医学课件革兰阴性菌感染治疗策略.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,2009,年,CHINET,耐药监测革兰阴性菌菌种分布,细菌,株数,细菌,株数,大肠埃希菌,7992,25.78,金杆菌属,208,0.67,克雷伯菌属,4959,16.00,摩根菌属,146,0.47,铜绿假单胞菌,4912,15.84,产碱杆菌,113,0.36,不动杆菌属,4796,15.47,气单胞菌属,113,0.36,肠杆菌属,1684,5.43,沙门菌属,99,0.32,嗜麦芽窄食单胞菌,1656,5.34,罗尔斯顿菌属,76,0.25,变形杆菌属,907,2.93,志贺菌属,74,0.24,流感嗜血杆菌,894,2.88,普罗威登菌属,37,0.12,沙雷菌属,389,1.25,博特菌属,36,0.12,柠檬酸杆菌属,345,1.11,多源菌属,32,0.10,其他假单胞菌,336,1.08,丛毛单胞菌,24,0.08,其他嗜血杆菌,311,1.00,奈瑟菌属,13,0.04,伯克霍尔德菌属,304,0.98,黄杆菌属,12,0.04,莫拉菌属,236,0.76,其他,298,0.96,合计,31002,100.0,超级细菌（,Superbugs,）,PDR,Superbugs:,are super-bacteria that are resistant to almost all antibiotics,。,MRSA,、,VRE,、,hVISA,、,VISA,、,VRSA,碳青霉烯耐药铜绿假单胞菌,碳青霉烯耐药鲍曼不动杆菌,碳青霉烯耐药肺炎克雷伯菌,（,KPC,、,IMP,、,NDM-1),碳青霉烯耐药其它肠杆菌科细菌,。,（是指对其有效治疗药物几乎均耐药的细菌）,主要超级细菌菌种：,2009,年,14,家医院,16750,株肠杆菌科细菌耐药率（,%,）,抗菌药物,耐药,敏感,亚胺培南,1.3,98.4,美罗培南,1.3,98.5,厄他培南,2.4,96.7,阿米卡星,10.5,86.5,头孢哌酮,/,舒巴坦,7.5,77.1,哌拉西林,/,他唑巴坦,9.2,80.0,头孢他啶,22.7,70.8,头孢吡肟,20.2,70.8,庆大霉素,42.0,56.0,2009,年,14,家医院,12823,株非发酵菌耐药率（,%,）,抗菌药物,耐药,敏感,头孢哌酮,/,舒巴坦,20.5,58.3,美罗培南,41.3,56.0,阿米卡星,36.3,59.8,头孢他啶,36.4,57.6,头孢吡肟,37.6,54.5,哌拉西林,/,他唑巴坦,39.0,55.9,亚胺培南,44.4,52.9,厄他培南,54.9,24.7,环丙沙星,40.0,53.0,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,PDR or,XDR,Prevalence of ESBLs,CHINET surveillance,China,2005-2009,染色体介导的头孢菌素酶,Enterobacter cloacae,ACT-1,DHA-1,CMY,(Peking),DHA-1,CIT,ACT-1,(Shanghai),DHA-1,(Zhejiang),DHA-1,ACT-1(GuangZhou),DHA-1 is The Predominant Type in China,质粒介导的头孢菌素酶,2005-2010,年,CHINET,耐药监测肺炎克雷伯菌对碳青霉烯类的耐药率（,%,）,肺杆,株数,2005,2136,2006,2834,2007,3037,2008,3435,2009,4556,2010,2093,年份,革兰阴性菌株数,非发酵菌株数,铜绿假单胞菌株数,菌株数,百分比,(%),菌株数,百分比,(%),2005,15234,6885,45.2,2646,17.4,2006,20783,8352,40.2,3591,17.3,2007,23637,9628,40.7,3988,16.9,2008,25184,10316,41.0,4130,16.4,2009,31002,12823,41.4,4912,15.8,2010,32284,13047,40.4,4782,14.8,2005-2010,年,CHINET,监测非发酵菌,在革兰阴性菌中所占的比例,05-09,年,CHINET,监测不动杆菌占革兰阴性菌比例,Acinetobacter,as,Nosocomial Pathogen,Mostly in ICU:mechanical ventilation,catheter,Ventilator-associated pneumonia,Skin and soft-tissue infections,Wound infections,Urinary tract infections,Secondary meningitis,Blood-stream infections,2009,年,11,家医院,1690,株铜绿假单胞菌耐药率（,%,）,对多数测试药的耐药率在,12,30,，近年来较稳定。