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1、多重耐药革兰阴性菌感染与治疗,细菌感染性疾病治疗,经验性治疗:根据病史、症状、体征及实验室检查,得出初步诊断,评估可能病原体和耐药性后,病情评估后使用抗菌药物。目标治疗:感染部位、病原菌及药敏已明确,有针对性的使用抗菌药物。,Antibiotic treatment,A balancing act,Appropriate initial antibiotic treatment,Avoidunnecessaryantibiotics,Appropriate therapyMatches antibiotic sensitivities of the organism to the antibi
2、otic usedADEQUATE therapyChoose an appropriate initial antibiotic therapyUse optimal dosing(PD profiling)Select correct route of administration to ensure antibiotic penetration at site of infectionUse combination therapy,if necessary,ATS/IDSA Guidelines.Am J Respir Crit Care Med.2005;171:388-416.,Im
3、proving the Probability of Positive Outcomes,Does Inappropriate Therapy Result From Antibiotic Resistance?,Inappropriate therapy is more likely if antibiotic resistance is presentAntibiotic-resistant organisms are more commonly associated with inappropriate therapy,Adapted from Kollef MH.Clin Infect
4、 Dis.2000;31(suppl 4):S131S138.,优化抗菌治疗的重要理论依据是药动学/药效学(PK/PD)研究的成果,以血浓度代表,-内酰胺类:优化药物暴露时间,PK/PD靶值:疗效最大化所需要的%TMIC 头孢菌素类60%70%青霉素类50%碳青霉烯类 40%4050临床疗效:85以上6070 最佳细菌学疗效,Drusano GL.Clin Infect Dis.2003;36(suppl 1):S42-S50.,肠杆菌科细菌 临床关注的主要-内酰胺酶,超广谱-内酰胺酶(ESBLs)高产头孢菌素酶(AmpC酶)极少数菌株产碳青霉烯酶(碳青霉烯酶KPC),MDR,XDR or P
5、DR,产ESBLs菌株血行感染死亡率显著增加(Meta分析),产ESBLs菌株与不产ESBLs菌株血行感染死亡率比较的Meta分析包括16个研究产ESBLs菌株菌血症死亡率显著增加(pooled RR 1.85,95%CI 1.392.47,P 0.001),Mortality and delay in effective therapy associated with extended-spectrum b-lactamase production in Enterobacteriaceae bacteraemia:a systematic review and meta-analysis.
6、Journal of Antimicrobial Chemotherapy(2007)60,913920,产ESBLs菌株亚胺培南MIC分布,美罗培南和亚胺培南的血浆浓度(1g),MIC90,Dreetz M et al.Antimicrob Agents Chemother 1996;40:105-109.,亚胺培南美罗培南,(常规剂量:0.5 Q6H;最少剂量:0.5 Q8H),TMICs 40%以上,抗菌药物对产ESBLs菌抗菌活性,3.0 Q12h,3.0 Q8h,8 218 430 817%1615%322%6410%耐药,MIC:64mg/L,MIC:16mg/L,头孢哌酮/舒巴坦
7、(2:1)PK/PD研究,MIC:32mg/L,选择哪种抗菌药物(which antibiotic?)感染部位的常见病原学(possible pathogens on site of infection)选择能够覆盖病原体的抗感染药物(antibiotics requirement)-抗菌谱/组织穿透性/耐药性/安全性/费用考虑药代动力学/药效动力学(PK/PD)考虑病人生理和病理生理状态(physiologic and pathophysiology)高龄/儿童/孕妇/哺乳(advanced age/children/pregnant women/breast feeding)肾功能不全/肝
