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1、重症感染的重要性 细菌耐药机制及ICU细菌流行情况 重症感染的治疗策略 感染灶的充分引流 早期经验性治疗 正确的目标性治疗,内 容 提 要,Sepsis = Infection+SIRS,细菌侵入,临床体征,infection 损伤 SIRS sepsis severe sepsis septic shock MODS/ MOF,感染过程,Impact of adequate empirical antibiotic therapy on the outcome of pats admitted to ICU with sepsis,CCM, 2003, 31: 2742,Annual inc
2、idence of severe sepsis: 3 cases/ 1,000 Kill: 1,400 people worldwide /d 25 people /h Moreover, No. of sepsis pats is projected to increase by 1.5% per annum 严重感染的病死人数超过乳腺癌、直肠癌、结肠癌、胰腺癌和前列腺癌的总和 严重感染 vs AMI:发病率相同，病死率明显高,Sepsis in worldwide,Surviving Sepsis Compaign 拯救Sepsis运动,巴塞罗那宣言,ESICM SCCM ISF 2002
3、年10月2日, 西班牙,全球Sepsis的发病率和死亡率均很高，耗费大量的人力物力 呼吁全球 医务专业人员和组织、政府、卫生机构甚至公众支持该行动 Improve survival in severe sepsis AIM: 5年内Sepsis死亡率减少25%,第一阶段/Phase I,Develop guidelines Bedside clinician could use to improve outcome in severe sepsis ans septic shock,第二阶段/Phase II,ESICM SCCM ISF AACCN/ACCP/ACEP/ATS/ANZICS/
4、ESCMID/ERS/SIF,Guidelines for sepsis. Intensive Care Med 2004, 30: 536-555,Guidelines for management of severe sepsis/ septic shock Initial resuscitation: early goal-directed therapy Diagnosis: appropriate culture Antibiotic therapy: Early broad-spectrum, reassessed 2-3d Source control: Fluid therap
5、y: colloids=crystalloids,VLT Vasopressors: After VLS, NE vs Dopa, Low-dose dopa is not , cath for vaso Inotropic therapy: low CO-dobu, high CO is not Steroid: low dose rhAPC: APACHE II 25, sepsis-induced ARDS/MOF and no bleeding risk,第二阶段/Phase II,Guidelines for management of severe sepsis/septic sh
6、ock Blood product administration: target Hb 7-9g/dl, EPO only in renal failure Mechanical ventilation: Ppla30, Hypercapnia, optimal PEEP, Prone position Sedation, analgesia and NBMs: Protocol Glucose control: 150mg% Renal replacement: Bicarbonate: pH 7.15 DVT: UH/LMWH Stress ulcer prophylaxis: H2blo
7、cker,第二阶段/Phase II,To use the management guidelines To evalute the impact on clinical outcome of severe sepsis,第三阶段/Phase III,ESICM SCCM ISF AACCN/ACCP/ACEP/ATS/ANZICS/ESCMID/ERS/SIF,Guidelines for the Management of Adults with Hospital-acquired, Ventilator-associated, and Healthcare-associated Pneu
8、monia,This official statement American Thoracic Society (ATS) And Infectious Diseases Society of America (ISDA) Approved by the ATS Board of Directors, December 2004 and the IDSA Guideline Committee, October 2004,Am J Respir Crit Care Med 2005, 171. 388416,Epidemiology,2nd most common nosocomial inf
9、ection 5-10 cases/ 1000 admissions 6- to 20-fold higher in those mechanically ventilated 25% of all ICU infections 50% of all antibiotics prescribed for this indication High morbidity and mortality 33-50% attributable mortality Frequently polymicrobial Gram-negative bacilli frequently predominate An
