抗菌药物经验用药的精准化.ppt

抗菌药物经验用药的精准化,卓超 广州呼吸疾病研究所 ,全球重要的耐药菌,中国耐药菌的主要问题,革兰阳性菌 相对乐观的问题：甲氧西林耐药金葡菌MRSA 相对较小的问题：万古霉素耐药肠球菌属VRE 革兰阴性菌 肠杆菌科细菌（大肠埃希菌、克雷伯菌属） 不易解决的老问题：对头孢菌素的耐药：产ESBL 愈演愈烈的新问题：对碳青霉烯类耐药CRE 非发酵糖细菌（铜绿假单胞菌、不动杆菌属） 变化不大的问题：铜绿假单胞菌耐药 习惯了的老问题：不动杆菌属耐药,Changes of antiobiotic resistance of bacteria in China,CHINET & Mohnarin data,产ESBL菌检出率(%),1、汪复,等.中国感染与化疗杂志.2006;6(5):289-295. 2、汪复.中国感染与化疗杂志.2008年;8(1):1-9. 3、汪复 等.中国感染与化疗杂志.2008;8(5):325-333. 4、汪复等.中国感染与化疗杂志.2009;9(5):321-330. 5、汪复等.中国感染与化疗杂志.1010;10(5):325-334. 6、朱德妹,等.中国感染与化疗杂志.2011;11(5):321-330. 7、胡付品,等.中国感染与化疗杂志.2012;12(5):321-330. 8、汪复 等.中国感染与化疗杂志.2013;13(5):321-330.,The prevalence of ESBLs in Enterobacter clinical isolates in China during 2005 to 2013,中国乡村医疗机构耐药菌发生情况,Microbes and Infection (2015),CR-KPN from blood in China in 2013,Zhuo C, et al .CMI 2015, accepted,耐药菌：基于微生物的精准化治疗,以药物敏感率指导药物选择（正确） 敏感率提示可选药物，耐药率提示可排除药物、 以药物MIC和耐药机制指导用药（准确） 同类药物，MIC越低，体外抗菌活性越强 契合PK/PD原则,Forest plot depicting the risk ratios (RR) of all-cause mortality of patients with infection with high-MIC versus low-MIC Gram-negative isolates.,Falagas M E et al. Antimicrob. Agents Chemother. 2012;56:4214-4222,ESBLs菌株感染治疗,1. 碳青霉烯类 (严重感染 ?) 2. 复合制剂（轻中度感染?) 3. 头霉素? 4. 头孢他定？头孢吡肟？ 4. 其他药物？ -环丙沙星85%耐药；阿米卡星50%左右耐药。,全国产ESBL大肠埃希菌药敏MIC比较,Zhuo C, plos one 2014, 9(7): e100707,与碳氢霉烯相比，TZP治疗ESBL菌血症的生存率仍难逾越 -从感染类型与严重程度,TZP与碳氢霉烯治疗ESBL的定位 -从病原菌种类,对ESBL-EC感染疗效优于其它肠杆菌（肺克） 其它耐药机制存在，OXA-30或AmpC合并存在 接种效应,Clinical Infectious Diseases Advance Access published January 13, 2015,与-内酰胺类/ -内酰胺酶抑制剂剂相比, 碳青霉烯治疗产ESBL细菌感染有降低全因死亡率的趋势3,一项纳入21个RCT的meta分析报道，与-内酰胺类/ -内酰胺酶抑制剂相比，碳青霉烯组治疗ESBL感染有全因死亡率更低的趋势3,3. Vardakas KZ, et al. J Antimicrob Chemother. 2012 Dec;67(12):2793-803.,一项针对21项RCT研究的荟萃分析结果显示：,不利于-内酰胺类/-内酰胺酶抑制剂,不利于碳青霉烯类,(研究设计见备注),Bacteremia Caused by ESBL-Producing Enterobacteriaceae Mortality,%,Cefepime group (n=33),Lee NY, Ko WC PR, Hsueh PR. Clin Infect Dis 2012 October 22,ESBL对CAZ和FEP都存在适应性耐药的现象,CRE /KPC感染的治疗,一直是各领域讨论的热点 联合治疗是基本认同 碳青霉烯的联合从未被忽略 观念的博弈 方案的优化,Treatment Options for CRE/KPC Combination Therapy is the Mainstream,High-dose and prolonged-infusion carbapenem therapy as part of a combination regimen for CRE with carbapenem MICs 4 mg/L Carbapenem-based combinations Plus colistin, tigecycline, or an aminoglycoside Colistin-based combinations Plus a carbapenem, tigecycline, or an aminoglycoside Tigecycline-based combinations Plus gentamicin or colistin Double-carbapenem therapy = “doripenem + ertapenem”,Tzouvelekis LS, et al. Clin Microbiol Rev 2012;25:682-707.,Outcomes of Infections Caused by KPC-KP According to Treatment Regimen,A: 2 active drugs with a carbapenem B: 2 active drugs, not a carbapenem C: Monotherapy with an aminoglycoside D: Monotherapy with a carbapenem E: Monotherapy with tigecycline F: Monotherapy with colistin G: iInappropriate therapy,Tzouvelekis LS, et al. Clin Microbiol Rev 2012;25:682-707.,历时4年，5家大型医院661例患者入组,对不同类型CRE感染联合治疗疗效评估,对不同类型CRE感染联合治疗疗效评估 （续）,对不同症候CRE感染联合治疗疗效评估,对不同耐药状况CRE感染联合治疗疗效评估,该文献将碳青霉烯的MIC放宽至8-16,CRE所致不同部位感染的治疗推荐,Open Forum Infect Dis. 2015 Apr; 2(2): ofv050.,MIC distributions of 333 CRKP isolates from blood in 2013 in China,Zhuo C, et al .CMI 2015, in