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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 incidence of
2、severe sepsis:3 cases/1,000 Kill:1,400 people worldwide/d 25 people/hMoreover,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年10月2日,西班牙,全球Sepsis的发
3、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 sepsisAIM: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 ISFAACCN/ACCP/ACEP/ATS/ANZICS/ESCMID/ERS/SIF,Guidelines f
4、or sepsis.Intensive Care Med 2004,30:536-555,Guidelines for management of severe sepsis/septic shockInitial resuscitation:early goal-directed therapyDiagnosis:appropriate cultureAntibiotic therapy:Early broad-spectrum,reassessed 2-3d Source control:Fluid therapy:colloids=crystalloids,VLTVasopressors
5、: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/MOF and no bleeding risk,第二阶段/Phase II,Guidelines for management of severe sepsis/septic shockBlood product administration:target Hb 7-9g/dl,EP
6、O only in renal failureMechanical ventilation:Ppla30,Hypercapnia,optimal PEEP,Prone positionSedation,analgesia and NBMs:ProtocolGlucose control:150mg%Renal replacement:Bicarbonate:pH 7.15DVT:UH/LMWHStress ulcer prophylaxis:H2blocker,第二阶段/Phase II,To use the management guidelinesTo evalute the impact
7、 on clinical outcome of severe sepsis,第三阶段/Phase III,ESICM SCCM ISFAACCN/ACCP/ACEP/ATS/ANZICS/ESCMID/ERS/SIF,Guidelines for the Management of Adults with Hospital-acquired,Ventilator-associated,and Healthcare-associated Pneumonia,This official statement American Thoracic Society(ATS)And Infectious D
8、iseases 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 infection 5-10 cases/1000 admissions6-to 20-fold higher in those mechanically ventilate
9、d25%of all ICU infections50%of all antibiotics prescribed for this indicationHigh morbidity and mortality 33-50%attributable mortalityFrequently polymicrobialGram-negative bacilli frequently predominate Antibiotic resistance complicates management,Chastre J,Fagon JY.Am J Respir Crit Care 2002;165:86
10、7Tablan 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VRSAPRP 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KPN和EcoAmpC 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
11、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 6
12、6,319 263,260 229,356 270,300 150,158 164,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
13、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/mlmg/ml使用天数头孢唑肟头孢唑肟8324头孢他啶，庆大霉素头孢他啶2165头孢噻肟，阿米卡星头孢噻肟4326头孢噻肟，庆大霉素头孢噻肟8327头孢噻肟头孢噻肟4
14、3216头孢他啶，妥布霉素头孢他啶21618,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.1991;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AmpC34.0%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
15、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：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
16、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 0ESBL+4 4 2 4 0AmpC+ESBL+5 5 5 20From 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
17、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,ImipenemPseudomonas aeruginosa,Acinetobacter speciesESBLs/AmpCG+MRSA,非发酵糖细菌,1994-2001年，全国32家医院ICU分离的102
18、79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
19、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,2003,83(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
20、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 hospN=924 pats with GNR infectionsOutcomes were compared between GNR infections with and without antibiotic resrGNRs:resistant to one or more of the followingall aminoglycosides,inc
21、luding amikacinall cephalosporinsall carbapenemsall 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 hospN=924 pats with GNR infectionsOutcomes were comp
22、ared between GNR infections with and without antibiotic resrGNRs:resistant to one or more of the followingall aminoglycosides,including amikacinall cephalosporinsall carbapenemsall fluoroquinolones,Crit Care Med 2003;31:10351041,rGNR:入住ICUMVCRRT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导致
23、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/胃肠道返流营养途径口鼻咽腔/肠道定植溃疡
24、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 measuresDrainage of an abscess or local focus of infectionRemoval of a potientially infected device,Guidelines for sepsis.Intensive Care Med