10、tibiotic resistance complicates management,Chastre J, Fagon JY. Am J Respir Crit Care 2002;165:867 Tablan OC, et al. MMWR Recomm Rep 2004;53(RR-3):1-36,重症感染的重要性 细菌耐药机制及ICU细菌流行情况 重症感染的治疗策略 感染灶的充分引流 早期经验性治疗 正确的目标性治疗,内 容 提 要,MRS 耐苯唑西林，对Vaco敏感性降低 VRSA PRP 耐青霉素和多重耐药的肺炎链球菌 VRE 耐万古霉素的肠球菌 ESBL 产生超广谱-Lac酶的KP
11、N和Eco AmpC 持续高产AmpC酶的阴沟、肠杆菌和弗 劳地枸橼酸杆菌等 Multi-res 多重耐药铜绿、嗜麦芽和不动杆菌,细菌耐药-全球性难题,细菌的抗生素耐药机制,改变细胞膜的通透性 使抗生素渗透障碍 产生灭活酶和钝化酶 改变抗生素作用靶位,ESBLs Plasmid-Mediated Extended Spectrum Beta-Lactamase,对三代头孢菌素如头孢他啶、头孢曲松、头孢噻肟或氨曲南的抑菌圈减小(R、I、S) 加克拉维酸可使抑菌圈扩大(5 mm) 如为ESBL，应报告所有青霉素类，头孢菌素类，氨曲南耐药，即使体外敏感，也应视为耐药,ESBLs产生/增加的原因 3年
12、北京30家医院他啶和噻肟消耗量,年,kg,肺克和大肠对他啶和噻肟的耐药率,年(初代分离株数),R%,大肠杆菌,肺炎克雷伯菌和产酸克雷伯菌,32个医院1994-2001年 大肠杆菌及肺炎克雷伯菌产生ESBLs百分率,101 66,319 263,260 229,356 270,300 150,158 164,数字为株数,%,年,ESBLs对重症感染患者的预后有明显影响,临床研究证明： ESBL组死亡率(40%)明显高于无ESBL组(18%）,（P=0.06),抗生素治疗过程中诱导产生 并可选择出持续高产AmpC突变体 第三代头孢菌素是弱诱导剂，但具有选择去阻遏突变株作用 -内酰胺酶抑制剂均不能抑
13、制AmpC酶 相反，克拉维酸是强诱导剂 突变株不仅对第三代头孢菌素耐药，对-内酰胺类抗生素/酶抑制剂复合物也耐药 碳青霉烯对AmpC酶高度稳定，没有选择去阻遏突变株作用,I型-内酰胺酶(AmpC酶),抗生素应用与AmpC突变,抗生素种类 治疗后耐药的发生率 三代头孢菌素 19%(6/13) 氨基糖苷类 1%(1/89) 亚胺配南 0%(0/17) 其他 0%(0/33) 最初敏感的菌株，经治疗后出现耐药,Joseph W. Chow, et al. Ann Int Med, 1991, 115(8):585-590,三代头孢不仅可诱导ESBLs，也可选择出AmpC,三代头孢选择出高产AmpC耐
14、药菌的速度,使用的 出现耐药的 MIC(治疗前) MIC(治疗后) 抗菌药物 抗菌药物 抗菌药物 mg/ml mg/ml 使用天数 头孢唑肟 头孢唑肟 8 32 4 头孢他啶，庆大霉素 头孢他啶 2 16 5 头孢噻肟，阿米卡星 头孢噻肟 4 32 6 头孢噻肟，庆大霉素 头孢噻肟 8 32 7 头孢噻肟 头孢噻肟 4 32 16 头孢他啶，妥布霉素 头孢他啶 2 16 18,高产AmpC肠杆菌耐药与三代头孢使用的关系,三代头孢使用4-18天后就可选择出高产AmpC霉肠杆菌耐药菌,Joseph W. Chow, MD, et al. Annals of Internal Medicine. 1
15、991; 115:585-590,AmpC酶流行情况,约30-50%肠杆菌属 (弗劳地枸橼酸菌,沙雷氏菌)高产AmpC酶 131株三代头孢耐药的E coli的耐药分析 ESBLs 13.7% 高产AmpC 34.0% 其他酶机制 6.5%,JAMA 2000,产AmpC酶耐药菌引发的临床后果更加严重,产AmpC霉肠杆菌属感染患者死亡率是非耐药菌感染患者的2倍,产AmpC酶细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,持续高产AmpC酶的对策,中重度感染应选择的抗生素：
16、碳青霉烯类、四代头孢、氟喹喏酮类、氨基糖苷类 避免使用第三代头孢、酶抑制剂复合药,AmpC 酶,Inoue K, et al. Chemotherapy 1995, 41(4): 257-266,ESBLs与高产AmpC的差异,ESBLs 高产AmpC 耐药谱 多重 多重 三代头孢 耐药 耐药 四代头孢 部分敏感 敏感 棒酸 敏感 不敏感 哌酮/舒巴坦 多敏感 耐药 PIP/三唑 多敏感 耐药 头霉素 敏感 耐药 碳青霉烯类 敏感 敏感,SSBL-24株阴沟肠杆菌的耐药情况,酶型 株数 三嗪 他啶 吡肟 亚胺配南 AmpC+ 14 14 14 0 0 ESBL+ 4 4 2 4 0 AmpC+
17、ESBL+ 5 5 5 2 0 From PUMC hospital,超级内酰胺酶耐药(SSBL) Super Spectrum Beta Lactamases,ESBLs/高产AmpC酶位于同一细菌或细菌质粒,NPRS-7年最常见的G-菌（株数）,铜绿假单胞菌 大肠埃希菌 克雷伯菌属 不动杆菌属 肠杆菌属 嗜麦芽窄单胞菌 变形杆菌属 沙雷菌属 其它假单胞菌属 枸橼酸杆菌属,时间：1994年2001年 医院：414家 菌株：5541949株,NPRS-7年最常见的革兰阴性菌（株数）,菌株数,554 1048 1348 1542 1291 1678 1949,总菌株,19942001年主要抗菌素
18、对革兰阴性菌 敏感率变化趋势,敏感率,19942001年亚胺培南等主要抗菌素 对革兰阴性菌敏感率变化趋势,敏感率,MDRMulti-Drug-resistance,G-菌对四类抗生素中3/4类耐药 Ceftazidine, Ciprofloxacin, Gentamicin, Imipenem Pseudomonas aeruginosa, Acinetobacter species ESBLs/AmpC G+ MRSA,非发酵糖细菌,1994-2001年，全国32家医院ICU分离的10279株 G-菌中，分离4450株非发酵糖细菌),19942001年中国重症监护病房非发酵糖细菌的耐药变迁