,对美罗培南和亚胺培南耐药率分别为,24.3,和,30.1%,，与,2008,年相仿,2005-2010,年,CHINET,耐药监测铜绿假单胞菌对碳青霉烯类的耐药率（,%,）,铜绿,株数,2005,2646,2006,3591,2007,3988,2008,4130,2009,4912,2010,2265,碳青霉烯类抗生素耐药菌株耐药机制研究,外膜孔蛋白,OprD,2,（,mRNA,的相对表达水平）,7%,61%,19%,13%,OprD,缺失,OprD,表达显著降低,OprD,表达降低,OprD,表达不降低,碳青霉烯类抗生素耐药,铜绿假单胞菌,Real-time RT-PCR,外膜孔蛋白,OprD2,转录水平,与亚胺培南,MICs,值之间的关系,以管家基因,rspL,为参照基因,以野生株,PAO1,为对照菌株,2009,年不动杆菌碳青霉烯类耐药率（,%,）,(CHINET,数据）,碳青霉烯类抗生素耐药性逐年增加,%,year,耐药性,(CHINET,数据；不动杆菌）,鲍曼不动杆菌耐药机制,L.Silvia Munoz-Price,&,Robert A.Weinstein.N Engl J Med.2008;358:1271-81.,OXA-23,是我国,CRAB,最主要的碳青霉烯酶,Zhou H,et al.JCM.2007,45:4054-4057,Incidence of Pathogens Isolated from Patients,Hospitalized with,Pneumonia,Clin Infect Dis,2010;51 Suppl 1:S81-7.,SENTRY Antimicrobial Surveillance Program(2003-2008),Percentage of bacterial isolates associated with nosocomial infection(NNIS),Clin Infect Dis,2005;41:848-54.,In 1975,In 2003,非发酵菌耐药率变化（上海地区）,2000,年,-2009,年上海地区细菌耐药性监测数据,鲍曼不动杆菌占,ICU,院内获得性肺炎病原菌的比例及对常用抗菌药物的耐药率,Clin Infect Dis,2005:41:848-854,ICU,病房不动杆菌流行状况,The clinical impact of hospital acquired,Acinetobacter,infection is variable,Study,Infection,Longer ICU stay,Longer ventilator dependence,Higher Mortality,reference,Retrospective,matched cohort study,Nosocomial bacteremia,Yes,Yes,No,Intensive Care Med 2003;29:4715,Retrospective matched case-control study,VAP,Yes,Yes,Yes,Crit Care,Med 2003;,31:2478-82,Systematic,review,VAP and bacteremia,Yes,-,Yes,Crit Care.2006;10(2):R48.,Retrospectivematched cohort study,Trauma patients,Yes,-,No,Crit Care Med 2010;38:2133-38,解决耐药菌感染的治疗问题：是巨大挑战,甲氧西林耐药金黄色葡萄球菌（,MRSA)-,多药耐药,医院获得,MRSA-55.9%,社区获得,MRSA-,毒力强,万古霉素耐药肠球菌,VRE)-,耐青霉素、氨基糖苷类、万古霉素,万古霉素耐药金黄色葡萄球菌（,VRSA)-,我国还没有,多药耐药鲍曼不动杆菌,多药耐药铜绿假单胞菌,产超广谱,-,内酰胺酶（,ESBL,S,）革兰阴性菌,高产头孢菌素酶革兰阴性菌,碳青霉烯类抗生素耐药的肠杆菌科细菌,喹诺酮类药物耐药的细菌,MIC(,g/mL),S,I,R,S=Susceptible,I=Intermediate,R=Resistant,Low,High,Bacterial