亞胺配南AmpC+14 14 14 0 0ESBL+4 4 2 4 0AmpC+ESBL+5 5 5 20From PUMC hospital,,,,超級?內酰胺酶耐藥(SSBL) Super Spectrum

25、Beta Lactamases,ESBLs/高產AmpC酶位于同一細菌或細菌質粒,,NPRS-7年最常見的G-菌（株數(shù)）,銅綠假單胞菌大腸埃希菌克雷伯菌屬不動桿菌屬腸桿菌屬嗜麥芽窄單胞菌變形桿菌屬沙雷菌屬其它假單胞菌屬枸櫞酸桿菌屬,,時間：1994年～2001年醫(yī)院：4～14家菌株：554～1949株,,NPRS-7年最常見的革蘭陰性菌（株數(shù)）,,菌株數(shù),554 1048 1348 1542 12

26、91 1678 1949,總菌株,,1994～2001年主要抗菌素對革蘭陰性菌敏感率變化趨勢,,敏感率％,,1994～2001年亞胺培南等主要抗菌素對革蘭陰性菌敏感率變化趨勢,,敏感率％,MDR－Multi-Drug-resistance,G-菌對四類抗生素中3/4類耐藥Ceftazidine, Ciprofloxacin, Gentamicin, ImipenemPseudomonas aeruginosa, Acine

27、tobacter speciesESBLs/AmpCG+MRSA,非發(fā)酵糖細菌,1994-2001年，全國32家醫(yī)院ICU分離的10279株 G-菌中，分離4450株非發(fā)酵糖細菌),,,1994－2001年中國重癥監(jiān)護病房非發(fā)酵糖細菌的耐藥變遷中華醫(yī)學雜志,2003,83(5):385-390,近3年, 非發(fā)酵糖細菌的比例從41.2%升高到47.9%銅綠假單胞菌、不動桿菌屬、嗜麥芽窄食單胞菌分別位居1、4、7位,銅綠假單孢菌

28、的耐藥性(2001年),,1994－2001年中國重癥監(jiān)護病房非發(fā)酵糖細菌的耐藥變遷中華醫(yī)學雜志,2003,83(5):385-390,不動桿菌屬的耐藥性(2001年),,46%,1994－2001年中國重癥監(jiān)護病房非發(fā)酵糖細菌的耐藥變遷中華醫(yī)學雜志,2003,83(5):385-390,R%,7年嗜麥芽窄食單胞菌耐藥率變遷(%),1994－2001年中國重癥監(jiān)護病房非發(fā)酵糖細菌的耐藥變遷中華醫(yī)學雜志,2003,83(5):385

29、-390,,,腸桿菌科細菌對三種碳青霉烯的敏感性,中國抗感染化療雜志2002年3月30日第二卷第一期,(3051) (357) (2118) (208) (1143) ( 22),微生物學資料,腸肝菌科細菌對三種碳青霉烯的敏感性,李家泰 中華檢驗醫(yī)學雜志, 2005, 28(1): 25,,,非發(fā)酵革蘭陰性桿菌對三種碳青霉烯的敏感性,中

30、國抗感染化療雜志2002年3月30日第二卷第一期,(1790) (169) (1365) (142 ) (323),,微生物學資料,非發(fā)酵革蘭陰性桿菌對三種碳青霉烯的敏感性,李家泰 中華檢驗醫(yī)學雜志, 2005, 28(1): 25,G-桿菌耐藥對預后的影響,Prospective cohort study.Dec 1996 to S

31、ep 2000 Inpatient surgical wards at a university hospN=924 pats with GNR infectionsOutcomes were compared between GNR infections with and without antibiotic resrGNRs: resistant to one or more of the followingall

32、aminoglycosides, including amikacinall cephalosporinsall carbapenemsall fluoroquinolones,Crit Care Med 2003; 31:1035–1041,,,非發(fā)酵革蘭陰性桿菌對三種碳青霉烯的敏感性,李家泰 中華檢驗醫(yī)學雜志, 2005, 28(1): 25,G-桿菌耐藥對預后的影響,Prospective cohort study.

33、Dec 1996 to Sep 2000 Inpatient surgical wards at a university hospN=924 pats with GNR infectionsOutcomes were compared between GNR infections with and without antibiotic resrGNRs: resistant to one or more of the f

34、ollowingall aminoglycosides, including amikacinall cephalosporinsall carbapenemsall fluoroquinolones,Crit Care Med 2003; 31:1035–1041,rGNR:入住ICUMVCRRT抗生素更換住院時間病死率,,小 結,ESBL和AmpC是ICU重癥感染致病菌耐藥的重要原因三代頭胞

35、大量使用是導致G-菌出現(xiàn)ESBL和AmpC 的 主要原因ESBL和AmpC使ICU重癥感染患者的病死率明顯增加近3年, ICU非發(fā)酵糖細菌的比例從41.2%升高到47.9%銅綠假單胞菌、不動桿菌屬、嗜麥芽窄食單胞菌分別位居1、4、7位碳青霉烯類抗生素、酶抑制劑制劑等敏感性較高,ICU重癥感染的重要性 細菌耐藥機制及ICU細菌流行情況 重癥感染的治療策略 －感染灶的充分引流 －早期經驗性治療與降階梯策略