8、功能不全/肝肾功能联合不全(renal/heptic dysfunction/combined)其它因素(other considerations)杀菌和抑菌/单药和联合/静脉和口服/疗程(cidal vs static/mono vs combination/IV vs PO/duration),经验性抗感染合理选择药物-considerations in choosing antibiotic for empiric therapy,评估病原体(肠杆菌科细菌?)有的而放矢!评估耐药性(是否产ESBLs)到位不越位!,评估病情严重性 广谱 VS 窄谱?单药 VS 联合?,临床病情的判定,发热
9、(38C)或低温(36C)寒战 白细胞增多(计数大于10,000109/L,特别有“核 左移”未成熟的或杆状核的白细胞)粒细胞减少(成熟的多核白细胞1000109/L)血小板减少 皮肤粘膜出血 昏迷,休克多器官衰竭 CRP升高,PCT值,如果是腹腔,胆道,泌尿道感染时:,经验性治疗首先要覆盖:大肠埃希菌肺炎克雷伯菌,大肠埃希菌和肺炎克雷伯菌,可能产ESBLs的危险因素 反复使用抗菌药物 结石梗阻和结构异常等,实验对象,西班牙13家三甲医院2004年10月至2006年1月6000,000病人Case patients:were prospectively recruited by daily r
10、eview of blood culture results in the participating centersControl patients:Control patients from both populations were matched to case patients on the basis of hospital and time period,and were randomly selected from among eligible patients by a computerized method using the blood culture register
11、numbers in the microbiology laboratory of each participating hospital.,产ESBLs菌株血行感染:不同抗菌药物经验性治疗疗效比较,Clinical Infectious Diseases 2003;39:317,碳青霉烯类抗生素,产ESBLs菌株血行感染:不同抗菌药物经验性治疗疗效比较,不同抗菌药物治疗方案30天病死率比较:Thirty-day mortality rates碳青霉烯类 12.9%(8 of 62)头孢菌素 26.9%(7 of 26)氨基糖苷类26.9%(7 of 26),选择碳青霉烯类抗生素作为产ESBL
12、s菌株感染的经验性治疗的合理性!,Bloodstream Infections Due to Extended-SpectrumBeta-Lactamase-Producing Escherichia coli and Klebsiella pneumoniae:Risk Factors for Mortality and Treatment Outcome,with SpecialEmphasis on Antimicrobial Therapy.AAC.2004,48,(12),p.45744581,存活率,临床病例,患者曹,女,70岁,发热、呕吐伴腹泻2天,就诊肠道门诊血常规:WBC 2
13、2.4*109/L,N 93.7%CRP:258.5mg/L;PCT:20.8ng/ml肾功能:Bun 11.21mmol/L,Cr 236umol/L,大便常规,治疗及体温变化,临床病例,患者顾,男,61岁发热1周,Tmax 39.8度,伴畏寒,无明显定位症状及体征1天前就诊当地卫生院,查血WBC4.7*109/l,N86.6%,CRP146.5mg/l,“克林霉素针0.75g+利巴韦林针0.5g”抗感染5年前因“胆囊结石、胆囊炎”行腹腔镜下胆囊切除术,3年前因“胆源性胰腺炎”行手术治疗,治疗及转归,舒普深3g,q8h 3天后复查WBC 2.2*109/L,N50.4%,CRP 12.8mg
14、/L,国内ESBLs菌株感染治疗,1.严重感染的病人:碳青霉烯类;2.轻中度的感染:可选择复合制剂(舒普深或特治星),应用时剂量应适当加大;疗效不佳 时可改碳青霉烯类;3.头霉素也可应用,但耐药比国外严重;4.环丙沙星85%左右耐药;阿米卡星50%左右耐药。,铜绿假单胞菌特性,铜绿假单胞菌:革兰阴性杆菌,宽0.5-1.0m,长1.5-3.0m无芽孢,有单鞭毛临床分离的菌株常有菌毛和微荚膜,在自然界中广泛分布:水、土壤及动植物可存在于人体皮肤粘膜表面,构成人体正常菌群的一部分,属于条件致病菌还可污染医疗器械甚至消毒液,从而导致医源性感染,角膜炎,医院获得性泌尿系感染 12%,烧伤感染死亡率达60