25、 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 RelloProfessor of Critical Care,University Rovira&virgili Tarragona,Spain,死亡：绝对危险度下降6.1%,
26、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,Adequate38%(6/16)Not-adequate/not-ANT81.6%(40/49),132 pats with suspected NPBAL in 55 pats,Bloodstream infections,Leibovici et alAdequate vs inadequa
27、te 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 patientsAdministering antibiotics within 4 h of hospital arrival was associated with improved survival.,Houck PM et al.Arch Intern Med.2004,164:637644,Antibiot
28、ic therapy,1.Grade EIntravenous 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,2.Grade DInitial empiric anti-infective therapy should include o
29、ne or more drugs that have activity against the likely pathogensThe 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
30、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 GattinoniProfessor 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 guidelines-important tool for optimal therapy Establishing local susceptibility pr
31、ofiles 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Getting 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
32、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 able to recognize those pats who are treatment failure,CCM 2003，31：676,抗生素治疗3dVAP无效-tend
33、ed to be survivors有效-tended to be non-SMore importantlyThose pats who had no clinical response within the first 3d were receiving inadequate antimicrobial therapy,Most common pathogens associated with inadequate initial antimicrobial threapy,PA:Pseuso aeruginosa;SA:Staphylococcus aureus;AS:Acinetoba
34、cter species;KP:Klebsiella pneumoniae;ES:Enterobacter species;SP:Strep pneumoniaeOther: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VAP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 th
35、erapy in preceding 90 daysCurrent hospitalization of 5 days or moreHigh frequency of antibiotic resistance in the community or in the spesific hospitalPresence of risk factors for HCAPImmunosuppressive disease and/or therapy,ATS.Am J Respir Care Med 2005;171:388,联合用药,16 beds MICU of 1300 beds teachi
36、ng hospital1993.51995.6VAP 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 PointsTem
37、perature C 36.5 and 38.5 and 39 or 4,000 and 11,000 1 Tracheal secretions Few0 Moderate1 Large2 PaO2/FiO2,mmHg 240 or present ARDS1 240 and absent ARDS 0 Pulmonary radiography no infiltrate 0 Patchy or diffuse infiltrate 1 localized infiltrate 2,Luna CM.CCM,2003,31:676,Empiric Antibiotic Therapy for
38、 HAP,HAP,VAP,or HCAP suspected(all disease severity),Late onset(5 days)or risk factors forMDR Pathogens,No,Yes,Limited 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 Antibioti
39、c Therapyfor Patients with No Risk Factors,Potential PathogenStreptococcus pneumoniaeHaemophilus influenzaeMethicillin-sensitive Staphylococcus aureusEnteric gram-negative bacilli(Antibiotic sensitive)Enterobacter species Escherichia coli Klebsiella species Proteus species Serratia marcescens,Recomm
40、ended AntibioticCeftriaxoneorLevofloxacin,moxifloxacin,or ciprofloxacinorAmpicillin/sulbactamorErtapenem,ATS.Am J Respir Crit Care Med 2005;171:388-416,Potential PathogensP.aeruginosaESBL(+)K.pneumoniaeAcinetobacter speciesMRSAL.pneumophila,TherapyAntipseudomonal cephalosporin(cefepime,ceftazidime)o
41、rAntipseudomonal carbapenem(İmipenem,meropenem)orPiperacillin-tazobactamplusCiprofloxacin or levofloxacin orAminoglycosideLinezolid or vancomycin,Initial Empiric Antibiotic Therapyfor 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
42、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 EThe antimicrobial regimen should 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
43、,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
44、Serum levelTissue level,EffectGrowth inhibitionKillingClinical cureClinical failure,如何实现正确的目标性治疗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 PrincipleThe Need for Appropriate Dosing,ATS/IDSA.Am J Respir Crit Care Med 2005;171:388-416,Initial Intravenous Adult Doses for Empiric
45、Therapy of HAP,VAP,HCAP,Relevant Clinical Definitions,AppropriateThe etiologic 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,
