抗菌药物经验用药的精准化

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 EnterobacteriaceaeMortality,%,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/KPCCombination Therapy is the Mainstream,High-dose and prolonged-infusion carbapenem therapy as part of a combination regimen for CRE with carbapenem MICs 4 mg/LCarbapenem-based combinationsPlus colistin, tigecycline, or an aminoglycoside Colistin-based combinationsPlus a carbapenem, tigecycline, or an aminoglycosideTigecycline-based combinationsPlus gentamicin or colistinDouble-carbapenem therapy = “doripenem + ertapenem”,Tzouvelekis LS, et al. Clin Microbiol Rev 2012;25:682-707.,Outcomes of Infections Caused by KPC-KPAccording to Treatment Regimen,A: 2 active drugs with a carbapenemB: 2 active drugs, not a carbapenemC: Monotherapy with an aminoglycosideD: Monotherapy with a carbapenemE: Monotherapy with tigecyclineF: Monotherapy with colistinG: 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/KPCCombination Therapy is the Mainstream,High-dose and prolonged-infusion carbapenem therapy as part of a combination regimen for CRE with carbapenem MICs 4 mg/LCarbapenem-based combinationsPlus colistin, tigecycline, or an aminoglycoside Colistin-based combinationsPlus a carbapenem, tigecycline, or an aminoglycosideTigecycline-based combinationsPlus gentamicin or colistinDouble-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,Ertapenemalone,Doripenemalone,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.,1g ertapenem IV daily, followed 1hour later by meropenem (2g) or imipenem (1g) every 8hours infused over 3hours.,高致病性肺炎克雷伯菌,K1,K2, K5, ,K16,K20, K54, and K57 serotypesString 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 agentsCarbapenems (imipenem, meropenem and doripenem) prolonged infusion plus sulbactam (6-8g/d) or sulbactam-containing agentsAlternative agentsIV colisin (2 MU every 8h) plus IV rifampicin (10 mg/kg) or carbapenemTigecycline (high dose) plus carbapenemTigecycline (high dose) plus colistin,Pharmacother 2011; 12: 2145-8.,Colistin dosing: high dosesA 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.,MICMSW更容易达标,Facing the Gram-Negative MDROOptimizing Antibiotic Empi