Population,32,Assessment of,In Vitro,Potency MIC Breakpoints,针对耐药菌人类应对策略,开发新的抗菌药物,头孢菌素一代到四代（四代半甚至五代）,碳青霉烯类,替加环素,开发灭活酶抑制剂,最主要的是,-,内酰胺酶抑制剂,通过现有抗菌药物的联合,利用抗菌药物的,PK/PD,参数设计给药方案,应对,-,内酰胺抗生素耐药策略,开发对,-,内酰胺酶更稳定的抗生素,头孢菌素一代到四代（四代半甚至五代）,碳青霉烯类,开发,-,内酰胺酶抑制剂,开发,-,内酰胺抗生素和,-,内酰胺酶抑制剂的复合制剂,利用抗菌药物的,PK/PD,参数设计给药方案,site of action of beta-lactamases,Chemical structures of beta-lactams,chemical structures of beta-lactamase inhibitors used in clinicalpractice,Introduction,克拉维酸,小棒链霉菌,舒巴坦,制药工业,他唑巴坦,制药工业,其他,研制开发,1970,1978,1980,2010,三种,-,内酰胺酶抑制剂均与,青霉素结构类似（,右图：青霉素,G,钠,）,抑制剂作用,克拉维酸,VS,舒巴坦,克拉维酸,可在,G-,细菌中诱导产生,-,内酰胺酶，舒巴坦未有此类报道,：舒巴坦优于克拉维酸,CLINICAL MICROBIOLOGY REVIEWS,Jan.2010,p.160201,F.D.Wang et al.International Journal of Antimicrobial Agents 23(2004)590595,舒巴坦联合制剂对革兰阴性杆菌活性研究,头孢哌酮,-,舒巴坦与其他,-,内酰胺类抗菌活性比较,J.Clin.Microbiol.25(9):1725-1729,20,株酶抑制剂耐药的肺炎克雷伯菌对各抗菌药物的,MIC,结果*,抗菌药物,MIC(g/ml),药敏结果,MIC,范围,MIC50,MIC90,S,I,R,PRL,256-512,512,512,100%,PRL/CA,#,8-512,256,512,30%,20%,50%,TZP,64-512,128,512,30%,70%,TZP/CA,8-512,16,512,55%,20%,25%,SCF,16-128,64,128,5%,25%,75%,SCF/CA,0.5-32,2,32,85%,15%,0%,CEP,256,256,256,100%,CEP/CA,1-256,4,256,70%,10%,20%,CAZ,8-256,16,256,15%,50%,35%,CAZ/CA,1-128,4,128,75%,25%,CTX,64-256,128,256,0%,100%,CTX/CA,256,0.25,256,75%,25%,CN,0.5-256,8,256,45%,55%,AK,2-256,4,256,50%,50%,FEP,256,70%,5,25%,IMP,256,40%,60%,FOX,2-256,4,256,60%,5,35%,复合制剂的作用问题,在极大多数情况下，发挥抗菌作用的是母体,酶抑制剂所起的作用仅仅是保护母体或恢复母体抗菌活性的作用,大多数情况下，母体和酶抑制剂有较好的协同作用,母体和酶抑制剂均需要一定的和合适的量,-,内酰胺酶抑制剂抗菌活性,一般来说，抑制物不灭活,PBPs,，因此其本身抗菌活性可忽略不计，但是以下情况例外,:,Sulbactam,：拟杆菌属、不动菌属、淋病奈瑟菌,(Binding to PBP2),Clavulanate,：流感嗜血杆菌、淋病奈瑟菌,Tazobactam,：伯氏疏螺旋体,肠杆菌科细菌复合制剂的作用,发挥抗菌作用的是母体,酶抑制剂保护母体的抗菌活性,母体和酶抑制剂有较好的协同作用,母体和酶抑制剂均需要合适的量,头孢哌酮,/,舒巴坦,铜绿假单胞菌：,主要抗菌作用成份头孢哌酮,鲍曼不动杆菌：,主要抗菌作用成份舒巴坦,嗜麦芽窄食单胞菌：主要抗菌作用成份头孢哌酮,伯克霍尔德菌属：主要抗菌作用成份头孢哌酮,肠杆菌科细菌：主要抗菌作用成份头孢哌酮,厌氧菌：主要抗菌作用成份舒巴坦,MIC,Strategies to Improve Efficacy:Dose Escalation,0.1,10,100,1000,1,Concentration(,g/mL),0,12,24,20,4,8,16,Time(hours),Dose(g),2 x Dose(g),Nicolau DP.,Critical Care,2008;12(Suppl 4):1-5.,MIC,舒普深1.5g可提供更好的PK/PD,舒普深两种剂型常规剂量的TMIC比较显示，给药方式优先度为,3g q12h 2g,q,12h,。