press,XDR-肠杆菌科细菌的MIC分布（Vitek 16卡）,Treatment Options for CRE/KPC Combination Therapy is the Mainstream,High-dose and prolonged-infusion carbapenem therapy as part of a combination regimen for CRE with carbapenem MICs 4 mg/L Carbapenem-based combinations Plus colistin, tigecycline, or an aminoglycoside Colistin-based combinations Plus a carbapenem, tigecycline, or an aminoglycoside Tigecycline-based combinations Plus gentamicin or colistin Double-carbapenem therapy = “doripenem + ertapenem”,Tzouvelekis LS, et al. Clin Microbiol Rev 2012;25:682-707.,Double-Carbapenem Therapy for Carbapenemase-Producing K. pneumoniae,Bacterial densities of KPC 354 over 24 h in the in vitro chemostat model (doripenem MIC, 4 mg/L).,Control,Ertapenem alone,Doripenem alone,Doripenem- plus-ertapenem,Comparative efficacies of various dosing regimens of doripenem with or without ertapenem against KPC 354 in the in vivo murine thigh infection model,Antimicrob Agents Chemother 2011;55:30024,doripenem 2 g q8h (3-h infusion) + ertapenem 1 g q24h,Hypothesis: KPCs preferential affinity for ertapenem, due to the ease of hydrolysis vs. that of doripenem; thus, ertapenem acts as an KPC consumer,Double-carbapenem therapy for PDR-KPN （碳青霉烯MIC32）,Clin Infect Dis. (2014) 58 (9): 1274-1283.,1 g ertapenem IV daily, followed 1 hour later by meropenem (2g) or imipenem (1g) every 8 hours infused over 3 hours.,高致病性肺炎克雷伯菌,K1,K2, K5, ,K16,K20, K54, and K57 serotypes String test positive,警惕：重症感染耐药菌感染,Clinical characterics,1、多见于亚洲，糖尿病患者 2、和糖尿病密切相关，男性多 3、多为全身系统性感染，常累及肝、肺、眼 4、脓肿表现多，多有气腔 5、进展快，死亡率高 6、多为敏感菌2、 7、高效和广谱的抗生素，以及局部引流,Lancet Infect Dis. 2012 Nov;12(11):881-7,Clostridium difficile Escherichia coli (O104:H4) CA-MRSA -,由于进展快，死亡高，无论表型如何，碳氢霉烯覆盖很重要，并寻找脓肿灶，外科处理,Recommendations on Nosocomial Pneumonia caused by CR, XDR or PDR Ab.,Conventional agents Carbapenems (imipenem, meropenem and doripenem) prolonged infusion plus sulbactam (6-8g/d) or sulbactam-containing agents Alternative agents IV colisin (2 MU every 8h) plus IV rifampicin (10 mg/kg) or carbapenem Tigecycline (high dose) plus carbapenem Tigecycline (high dose) plus colistin,Pharmacother 2011; 12: 2145-8.,Colistin dosing: high doses A loading dose of 300 to 400 mg CBA followed by a maintenance dose of 150mg twice (CID 2013; 56: 398-404),基于CPM的联合治疗时，即使CPM的MIC32, 对死亡率不构成危险因素。,Crit Care Med 2015; 43:11941204,对于多粘菌素耐药的鲍曼不动杆菌感染,以碳青霉烯、多粘菌素和舒巴坦的联合治疗的死亡率最低，优于基于替加环素+舒巴坦的联合治疗方案,Clinical Infectious Diseases 2015;60(9):1295303,对于多粘菌素耐药的鲍曼不动杆菌感染,替加环素对鲍曼不动杆菌的MIC1mg/L,Ni WT, et al. Pak J Pharm Sci. 2014;27(3):463-7.,MIC1mg/L时，大、小剂量临床达标率相近,MIC1mg/L时，小剂量替加环素的临床达标率显著低于大剂量替加环素,临床达标率（%）,替加环素对鲍曼不动杆菌的MIC(mg/L),通过蒙特卡罗模型计算临床达标率与MIC间的关系，对多种耐药（MDR）鲍曼不动杆菌感染的院内肺炎进行给替加环素不同剂量治疗的分析,针对CRE或XDR的联合治疗方案,Expert Rev. Anti Infect. Ther. 11(12), 13331353 (2013),美罗培南与舒巴坦协同针对CRAB,新近研究，舒巴坦作用AB的靶位为PBP1 和 PBP3，而PBP3极少发生变异 美罗培南作用AB的靶位以PBP2和 PBP1a，而对铜绿假单胞菌以PBP1 和 PBP3为主 两者联合时，即保证对鲍曼的协同性，同时兼顾了对铜绿合并感染的覆盖。,Antimicrob Agents Chemother. 2015,59(3):1680-9.,New Microbiologica, 38, 67-73, 2015,碳氢霉烯联合药物的时间-杀菌效应（CRAB）,对于ABA和PA,MEM较IMP有更窄的MSW,The Scientific World Journal Volume 2014 (2014), Article ID 979648,MEM的TMSW更容易达标,