15、%,VAP 死亡率达38%-60%,肺炎 16%,铜绿假单胞菌感染的高死亡率,血流感染 10%,Cell-to-Cell Signaling and Pseudomonas aeruginosa Infections Emerging Infectious Diseases Vol.4,No.4,October.December 1998,手术伤口感染 8%,免疫抑制 死亡总数30%,AIDS死亡总数 50%,铜绿假单胞菌感染严重危及患者生命,铜绿假单胞菌感染者的死亡率达MRSA感染者死亡率的2倍以上,Osmon S,et al.CHEST 2004;125:607616.,死亡率,30.6%
16、,13.5%,铜绿假单胞菌组,P=0.007,n=148,MRSA组,n=49,耐药机制产金属酶(碳青霉烯类抗生素不敏感菌株中的金属酶分布,20062007,16个城市,28家医院),24 MBLs-positive isolates(9 PFGE types,A-I)low prevalence of MBL-producing strains among IRPA isolates from hospitals in mainland China,9(24/264),VIM-2,ShijiazhuangVIM-2,ShijiazhuangVIM-2,HangzhouVIM-2,Tianji
17、nVIM-2,WuhanVIM-2,ShijiazhuangVIM-2,ShijiazhuangIMP-9,GuangzhouIMP-9,GuangzhouIMP-9,GuangzhouIMP-9,GuangzhouIMP-9,GuangzhouIMP-9,GuangzhouIMP-9,GuangzhouIMP-9,GuangzhouIMP-9,GuangzhouIMP-9,GuangzhouIMP-9,GuangzhouIMP-9,GuangzhouIMP-9,GuangzhouVIM-2,TianjinIMP-9,GuangzhouVIM-2,ShanghaiIMP-1,Hangzhou,
18、Our study,pubulished in IJAA,2010,我国碳青霉烯耐药铜绿假单胞菌耐药机制研究 外膜孔蛋白OprD2缺失及表达量下降是主要耐药机制,Our study,pubulished in IJAA,2010,Real-time RT-PCR,耐药机制生物被膜(biofilm,BF),耐药机制生物被膜,铜绿假单胞菌可免受抗菌药物的破坏,成为亚休眠状态,导致反复感染,难以治愈 铜绿假单胞菌在BF的保护下易开启突变耐药基因,成为难以治疗的多重耐药菌株,临床分离菌主要为需氧革兰阴性菌以及革兰阳性球菌其中,铜绿假单胞菌、金葡菌以及肠道杆菌占主导地位,David R Park.Res
19、piratory Care,2005,50(6):742-765,HAP/VAP临床分离菌特点,铜绿假单胞菌定植菌 致病菌,即使经过有效的抗感染治疗,PA仍可在VAP发生后8天在肺部分离到铜绿假单胞菌性VAP的再发通常由前一次感染的PA持续存在引起,某研究显示,ICU中铜绿假单胞菌平均定植率达到34,其中呼吸道定植率为22,消化道定植率为12,Chest 2011;139;909-919,未能区分铜绿假单胞菌定植或感染导致临床的过度处理,临床医生正确判断的重要性!,定植vs感染抗感染,两者极易混淆,如何区分?,Chest 2011;139;909-919,根据细菌定量培养结果:抗感染,区分定植
20、或感染:建议参照细菌定量(或半定量)培养结果及患者临床症状判断 仍很困难,根据Clinical Pulmonary Infection Score(CPIS)CPIS 7 抗感染,用药3天后重新评估,研究一侵入性,研究二非侵入性,研究结果根据病死率判断,防污染气管镜毛刷 10 3 cfu/mL气管内吸引物肺泡灌洗液,定植or感染,CPIS 7,抗铜绿假单胞菌活性的抗菌药物,Tapper,Hilf,Mendelson,Igra,Kuikka,多药联合治疗降低铜绿感染死亡率,Does combination antimicrobial therapy reduce mortality in Gra
21、m-negative bacteraemia A meta-analysis Lancet Infect Dis 2004;4:51927,68.18,26.57,26.67,13.33,26.83,79.41,46.51,44.44,14.29,40,0,10,20,30,40,50,60,70,80,90,100,死亡率,(%),联合用药,单药治疗,铜绿假单胞菌感染治疗联合治疗优于单药治疗,Figure:Combined susceptibilities(%).This figure illustrates the percentage of isolates that were susc