,2,3,5,舒普深,(1:1)2g q12h,MIC,%TMIC,*,64,9,32,23,16,37,8,51,4,65,2,80,1,94,0.5,108,0.25,122,0.125,136,0.0625,150,舒普深,(2:1)3g q12h,MIC,%TMIC,*,64,22,32,35,16,48,8,62,4,75,2,88,1,102,0.5,115,0.25,128,0.125,142,0.0625,155,2.,舒普深,1.5g,说明书；,3.REITBERG DP,MARBLE DA,SCHULTZ RW,et al.ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,1988,p.503-509,；,5.REITBERG DP,WHALL TJ,CHUNG M,et al.ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,Jan.1988,p.42-46,*基于舒普深药代动力学参数计算。,如何选择抗菌药物？,社区获得革兰阴性菌感染,医院内获得革兰阴性菌感染,碳青霉烯类抗生素使用后（暴露后）的感染,一、社区获得性（发作的）革兰阴性菌感染,病原菌分布,耐药状况（危险因素评估）,抗菌药物选择,Guangzhou,Zhejiang,Shanghai,Beijing,Wuhan,Henan,Hong Kong,菌株来源,2002-2003,年,中国,7,个地区,社区获得性感染病人分离的革兰阴性菌共,2099,株,2099,株革兰阴性菌分布,Antimicrob Agents Chemother.2006 Jan;50(1):374-8.,主要肠杆菌科细菌耐药性,All,(1651),E.coli,(953),Klebsiella,(357),EnterobacterCitrobacter,Serratia(175),ESBL+,?,16,17,?,Imipenem,0,0,0,0,Ertapenem,0,0,0,0,Cefotaxime,14.7,14.4,15.4,25.1,Ceftazidime,(5.9),(2.7),(8.1),20.0,Pip/taz,9.5,7.1,13.2,21.7,Ciprofloxacin,40.8,50.6,25.2,22.9,Antimicrob Agents Chemother.2006 Jan;50(1):374-8.,Species Distribution of GNB Causing IAIs,2,2,92,Isolates,China,SMART,2002-200,7,Rates of ESBL-producing,E.coli,and,K.pneumoniae,from Community-onset,(Data from SMART 48 h in China),6000,，,000,病人,产,ESBL,大肠埃希菌引起社区发作性败血症危险因素的多变量分析,Clin Infect Dis.2010 Jan 1;50(1):40-8.,影响预后的因素,Clin Infect Dis.2010 Jan 1;50(1):40-8.,头孢哌酮,/,舒巴坦对产,ESBLs,菌株,MIC,分布,PK/PD,参数模拟（头孢哌酮,2g,）,MIC,90,（,64ug/ml),T,MICs 60%,以上,MIC,（,8ug/ml),MIC,32ug/ml,亚胺培南对产,ESBLs,菌株,MIC,分布,美罗培南和亚胺培南的血浆浓度（,1g,）,MIC,90,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,二、,医院内获得革兰阴性菌感染,ESBLs,高比例,不动杆菌明显增加,碳青霉烯类抗生素耐药不动杆菌明显增加,Prevalence of ESBLs,CHINET surveillance,China,2005-2009,Infect Control Hosp Epidemiol 2010;31(5):528-531,美国医护安全监测网（,NHSN,）：,多重耐药,G-,菌感染,05-09,年,CHINET,监测不动杆菌占革兰阴性菌比例,不动杆菌耐药性（,CHINET,数据）,%,year,2009,年,11,家医院,1900,株不动杆菌属,(,鲍曼不动,86.1%),细菌的耐药率（,%,）,汪复等，,CHINET,，,2009,恰当的抗菌药物选择？