36、 －正確的目標性治療,內 容 提 要,非抗生素治療策略,氣管插管與機械通氣插管路徑NIV/IV聲門下的積液氣囊的管理濕化與霧化管路與冷凝水MV時間ICU的醫(yī)療強度誤吸/體位體位/胃腸道返流營養(yǎng)途徑口鼻咽腔/腸道定植潰瘍預防/血糖控制,Source control-Grade E,Every pats presenting with severe sepsis should be evaluated for

37、 the presence of a focus of infection amenable to source control measuresDrainage of an abscess or local focus of infectionRemoval of a potientially infected device,Guidelines for sepsis. Intensive Care Med 2004, 30:

38、536-555,重癥感染的重要性 細菌耐藥機制及ICU細菌流行情況 重癥感染的治療策略－感染灶的充分引流－早期經驗性治療與降階梯策略－正確的目標性治療,內 容 提 要,早期經驗性治療的對象,對有急性而危及生命的全身性感染患者無法及時得到細菌學資料應根據本病房的細菌流行病學調查結果選擇對常見致病菌有效的廣譜抗生素經驗性治療＝推理性治療,提高患者的生存率降低細菌產生耐藥性,早期經驗性治療的目標,Dr. Jordi Rel

39、loProfessor of Critical Care ,University Rovira & virgili Tarragona, Spain,,死亡： 絕對危險度下降6.1%,早期有效抗感染治療的重要性,死亡： 絕對危險度下降9％,死亡： 絕對危險度下降4%,ICU嚴重感染病人起始抗生素治療覆蓋面不足--死亡率增加,ICU經驗性抗生素治療VAP:22-73%為抗生素起始治療不當,醫(yī)院獲得性肺炎--迅速恰當?shù)目股刂?/p>

40、療，明顯提高生存率,Luna CM et al.Chest 1997,Adequate38%(6/16)Not-adequate/not-ANT81.6%(40/49),132 pats with suspected NPBAL in 55 pats,Bloodstream infections,Leibovici et alAdequate vs inadequate initial antibiotic: Mortal

41、ity: 20% vs 34% From J Intern Med, 1998, 244: 379,早期及時抗生素治療的重要性,In a retrospective cohort study of pneumonia in 18,209 patientsAdministering antibiotics within 4 h of hospital arrival was associated with improved

42、survival.,Houck PM et al. Arch Intern Med. 2004, 164: 637–644,Antibiotic therapy,1. Grade EIntravenous antibiotic therapy should be started within 1st h of recognition of severe sepsis, after appropriate cultures hav

43、e been obtained,,Guidelines for sepsis. Intensive Care Med 2004, 30: 536-555,Antibiotic therapy,2. Grade DInitial empiric anti-infective therapy should include one or more drugs that have activity against the likely pa

44、thogensThe choice of drug should be guided by the susceptibility patterns of microorganisms in the community and the hospital,,Guidelines for sepsis. Intensive Care Med 2004, 30: 536-555,Antibiotic therapy,早期經驗性治療,是抗感

45、染的經驗性治療方案，具有如下兩個特性： 開始即使用廣譜抗生素以覆蓋所有可能的致病菌 隨后(48-72h)根據微生物學檢查結果調整抗生素的使用，使之更有針對性,Dr. Luciano GattinoniProfessor of Anesthesiology,Institute of Emergency Surgery,University of Milan, Italy,如何保證起始治療的準確性Getting it right (

46、A--protocol),Treatment protocols and guidelines---important tool for optimal therapy Establishing local susceptibility profiles that can be used to develop therapy protocols“Not only we did want to treat with the initi

47、al therapy that was appropriate, but we wanted to minimize the emergence of resistance”,CCM 2001， 29：1109－1115,如何保證起始治療的準確性Getting it right (A),CCM 2001， 29：1109－1115,如何保證起始治療的準確性Getting it right (A),“Not only we did w

48、ant to treat with the initial therapy that was appropriate, but we wanted to minimize the emergence of resistance”,CCM 2001， 29：1109－1115,如何保證起始治療的準確性Getting it right (B-Bacteria resis),It is essential to be able to rec

49、ognize those pats who are treatment failure,CCM 2003， 31：676,抗生素治療3d－VAP無效---tended to be survivors有效---tended to be non-SMore importantlyThose pats who had no clinical response within the first 3d were receiving i

50、nadequate antimicrobial therapy,Most common pathogens associated with inadequate initial antimicrobial threapy,PA: Pseuso aeruginosa; SA:Staphylococcus aureus; AS: Acinetobacter species; KP: Klebsiella pneumoniae; ES: E

51、nterobacter species; SP: Strep pneumoniaeOther: E coli, Haemophilus influ, Serratia,Kollef MH Clinical Inf Dis 2000, 31 (S4):131-8,機械通氣時間與既往抗生素治療是多重耐藥致病菌VAP的獨立危險因素,Trouillet JL et al.Am J Respir Crit Care Med 157:531-3