19、中华医学杂志,2003,83(5):385-390,近3年, 非发酵糖细菌的比例从41.2%升高到47.9% 铜绿假单胞菌、不动杆菌属、嗜麦芽窄食单胞菌分别位居1、4、7位,铜绿假单孢菌的耐药性(2001年),19942001年中国重症监护病房非发酵糖细菌的耐药变迁 中华医学杂志,2003,83(5):385-390,不动杆菌属的耐药性(2001年),46%,19942001年中国重症监护病房非发酵糖细菌的耐药变迁 中华医学杂志,2003,83(5):385-390,R%,7年嗜麦芽窄食单胞菌耐药率变迁(%),19942001年中国重症监护病房非发酵糖细菌的耐药变迁 中华医学杂志,2003,8
20、3(5):385-390,肠杆菌科细菌对三种碳青霉烯的敏感性,中国抗感染化疗杂志2002年3月30日第二卷第一期,(3051) (357) (2118) (208) (1143) ( 22),微生物学资料,肠肝菌科细菌对三种碳青霉烯的敏感性,李家泰 中华检验医学杂志, 2005, 28(1): 25,非发酵革兰阴性杆菌对三种碳青霉烯的敏感性,中国抗感染化疗杂志2002年3月30日第二卷第一期,(1790) (169) (1365) (142 ) (323),微生物学资料,非发酵革兰阴性杆菌对三种碳青霉烯的敏感性,李家泰 中华检验医学杂志, 2005, 28(1): 25,G-杆菌耐药对预后的影
21、响,Prospective cohort study. Dec 1996 to Sep 2000 Inpatient surgical wards at a university hosp N=924 pats with GNR infections Outcomes were compared between GNR infections with and without antibiotic res rGNRs: resistant to one or more of the following all aminoglycosides, including amikacin all cep
22、halosporins all carbapenems all fluoroquinolones,Crit Care Med 2003; 31:10351041,非发酵革兰阴性杆菌对三种碳青霉烯的敏感性,李家泰 中华检验医学杂志, 2005, 28(1): 25,G-杆菌耐药对预后的影响,Prospective cohort study. Dec 1996 to Sep 2000 Inpatient surgical wards at a university hosp N=924 pats with GNR infections Outcomes were compared between
23、GNR infections with and without antibiotic res rGNRs: resistant to one or more of the following all aminoglycosides, including amikacin all cephalosporins all carbapenems all fluoroquinolones,Crit Care Med 2003; 31:10351041,rGNR: 入住ICU MV CRRT 抗生素更换 住院时间 病死率,小 结,ESBL和AmpC是ICU重症感染致病菌耐药的重要原因 三代头胞大量使用是
24、导致G-菌出现ESBL和AmpC 的 主要原因 ESBL和AmpC使ICU重症感染患者的病死率明显增加 近3年, ICU非发酵糖细菌的比例从41.2%升高到47.9%铜绿假单胞菌、不动杆菌属、嗜麦芽窄食单胞菌分别位居1、4、7位 碳青霉烯类抗生素、酶抑制剂制剂等敏感性较高,ICU重症感染的重要性 细菌耐药机制及ICU细菌流行情况 重症感染的治疗策略 感染灶的充分引流 早期经验性治疗与降阶梯策略 正确的目标性治疗,内 容 提 要,非抗生素治疗策略,气管插管与机械通气 插管路径 NIV/IV 声门下的积液 气囊的管理 湿化与雾化 管路与冷凝水 MV时间 ICU的医疗强度 误吸/体位 体位/胃肠道返
25、流 营养途径 口鼻咽腔/肠道定植 溃疡预防/血糖控制,Source control-Grade E,Every pats presenting with severe sepsis should be evaluated for the presence of a focus of infection amenable to source control measures Drainage of an abscess or local focus of infection Removal of a potientially infected device,Guidelines for seps
26、is. Intensive Care Med 2004, 30: 536-555,重症感染的重要性 细菌耐药机制及ICU细菌流行情况 重症感染的治疗策略 感染灶的充分引流 早期经验性治疗与降阶梯策略 正确的目标性治疗,内 容 提 要,早期经验性治疗的对象,对有急性而危及生命的全身性感染患者 无法及时得到细菌学资料 应根据本病房的细菌流行病学调查结果 选择对常见致病菌有效的广谱抗生素 经验性治疗推理性治疗,提高患者的生存率 降低细菌产生耐药性,早期经验性治疗的目标,Dr. Jordi Rello Professor of Critical Care ,University Rovira & vi
27、rgili Tarragona, Spain,死亡： 绝对危险度下降6.1%,早期有效抗感染治疗的重要性,死亡： 绝对危险度下降9,死亡： 绝对危险度下降4%,ICU严重感染病人起始抗生素治疗覆盖面不足-死亡率增加,ICU经验性抗生素治疗VAP: 22-73%为抗生素起始治疗不当,医院获得性肺炎-迅速恰当的抗生素治疗，明显提高生存率,Luna CM et al.Chest 1997,Adequate 38%(6/16) Not-adequate/not-ANT 81.6%(40/49),132 pats with suspected NP BAL in 55 pats,Bloodstream