,需评估致病菌,肠杆菌可能性大？（,ESBLs,高）,非发酵菌可能性大？（不动杆菌：,CRAB,）,抗菌药物使用剂量,静脉给予美罗培南或亚胺培南,1g,后血浆浓度与重要革兰阴性菌,MIC,的关系,Antimicrob Agents Chemother.2005 Jan;49(1):461-3.,S.Rangar Norrby,et al.,世界医学杂志,.1998;2(7):59-62.,（不动杆菌）,不动杆菌,（泰能或美平剂量最小：,1.0Q8H,）,被,抑,制,不,动,杆,菌,累,计,%,舒巴坦的浓度,g/ml,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,PK/PD,参数模拟,(sulbactam 1.0g),MIC,值,（,8ug/ML,）,头孢哌酮,/,舒巴坦协同和相加作用,TMICs 50%,以上,如果CRAB治疗选舒普深,您认为舒巴坦的量应该是多少？,A,：,1.0 Q12H,B,：,1.0 Q8H,C,：,1.0 Q6H,D,：,1.0 Q4H,临床病例,患者沈,，女，,50,2010-5-11,行桥小脑角肿瘤切除术,术后患者出现鼻孔流液，考虑脑脊液鼻漏可能，于,5,月,16,日行腰大池持续引流,2010-5-20,开始,发热,，体温,39,度，,头痛,明显,5,月,21,，,23,，,24,，,27,，,29,，,31,日，,6,月,1,，,2,，,4,，,6,，,7,，,10,，,11,，,13,日,脑脊液培养结果一致,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,日期,WBC,个,/UL,N%,蛋白,mg/l,葡萄糖,mg/dl,氯化物,mmol/l,培养,5.20,2000,97.5,1873,52,121,醋酸钙鲍曼不动杆菌,5.21,7750,96,2162,23,122,5.22,2850,83,1697,24,116,5.25,180,31,1170,43,121,5.27,330,30,661,38,120,培养阳性,Population analysis profiles of,A.baumannii,Both the reference strain and the clinical isolate had an MIC of 1.0g/ml.,Resistant subpopulations,ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,Sept.2006,p.29462950,PAPs of ZP06,ZP06 Colistin MIC=0.5g/mL,Free,(1:10,6,dilution),0.5g/mL Colistin,(1:10,6,dilution),10g/mL Colistin,No dilution,Unpublicated data,A case:PDRAB meningitis,cefoperazone/sulbactam,35d,Polymyxin E,三、碳青霉烯类抗生素暴露后的革兰阴性菌感染,肠杆菌科细菌极少（除非为耐药株）,碳青霉烯类抗生素耐药非发酵菌（尤其是不动杆菌）明显增加,After Carbapenem Exposure,Carbapenem-Resistant,Enterobacteriaceae,Carbapenem-Resistant,Pseudomonas aeruginosa,Carbapenem-Resistant,Acinetobacter baumannii,Stenotrophomonas maltophilia,Clostridium difficile,MRSA,VRE,Fungi,碳青霉烯类的使用是,IR-MDRAB,出现的唯一独立的高危因子,应策略性地选用碳青霉烯类,Ye JJ,et al.PLoS One.2010 Apr 1;5(4):e9947,Suggestion:,R.Smolyakov et al.,Journal of Hospital Infection(2003)54,3238,患者存在,MDR-AB,危险因素时，可经验性使用,A/S,Carbapenem Exposure,Carbapenem-Resistant,Acinetobacter baumannii,Emergence and Rapid Spread of Carbapenem