1、邱海波东南大学医学院附属中大医院东南大学急诊与危重病医学研究所,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,医院内感染的发生率,普通病房中一般病人: 6-17%ICU病人：25-40%,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
2、 of pats admitted to ICU with sepsis,CCM, 2003, 31: 2742,Annual incidence of 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 worldwid
3、e,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 s
4、hock,第二阶段/Phase II,ESICM SCCM ISFAACCN/ACCP/ACEP/ATS/ANZICS/ESCMID/ERS/SIF,Guidelines for 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 bro
5、ad-spectrum, reassessed 2-3d Source control: Fluid therapy: 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/MOF and no bleeding risk,第二阶段/Phase
6、II,Guidelines for management of severe sepsis/septic shockBlood product administration: target Hb 7-9g/dl, EPO only in renal failureMechanical ventilation: Ppla30, Hypercapnia, optimal PEEP, Prone positionSedation, analgesia and NBMs: ProtocolGlucose control: 150mg%Renal replacement: Bicarbonate: pH
7、 165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43216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%,JAM
8、A 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：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,SSBL-24株阴沟肠杆菌的耐药情况,超级内酰胺酶耐
9、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
10、率,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,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 o
11、f a potientially infected device,Guidelines for sepsis. 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,34,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 RelloProf
12、essor of Critical Care ,University Rovira & virgili Tarragona, Spain,死亡： 绝对危险度下降16%,死亡： 绝对危险度下降8%,早期有效抗感染治疗的重要性,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,Impact of adequate empirical antibiotic therapy on the outcome of pats admitted to ICU with sepsis,CCM, 2003, 31: 2742,死亡： 绝对危险度下降23%,不适当的经验性治疗-概
13、念,根据细菌培养结果起始治疗的抗生素未能针对引起感染的某一种或多种细菌或细菌对所用的抗生素耐药认为经验性治疗是不恰当的。 （Kollef和 Ibrahim分别于 1999和 2000年的研究）,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,
14、Bloodstream infections,Leibovici et alAdequate vs inadequate initial antibiotic: Mortality: 20% vs 34% From J Intern Med, 1998, 244: 379,Antibiotic therapy,1. Grade EIntravenous antibiotic therapy should be started within 1st h of recognition of severe sepsis, after appropriate cultures have been ob
15、tained,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 pathogensThe choice of drug should be guided by the susceptibility patterns of microorganisms
16、in the community and the hospital,Guidelines for sepsis. Intensive Care Med 2004, 30: 536-555,Antibiotic therapy,降阶梯治疗策略的特性 (De-Escalation Therapy),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 GattinoniProfessor of Anesthesiology,Institute of Emergenc
17、y 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 profiles that can be used to develop therapy protocols“Not only we did want to treat with the initial therapy that wa
18、s 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 (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
19、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 inadequate antimicrobial therapy,Most common pathogens associated with inadequate initial antimicrobial threapy,PA: Pseuso aeruginosa; SA:Staphylococcus aureus; AS:
20、 Acinetobacter 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,不动杆菌的问题,院内肺炎常见病因环境中普遍存在对抗菌素耐药严重耐受肥皂医务工作者手上最常分离到的G,抗菌素对不动杆菌属敏感性,敏感菌的比例%,铜绿假单胞菌的问题,院内获得性呼吸机相关性肺炎的首位病因引起的菌血症死亡率70%所有
21、广谱抗菌素对其耐药已升至2037%,2001年抗菌素对铜绿假单胞菌活性,中介加耐药率,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,铜绿假单胞菌建议治疗方案联合用药,亚胺培南与阿米卡星联用，耐药率降至7亚胺培南与环丙沙星联用，耐药率降至10,19942001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；385340,细菌交叉耐药,一类抗生素的应用可导致细菌对另一类抗生素的耐药,铜绿假单胞菌,经验性治疗,外排泵MexAB-O
22、prM系统的表达增加,膜孔蛋白OprD表达 降低,喹诺酮类,对喹诺酮类耐药,对碳青霉烯类的耐药,对喹诺酮类选择性的nfxc(mexT)突变株,大多数 beta-内酰胺类药物 (包括美罗培南，但不包括IMP) 喹诺酮类, 四环素类, 氯霉素类, TMP,14th ECCMID,联合用药,16 beds MICU of 1300 beds teaching hospital1993.51995.6VAP occurring after 7 d of MV and prior antibiotic use,Trouillet JL. Am J Respir Crit Care Med 1998, 1
23、57: 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,联合用药,Laforce: noncritically ill pts with NPSchleupner: noncritically ill pts with NP (S pneumo, H influ )Hilf: pats with bacteremia involving P aeruginosa,Prospective, multicenter6
24、 ICU in Argentina63Pats, MV72hClinical evidence of VAP and bacteriologic confirmation by BAL or blood culturesCPIS measured at 3 d before VAP (VAP-3); at the onset of VAP (VAP); and at 3 (VAP+3), 5 (VAP+5), and 7 (VAP+7) days after onset,Luna CM.Crit Care Med 2003,31(3) 676-82,降阶梯治疗,如何保证起始治疗的准确性Gett
25、ing it right (C-Clinical evaluation),简化的临床诊断标准Clinical Pulmonary Infection Score,Value PointsTemperature 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 克倍宁美平 泰能分子量小（299），且电荷中性； 美平分子量（437.51） 泰能比美平更快速地进入细菌Evaluation of antib
26、iotics by the method of initial bactericidal activity Matsuda K,Inoue M. Banyu Pahrnaceutical Co.,Ltd.,2-3 Nihonbashi-Honcho 2-Chome,Chuo-ku, Tokyo 103-8416,Japan,76,目标性治疗 组织渗透能力,血浆浓度组织浓度,Prospective multicenter randomized studyPats with microbiologically proven VAPReceive appropriate initial empiri
27、c treatment for 8 (n=197) vs 15 d (n=204)Mortality and recurrent infection: No diffAntibiotic-free days: 13.1d vs 8.7d (P0.001)Multirsistance pathogens emerged significantly less frequently in 8d group than 15d group (42.1% vs 62.4%, P=0.04),减少抗生素疗程Safety,JAMA, 2003, 290: 2598,早期经验性治疗,严重感染抗菌药物的原则,碳青霉烯类/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,STAGE I广覆盖,STAGE II保证疗效降低耐药,THANKS,