28、infections,Leibovici et al Adequate vs inadequate initial antibiotic: Mortality: 20% vs 34% From J Intern Med, 1998, 244: 379,早期及时抗生素治疗的重要性,In a retrospective cohort study of pneumonia in 18,209 patients Administering antibiotics within 4 h of hospital arrival was associated with improved survival.,
29、Houck PM et al. Arch Intern Med. 2004, 164: 637644,Antibiotic therapy,1. Grade E Intravenous antibiotic therapy should be started within 1st h of recognition of severe sepsis, after appropriate cultures have been obtained,Guidelines for sepsis. Intensive Care Med 2004, 30: 536-555,Antibiotic therapy
30、,2. Grade D Initial empiric anti-infective therapy should include one or more drugs that have activity against the likely pathogens The 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, 3
31、0: 536-555,Antibiotic therapy,早期经验性治疗,是抗感染的经验性治疗方案，具有如下两个特性： 开始即使用广谱抗生素以覆盖所有可能的致病菌 随后(48-72h)根据微生物学检查结果调整抗生素的使用，使之更有针对性,Dr. Luciano Gattinoni Professor of Anesthesiology,Institute of Emergency Surgery,University of Milan, Italy,如何保证起始治疗的准确性 Getting it right (A-protocol),Treatment protocols and guide
32、lines-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 initial therapy that was appropriate, but we wanted to minimize the emergence of resistance”,CCM 2001， 29：11091115,如何保证起始治疗的准确性 Ge
33、tting it right (A),CCM 2001， 29：11091115,如何保证起始治疗的准确性 Getting it right (A),“Not only we did want to treat with the initial therapy that was appropriate, but we wanted to minimize the emergence of resistance”,CCM 2001， 29：11091115,如何保证起始治疗的准确性 Getting it right (B-Bacteria resis),It is essential to be
34、 able to recognize those pats who are treatment failure,CCM 2003， 31：676,抗生素治疗3dVAP 无效-tended to be survivors 有效-tended to be non-S More importantly Those pats who had no clinical response within the first 3d were receiving inadequate antimicrobial therapy,Most common pathogens associated with inade
35、quate initial antimicrobial threapy,PA: Pseuso aeruginosa; SA:Staphylococcus aureus; AS: Acinetobacter species; KP: Klebsiella pneumoniae; ES: Enterobacter species; SP: Strep pneumoniae Other: E coli, Haemophilus influ, Serratia,Kollef MH Clinical Inf Dis 2000, 31 (S4):131-8,机械通气时间与既往抗生素治疗是 多重耐药致病菌V
36、AP的独立危险因素,Trouillet JL et al.Am J Respir Crit Care Med 157:531-39, 1998,HAP / VAP / HCAP合并MDR感染 危险因素,Antimicrobial therapy in preceding 90 days Current hospitalization of 5 days or more High frequency of antibiotic resistance in the community or in the spesific hospital Presence of risk factors for
37、HCAP Immunosuppressive disease and/or therapy,ATS. Am J Respir Care Med 2005;171:388,联合用药,16 beds MICU of 1300 beds teaching hospital 1993.51995.6 VAP occurring after 7 d of MV and prior antibiotic use,Trouillet JL. Am J Respir Crit Care Med 1998, 157: 531539,% susceptibility,细菌耐药特点,VAP病原菌耐药的危险因素: 最