Resistance during a Large and Sustained Hospital Outbreak of Multiresistant Acinetobacter baumannii.,JOURNAL OF CLINICAL MICROBIOLOGY,Nov.2000,p.40864095,Carbapenem Exposure,Carbapenem-Resistant,Pseudomonas aeruginosa,(CR-PA),Carbapenem Exposure,CR-PA,RISK OF CR-PA CARRIAGE IN ICU PATIENTS,.,PENA ET AL.,AAC,June 2007,p.19671971,Journal of Hospital Infection(2005)59,96101,我国碳青霉烯耐药铜绿假单胞耐药机制研究,外膜孔蛋白,OprD2,缺失及表达量下降是主要耐药机制,7%,61%,19%,13%,OprD,缺失,OprD,表达显著降低,OprD,表达降低,OprD,表达不降低,碳青霉烯类抗生素耐药,铜绿假单胞菌,Real-time RT-PCR,绿脓杆菌感染：治疗原则,首先区别定植和感染,绿脓杆菌感染单药,/,联合治疗的争论还没有结束,缺乏严格的大规模、随机、对照临床实验,下列情况下考虑联合治疗,绿脓杆菌肺炎合并菌血症,感染性心内膜炎,在细菌耐药高发地区，先联合用药，等药敏结果明确后再考虑是否停用一种药物,。,权衡利弊，使用多粘菌素,ATS,指南推荐联合抗绿脓,：若疑为,ESBLs,，如肺炎克雷伯菌或不动杆菌，碳青霉烯类抗生素是可以信赖的选择。,若疑为嗜肺军团菌，则应考虑与大环内酯类（如阿齐霉素）或氟喹诺酮类（如环丙沙星或左氧氟沙星）联合治疗，而不是氨基糖酐类。,：如果有,MRSA,风险存在，或当地有较高的发病率。,*：帕尼培南尚未在欧美上市，因此,ATS,指南尚未提及。经大量体外及临床试验证明帕尼培南对铜绿假单胞菌具有可靠的杀菌作用。,头孢哌酮,/,舒巴坦,Carbapenem Exposure,Stenotrophomonas maltophilia,Risk Factors for Infections With Multidrug-Resistant,Stenotrophomonas maltophilia in Patients With Cancer,.,CANCER June 15,2007/Volume 109/Number 12,F.D.Wang et al.International Journal of Antimicrobial Agents 23(2004)590595,舒巴坦联合制剂对革兰阴性杆菌活性研究,2009,年,14,家医院,12823,株非发酵菌耐药率（,%,）,抗菌药物,耐药,敏感,头孢哌酮,/,舒巴坦,20.5,58.3,美罗培南,41.3,56.0,阿米卡星,36.3,59.8,头孢他啶,36.4,57.6,头孢吡肟,37.6,54.5,哌拉西林,/,他唑巴坦,39.0,55.9,亚胺培南,44.4,52.9,厄他培南,54.9,24.7,环丙沙星,40.0,53.0,汪复等，,CHINET,，,2009,2009,年,14,家医院嗜麦芽窄食单胞菌和伯克霍尔德菌属的耐药率（,%,）,抗菌药物,嗜麦芽窄食单胞菌（,1656,株）,抗菌药物,伯克霍尔德菌属（,304,株）,耐药,敏感,耐药,敏感,头孢哌酮,/,舒巴坦,15.1,62.2,哌拉西林,/,他唑巴坦,13.9,77.6,左氧氟沙星,12.4,83.1,头孢他啶,11.1,86.5,复方磺胺甲噁唑,13.2,83.0,美罗培南,12.3,84.8,米诺环素,1.8,83.5,复方磺胺甲噁唑,16.8,74.5,米诺环素,11.6,78.3,碳青霉烯类抗生素暴露后抗菌药物选择,最可能的病原菌什么？,耐药性的评估,:,是否为耐药菌？,病情的评估：是否重症感染？,合理给药方案：,PK/PD,参数优化,总 结,复合制剂：,母体和酶抑制剂均需一定的量，舒普深（,2,：,1,剂型更符合,PK/PD,要求）,社区获得性感染：,评估,ESBLs,可能性，覆盖,ESBLs,舒普深给药常规剂量,3g,，,Q8H,医院获得性感染：,非发酵菌可能性明显增加，需评估肠杆菌还是非发酵菌可能性大，如非发酵菌可能性大，首选可以是头孢哌酮,/,舒巴坦,使用碳青霉烯类后：,非发酵菌明显增加，尤其是碳青霉烯类耐药非发酵菌明显增加，继续治疗抗生素可替换为头孢哌酮,/,舒巴坦，剂量可能需要,3g,，,Q6H,Thank you for attention!,