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革兰阴性菌感染治疗策略(11326俞云松昆明)课件

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革兰阴性菌感染治疗策略11326俞云松昆明课件
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Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 革兰阴性菌感染治疗策略 浙江大学医学院附属邵逸夫医院 感染科 俞云松 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 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799225.78 金杆菌属2080.67 克雷伯菌属495916.00 摩根菌属1460.47 铜绿 假单胞菌491215.84 产碱杆菌1130.36 不动杆菌属479615.47 气单胞菌属1130.36 肠杆菌属16845.43 沙门菌属990.32 嗜麦芽窄食单胞菌16565.34 罗尔斯顿菌属760.25 变形杆菌属9072.93 志贺菌属740.24 流感嗜血杆菌8942.88 普罗威登菌属370.12 沙雷菌属3891.25 博特菌属360.12 柠檬酸杆菌属3451.11 多源菌属320.10 其他假单胞菌3361.08 丛毛单胞菌240.08 其他嗜血杆菌3111.00 奈瑟菌属130.04 伯克霍尔德菌属3040.98 黄杆菌属120.04 莫拉菌属2360.76 其他2980.96 合计31002100.0 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 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: Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 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1.398.4 美罗培南1.398.5 厄他培南2.496.7 阿米卡星10.586.5 头孢哌酮 /舒巴坦7.577.1 哌拉西林/他唑巴坦9.280.0 头孢他啶22.770.8 头孢吡肟20.270.8 庆大霉素42.056.0 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 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20.558.3 美罗培南41.356.0 阿米卡星36.359.8 头孢 他啶36.457.6 头孢 吡肟37.654.5 哌拉西林/他唑巴坦39.055.9 亚胺培南44.452.9 厄他培南54.924.7 环丙沙星40.053.0 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 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 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process Prevalence of ESBLs CHINET surveillance, China, 2005-2009 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 染色体介导的头孢菌素酶 Enterobacter cloacae Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 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 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 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 20052136 20062834 20073037 20083435 20094556 20102093 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 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 (%) 200515234688545.2 264617.4 200620783835240.2 359117.3 200723637962840.7 398816.9 2008251841031641.0 413016.4 2009310021282341.4 491215.8 201032284 1304740.4 478214.8 2005-2010年CHINET监测非发酵菌 在革兰阴性菌中所占的比例 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 05-09年 CHINET监测不动杆菌占革 兰阴性菌比例 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process Acinetobacter as Nosocomial Pathogen ØMostly in ICU: mechanical ventilation, catheter ØVentilator-associated pneumonia ØSkin and soft-tissue infections ØWound infections ØUrinary tract infections ØSecondary meningitis ØBlood-stream infections Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 2009年11家医院1690株铜绿铜绿 假单单胞菌耐药药率(%) 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 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 2005-2010年CHINET耐药监测铜绿药监测铜绿 假单单胞菌 对对碳青霉烯类烯类 的耐药药率(%) 铜绿株数 20052646 20063591 20073988 20084130 20094912 20102265 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 碳青霉烯类抗生素耐药菌株耐药机制研究-外膜 孔蛋白OprD2 (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 l以管家基 因rspL为参 照基因 l以野生株 PAO1为对 照菌株 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 2009年不动杆菌碳青霉烯类耐药率(%) (CHINET数据) Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 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) Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 鲍曼不动杆菌耐药机制 L. Silvia Munoz-Price 358:1271-81. Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process OXA-23是我国CRAB最主要的碳青霉烯酶 Zhou H, et al. JCM. 2007, 45:4054-4057 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process Incidence of Pathogens Isolated from Patients Hospitalized with Pneumonia Clin Infect Dis 2010; 51 Suppl 1: S81-7. SENTRY Antimicrobial Surveillance Program (2003-2008) Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process Percentage of bacterial isolates associated with nosocomial infection (NNIS) Clin Infect Dis 2005; 41: 848-54. In 1975 In 2003 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 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 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 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 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process The clinical impact of hospital acquired Acinetobacter infection is variable StudyInfection Longer ICU stay Longer ventilator dependence Higher Mortality reference Retrospective matched cohort study Nosocomial bacteremia YesYesNo Intensive Care Med 2003; 29:471 –5 Retrospective matched case- control study VAPYesYesYes Crit Care Med 2003; 31:2478-82 Systematic review VAP and bacteremia Yes-Yes Crit Care. 2006; 10(2): R48. Retrospectivem atched cohort study Trauma patients Yes -No Crit Care Med 2010; 38:2133-38 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 解决耐药菌感染的治疗问题:是巨大挑战 Ø 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 Ø 万古霉素耐药肠球菌VRE)-----耐青霉素、氨基糖苷类、万古霉素 Ø 万古霉素耐药金黄色葡萄球菌(VRSA)------我国还没有 Ø 多药耐药鲍曼不动杆菌 Ø 多药耐药铜绿假单胞菌 Ø 产超广谱β-内酰胺酶(ESBLS)革兰阴性菌 Ø 高产头孢菌素酶革兰阴性菌 Ø 碳青霉烯类抗生素耐药的肠杆菌科细菌 Ø 喹诺酮类药物耐药的细菌 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process MIC (µg/mL) SIR S = Susceptible I = Intermediate R = Resistant LowHigh Bacterial Population 32 Assessment of In Vitro Potency MIC Breakpoints Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 针对耐药菌人类应对策略 Ø 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 Ø 开发灭活酶抑制剂 最主要的是β-内酰胺酶抑制剂 Ø 通过现有抗菌药物的联合 Ø 利用抗菌药物的PK/PD参数设计给药方案 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 应对β-内酰胺抗生素耐药策略 Ø 开发对β-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 Ø 开发β-内酰胺酶抑制剂 Ø 开发β-内酰胺抗生素和β-内酰胺酶抑制剂的复合制剂 Ø 利用抗菌药物的PK/PD参数设计给药方案 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process site of action of beta-lactamases Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process Chemical structures of beta-lactams Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process chemical structures of beta-lactamase inhibitors used in clinical practice Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 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 1970197819802010 三种β-内酰胺酶抑制剂均与 青霉素结构类似(右图:青霉素G钠) Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 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β-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. 160–201 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process F. D. Wang et al. International Journal of Antimicrobial Agents 23 (2004) 590–595 舒巴坦联合制剂对革兰阴性杆菌活性研究 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 头孢哌酮-舒巴坦与其他β-内酰胺类抗菌活性比较 J. Clin. Microbiol. 25(9):1725-1729 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 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 (μg/ml) 药敏结果 MIC范围MIC50MIC90 SIR PRL256-512512512 100% PRL/CA#8-512256512 30%20%50% TZP64-512128512 30%70% TZP/CA8-51216512 55%20%25% SCF16-12864128 5%25%75% SCF/CA0.5-32232 85%15%0% CEP256256256 100% CEP/CA1-2564256 70%10%20% CAZ8-25616256 15%50%35% CAZ/CA1-1284128 75% 25% CTX64-256128256 0% 100% CTX/CA2560.25256 75% 25% CN0.5-2568256 45% 55% AK2-2564256 50% 50% FEP256 70%525% IMP25616256 40% 60% FOX2-2564256 60%535% Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 复合制剂的作用问题 Ø在极大多数情况下,发挥抗菌作用的是 母体 Ø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 Ø大多数情况下,母体和酶抑制剂有较好 的协同作用 Ø母体和酶抑制剂均需要一定的和合适的 量 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process β-内酰胺酶抑制剂抗菌活性 Ø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: Ø Sulbactam:拟杆菌属、不动菌属、淋病奈瑟菌 (Binding to PBP2) Ø Clavulanate:流感嗜血杆菌、淋病奈瑟菌 Ø Tazobactam:伯氏疏螺旋体 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 肠杆菌科细菌复合制剂的作用 Ø发挥抗菌作用的是母体 Ø酶抑制剂保护母体的抗菌活性 Ø母体和酶抑制剂有较好的协同作用 Ø母体和酶抑制剂均需要合适的量 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 头孢哌酮/舒巴坦 Ø铜绿假单胞菌:主要抗菌作用成份头孢哌酮头孢哌酮 Ø鲍曼不动杆菌:主要抗菌作用成份舒巴坦 Ø嗜麦芽窄食单单胞菌:主要抗菌作用成份头孢哌酮头孢哌酮 Ø伯克霍尔德菌属:主要抗菌作用成份头孢哌酮头孢哌酮 Ø肠肠杆菌科细细菌:主要抗菌作用成份头孢哌酮头孢哌酮 Ø厌厌氧菌:主要抗菌作用成份舒巴坦 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process MIC Strategies to Improve Efficacy: Dose Escalation 0.1 10 100 1000 1 Concentration (µg/mL) 01224204816 Time (hours) Dose (g) 2 x Dose (g) Nicolau DP. Critical Care 2008;12(Suppl 4):1-5. Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process MIC Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 舒普深1.5g可提供更好的PK/PD Ø 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 q12h。2,3,5 舒普深(1:1) 2g q12h MIC%TMIC* 649 3223 1637 851 465 280 194 0.5108 0.25122 0.125136 0.0625150 舒普深(2:1) 3g q12h MIC%TMIC* 6422 3235 1648 862 475 288 1102 0.5115 0.25128 0.125142 0.0625155 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。 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 如何选择抗菌药物? Ø社区获得革兰阴性菌感染 Ø医院内获得革兰阴性菌感染 Ø碳青霉烯类抗生素使用后(暴露后) 的感染 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 一、社区获得性(发作的)革兰阴 性菌感染 Ø病原菌分布 Ø耐药状况(危险因素评估) Ø抗菌药物选择 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process GuangzhouGuangzhou ZhejiangZhejiang ShanghaiShanghai BeijingBeijing WuhanWuhan HenaHena n n Hong Hong KongKong 菌株来源 1. 2002-2003年 2. 中国7个地区 3. 社区获得性感染 病人分离的革兰 阴性菌共2099株 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 2099株革兰阴性菌分布 Antimicrob Agents Chemother. 2006 Jan;50(1):374-8. Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 主要肠杆菌科细菌耐药性 All (1651) E. coli (953) Klebsiella (357) EnterobacterC itrobacter, Serratia (175) ESBL +??1617?? Imipenem0000 Ertapenem0000 Cefotaxime14.714.415.425.1 Ceftazidime(5.9)(2.7)(8.1)20.0 Pip/taz9.57.113.221.7 Ciprofloxacin40.850.625.222.9 Antimicrob Agents Chemother. 2006 Jan;50(1):374-8. Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process Species Distribution of GNB Causing IAIs Species Distribution of GNB Causing IAIs 2,292 Isolates, ChinaChina, SMART, 2002-200, SMART, 2002-2007 7 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process Rates of ESBL-producing E. coli and K. pneumoniae from Community-onset (Data from SMART 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. Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 影响预后的因素 Clin Infect Dis. 2010 Jan 1;50(1):40-8. Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process 头孢哌酮/舒巴坦对产ESBLs菌株MIC分布 Asymptomatic ulcerative colitis patients on an ProDepression A Risk Factor for Infant Mental HealthMammography Benchmarks Angoff Process PK/PD参数模拟(头孢
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