22、eptible to that combination of antimicrobial agents.,VOL 24,NO 1 WINTER 2011 CLINICAL LABORATORY SCIENCE,铜绿假单胞菌感染治疗联合治疗优于单药治疗,Randomized trial of combination versus monotherapy for the empiric treatment of suspected ventilator-associated pneumonia Crit Care Med 2008 Vol.36,No.3,假单胞菌肺炎治疗指南推荐联合用药,抗假单胞
23、菌内酰胺类氨基糖苷类抗假单胞菌内酰胺类抗假单胞菌喹诺酮类抗假单胞菌喹诺酮类氨基糖苷类,2007 Infectious Diseases Society of America(IDSA)2005 the American Thoracic Society(ATS),抗假单胞菌内酰胺类,抗假单胞菌喹诺酮类,氨基糖苷类,头孢哌酮/舒巴坦,铜绿假单胞菌经验性治疗,经验性治疗,1,2,3,4,使用抗假单胞菌内酰胺类抗生素作为治疗的核心,不要使用最近一个月内应用过的内酰胺类抗生素,不要使用最近一个月内耐药的内酰胺类抗生素,内酰胺类抗生素与氨基糖苷类(阿米卡星)联合治疗,Bhat SV Int J Anti
24、microb Agents 2007,铜绿假单胞菌肺炎的治疗起始经验抗菌治疗,Drugs 2007;67 0):351-368,铜绿假单胞菌MIC分布比例,按照头孢哌酮计算MIC分布,MIC:64mg/L,MIC:16mg/L,头孢哌酮/舒巴坦(2:1)PK/PD研究,MIC:32mg/L,2008 CMSS Data on file,CMSS4个年度对2573株肠杆菌科细菌MIC,MIC Distribution to Two Carbapenems of P.aeruginosa from 23 U.S.Hospitals(n=652),MDR PA的治疗多粘菌素,多粘菌素MIC,临床疗效
25、,Clinical Infectious Diseases 2003;37:e15460,全耐药铜绿假单胞菌、鲍曼不动杆菌(包括多粘菌素)的治疗联合治疗,Antibiotic Combinations for Resistant Bacteria CID 2006:43(Suppl 2),临床联合治疗PDRPA:头孢吡肟阿米卡星;多粘菌素B抗假单胞菌碳青霉烯类/氨基糖苷类/喹诺酮类/抗假单胞菌内酰胺类,不动杆菌是不发酵糖的革兰阴性球杆菌至少可分29个基因组其中至少17个已命名:鲍曼不动杆菌(A baumanii)醋酸钙不动杆菌(A calcoacelicus)溶血性不动杆菌(A haemoly
26、ticus)约翰逊不动杆菌(A johnonii)洛菲不动杆菌(A lwoffii)琼氏不动杆菌(A junii)耐放射性不动杆菌(A radioresistens),The clinical impact of hospital acquired Acinetobacter infection is variable,Acinetobacter as Nosocomial Pathogen,Mostly in ICU:mechanical ventilation,catheterVentilator-associated pneumoniaSkin and soft-tissue infec
27、tionsWound infectionsUrinary tract infectionsSecondary meningitisBlood-stream infections,2010年14家医院5523株不动杆菌属(鲍曼不动89.6%)细菌的耐药率(%),除头孢哌酮/舒巴坦、米诺环素外,其余抗菌药的耐药率均50%亚胺培南和美罗培南的耐药率接近60%,SAM TZP MNO CPS COL SXT GEN CTX CAZ IPM MEN AMKATM CIP PIP FEP,F.D.Wang et al.International Journal of Antimicrobial Agent
28、s 23(2004)590595,舒巴坦联合制剂对革兰阴性杆菌活性研究,FASS RJ,et al.Antimicrobial agents and chemotherapy 1990;34(11):2256-2259.,舒巴坦对不动杆菌有内源性抗菌活性,按照舒巴坦计算MIC分布,如果CRAB治疗选舒普深,你认为舒普深的量应该是多少?A:3.0 Q12H(舒巴坦1.0 Q12H)B:3.0 Q8H(舒巴坦1.0 Q8H)C:3.0 Q6H(舒巴坦1.0 Q6H)D:3.0 Q4H(舒巴坦1.0 Q4H),MIC:64mg/L,MIC:16mg/L,头孢哌酮/舒巴坦(2:1)PK/PD研究,MI