52、9, 1998,HAP / VAP / HCAP合并MDR感染危險因素,Antimicrobial therapy in preceding 90 daysCurrent hospitalization of 5 days or moreHigh frequency of antibiotic resistance in the community or in the spesific hospitalPresence

53、 of risk factors for HCAPImmunosuppressive disease and/or therapy,ATS. Am J Respir Care Med 2005;171:388,聯(lián)合用藥,16 beds MICU of 1300 beds teaching hospital1993.5~1995.6VAP occurring after >7 d of MV and prior antibi

54、otic use,Trouillet JL. Am J Respir Crit Care Med 1998, 157: 531~539,% susceptibility,,細菌耐藥特點,VAP病原菌耐藥的危險因素:最重要的是最近接受過抗生素治療(最近15天)其次是機械通氣至少7天,經驗性治療,VAP的致病菌,敏感性最高,IMP＋Amikacin＋Vanco,簡化的臨床診斷標準Clinical Pulmonary Infectio

55、n Score,Value PointsTemperature C > 36.5 and 38.5 and 39 or 4,000 and 11,000 1 Tracheal secretions Few0 Moderate1 Large2 PaO2/FiO

56、2, mmHg > 240 or present ARDS1 < 240 and absent ARDS 0 Pulmonary radiography no infiltrate 0 Patchy or diffuse infiltrate 1

57、 localized infiltrate 2,,Luna CM. CCM, 2003, 31: 676,Empiric Antibiotic Therapy for HAP,HAP,VAP, or HCAP suspected(all disease severity),Late onset (>5 days) or risk factors forMDR Pathogens,No,Yes,L

58、imited Spectrum Therapy,Broad SpectrumTherapy for MDR Pathogens,Algorithm for Initiating Empiric Antibiotic Therapy,,,,,,,,ATS. Am J Respir Crit Care Med 2005;171:388-416,Initial Empiric Antibiotic Therapyfor Patient

59、s with No Risk Factors,Potential PathogenStreptococcus pneumoniaeHaemophilus influenzaeMethicillin-sensitive Staphylococcus aureusEnteric gram-negative bacilli(Antibiotic sensitive) Enterobacter species Escherich

60、ia coli Klebsiella species Proteus species Serratia marcescens,Recommended AntibioticCeftriaxoneorLevofloxacin, moxifloxacin, or ciprofloxacinorAmpicillin/sulbactamorErtapenem,ATS. Am J Respir Crit Care Med

61、 2005;171:388-416,Potential PathogensP. aeruginosaESBL (+) K. pneumoniaeAcinetobacter speciesMRSAL. pneumophila,TherapyAntipseudomonal cephalosporin(cefepime, ceftazidime) orAntipseudomonal carbapenem(?m

62、ipenem, meropenem) orPiperacillin-tazobactamplusCiprofloxacin or levofloxacin orAminoglycosideLinezolid or vancomycin,Initial Empiric Antibiotic Therapyfor Patients with Risk Factors for MDR Pathogens,ATS. Am J

63、Respir Crit Care Med 2005;171:388-416,ICU重癥感染的重要性 細菌耐藥機制及ICU細菌流行情況 重癥感染的治療策略 －感染灶的充分引流 －早期經驗性治療 －正確的目標性治療,內 容 提 要,Antibiotic therapy,3. Grade EThe antimicrobial regimen should always be reassessed after

64、 48~72h on the basis of using a narrow-antibiotic to prevent the development of resistance, to reduce toxicity, and costs,,Guidelines for sepsis. Intensive Care Med 2004, 30: 536-555,Antibiotic therapy,目標性治療,經驗性治療盡早轉為目標

65、性治療轉換所需時間反映抗感染治療水平,病原學診斷的作用,初始經驗性治療之前，應采集呼吸道標本呼吸道標本的病原學檢查結果并不總是可靠的,細菌耐藥性試驗(藥敏)及時、正確、反復標本采樣 標準化的細菌培養(yǎng)和藥敏試驗選擇敏感的抗生素監(jiān)測：細菌培養(yǎng)和藥敏,如何實現(xiàn)目標性治療Getting it right (A-Bac culture),目標性治療－藥代動力學與藥效學,Pharmacokinetics,Pharmacodynami

66、cs,,,Drug concentration at site of infectionSerum levelTissue level,EffectGrowth inhibitionKillingClinical cureClinical failure,如何實現(xiàn)正確的目標性治療Getting it right (C-Decrease Res),目標性治療－ 組織滲透能力,血漿濃度組織濃度,Therapeutic

67、 PrincipleThe Need for Appropriate Dosing,,ATS/IDSA. Am J Respir Crit Care Med 2005;171:388-416,Initial Intravenous Adult Doses for Empiric Therapy of HAP, VAP, HCAP,Relevant Clinical Definitions,AppropriateThe etiolo

68、gic organism is sensitive to the therapeutic agentAdequateCorrect antibioticOptimal doseCorrect route of administration to ensure penetration at the site of infectionUse of combination therapy if necessary,早期經驗性治療,