38、重要的是最近接受过抗生素治疗(最近15天) 其次是机械通气至少7天,经验性治疗,VAP的致病菌,敏感性最高,IMPAmikacinVanco,简化的临床诊断标准 Clinical Pulmonary Infection Score,Value Points Temperature C 36.5 and 38.5 and 39 or 4,000 and 11,000 1 Tracheal secretions Few 0 Moderate 1 Large 2 PaO2/FiO2, mmHg 240 or present ARDS 1 240 and absent ARDS 0 Pulmonary
39、 radiography no infiltrate 0 Patchy or diffuse infiltrate 1 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 for MDR Pathogens,No,Yes,Limited Spectrum Therapy,Broad Spectrum The
40、rapy for MDR Pathogens,Algorithm for Initiating Empiric Antibiotic Therapy,ATS. Am J Respir Crit Care Med 2005;171:388-416,Initial Empiric Antibiotic Therapy for Patients with No Risk Factors,Potential Pathogen Streptococcus pneumoniae Haemophilus influenzae Methicillin-sensitive Staphylococcus aure
41、us Enteric gram-negative bacilli (Antibiotic sensitive) Enterobacter species Escherichia coli Klebsiella species Proteus species Serratia marcescens,Recommended Antibiotic Ceftriaxone or Levofloxacin, moxifloxacin, or ciprofloxacin or Ampicillin/sulbactam or Ertapenem,ATS. Am J Respir Crit Care Med
42、2005;171:388-416,Potential Pathogens P. aeruginosa ESBL (+) K. pneumoniae Acinetobacter species MRSA L. pneumophila,Therapy Antipseudomonal cephalosporin (cefepime, ceftazidime) or Antipseudomonal carbapenem (İmipenem, meropenem) or Piperacillin-tazobactam plus Ciprofloxacin or levofloxacin or Amino
43、glycoside Linezolid or vancomycin,Initial Empiric Antibiotic Therapy for Patients with Risk Factors for MDR Pathogens,ATS. Am J Respir Crit Care Med 2005;171:388-416,ICU重症感染的重要性 细菌耐药机制及ICU细菌流行情况 重症感染的治疗策略 感染灶的充分引流 早期经验性治疗 正确的目标性治疗,内 容 提 要,Antibiotic therapy,3. Grade E The antimicrobial regimen shoul
44、d always be reassessed after 4872h 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,目标性治疗,经验性治疗尽早转为目标性治疗 转换所需时间反映抗感染治疗水平,病原学诊断的作用,初始经验性治疗之前，应采集呼吸道标本 呼吸道标本的病
45、原学检查结果并不总是可靠的,细菌耐药性试验(药敏) 及时、正确、反复标本采样 标准化的细菌培养和药敏试验 选择敏感的抗生素 监测：细菌培养和药敏,如何实现目标性治疗 Getting it right (A-Bac culture),目标性治疗药代动力学与药效学,Pharmacokinetics,Pharmacodynamics,Drug concentration at site of infection Serum level Tissue level,Effect Growth inhibition Killing Clinical cure Clinical failure,如何实现正确
46、的目标性治疗Getting it right (C-Decrease Res),目标性治疗 组织渗透能力,血浆浓度 组织浓度,Therapeutic Principle The 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,Appropriate The etiologic orga
47、nism is sensitive to the therapeutic agent Adequate Correct antibiotic Optimal dose Correct route of administration to ensure penetration at the site of infection Use of combination therapy if necessary,早期经验性治疗,严重感染抗菌药物的原则,碳青霉烯类/酶抑制剂复合制剂、四代头孢 或加Van(Teico) 或加抗真菌药物,目标性 治疗,根据细菌学结果+ 临床疗效,选用一 个广谱抗菌素或 几个抗菌素联用,THANKS,