29、C:32mg/L,头孢哌酮/舒巴坦(2:1)3g,q8h对非发酵菌不同MIC值时%TimeMIC,舒普深 3.0g Q6H,CSF:WBC 2000,N 97.5%,鲍曼,术后第二周,脑脊液常规、生化及培养,脑脊液培养结果,多重耐药鲍曼不动杆菌脑膜炎治疗方案,激素不推荐 去除分流或其他CSF装置,多粘菌素静脉用氨基糖苷类鞘注加或不加利福平静脉或口服,Volume 9,Issue 4,April 2009,Pages 245-255,.,MDR PA的治疗多粘菌素,Clinical Infectious Diseases 2003;37:e15460,注意肾脏毒性,临床病例,患者,男,57岁,上
30、腹痛伴皮肤发黄20天急诊放置左肝内PTCD,PTCD引流液培养:大肠埃希菌(ESBL+)诊断:化脓性胆管炎,PTCD内引流术后,痛风,糖尿病,肢体动脉闭塞症,高血压,EICU,WBC 11.2*109/L,N 89%CRP 97.5mg/LTB/DB 258/171umol/L,美平+万古,培养结果,头孢哌酮/舒巴坦3g,q6h磷霉素4g,q8h,病情转归,Jian Li,et al.AAC,2006,50:29462950,多粘菌素E用药期间鲍曼不动杆菌耐药水平可能上升,多粘菌素的异质性耐药,PAPs of ZP06,ZP06 Colistin MIC=0.5g/mL,Free(1:106
31、dilution),0.5g/mL Colistin(1:106 dilution),10g/mL ColistinNo dilution,Unpublicated data,In vitro activity of tigecycline against Acinetobacter spp.(2004-2008),Diagn Microbiol Infect Dis 2010;68:73-9.,Tigecycline Susceptibility Testing in Isolates of Acinetobacte from a U.S.Military Hospital,Antimicr
32、ob Agents Chemother 2009;53:2693-5.,替加环素治疗颅内不动杆菌感染?,药代动力学不支持,血脑屏障穿透力低 100 mg静脉给药 90 min后:CSF浓度 0015 g/mL(血清浓度 0306 SD 015 g/mL)24 h 后:CSF 浓度 0025 g/mL(血清浓度0062 g/mL)远低于鲍曼不动杆菌的MIC值,替加环素?,替加环素:负荷剂量 100mg;维持 50mg bid疗程:21天,至CSF培养阴性后一周,铜绿假单胞菌感染主要危险因素,皮肤黏膜发生破坏,免疫功能低下,菌群失调,如气管插管、烧伤、机械通气,如中性粒细胞缺乏、细胞免疫功能缺陷,
33、铜绿假单胞菌感染,铜绿假单胞菌血行感染危险因素,高危因素:严重的粒细胞减少及粘膜溃疡形成,如血液系统恶性肿瘤化疗器官移植,其他相关因素:糖尿病免疫球蛋白缺乏严重烧伤激素应用手术侵袭性装置的植入,Clinical Microbiology and Infection,Volume 11 Supplement 4,2005,血液病病人感染病原菌分布,Journal of Antimicrobial Chemotherapy,2008,During the period of the study(June 2004September 2005),823 patients were admitted
34、to the haematological ward ofour institution in Italy.Acute leukaemia(AL)was the underlying haematological disease in 30.1%of admissions,lymphoma in 28.3%and multiple myeloma in 23.7%.,血液病病人感染病原菌分布,CID 2007:45,2007-2009年血液科菌株分布(480株),分离前10位菌株,BSI in US Hospitals CID 2004:39(1 August),患者,男性,36岁,因“机械滚
35、压伤后45天,反复发热1月”3.14入院。,45天前,滚压伤后在当地诊断:多发伤,外伤性肝破裂、腹腔内出血、骨盆骨折,左耻骨上支骨折,左髋臼骨折,左股骨中上段粉碎性骨折,右髋关节脱位,急诊行:剖腹探查术+肝脏修补术+肠系膜修补术+左侧大腿、膝部、臀部、背部清创术,亚胺培南卡泊芬净,术后ICU逐渐好转并脱机,但仍有反复发热。1周前畏寒高热,再次插管。,美罗培南万古霉素12天,亚胺培南哌拉西林/他唑巴坦3天,血培养:鲍曼不动杆菌-败血症?拔除深静脉置管后体温曾好转,痰培养:大量白念珠菌少量金葡菌,入院后给予:亚胺培南利奈唑胺卡泊芬净,结局:4天后3.18死亡,3.17,3.17,3.17,Thank you for attention!,