感染病患者多重耐药菌感染风险的分层.ppt

陈陈 佰佰 义义 感染病患者多重耐药菌感染风险的分层感染病患者多重耐药菌感染风险的分层 谈耐药背景下的个体化抗感染治疗谈耐药背景下的个体化抗感染治疗 抗感染药物发展简史 1929 alexander fleming 发现青霉素 1939 howard florey 和 ernst chain分离获得青霉素，用于动物试验 1942 青霉素首次用于救治战伤患者，拯救了许多人的生命 1950s 大量抗生素用于临床 a poster from world war ii, dramatically showing the virtues of the new miracle drug, and representing the high level of motivation in the country to aid the health of the soldiers at war. discovery of antibacterial agents cycloserine erythromycin ethionamide isoniazid metronidazole pyrazinamide rifamycin trimethoprim vancomycin virginiamycin imipenem 19301940 195019601970198019902000 penicillin prontosil cephalosporin c ethambutol fusidic acid mupirocin nalidixic acid oxazolidinones cecropin fluoroquinolones newer aminoglycosides semi-synthetic penicillins 119;405-411 control of antibiotic resistance no simplistic policy homogenous protocol mixing 经验性抗感染治疗的基本原则 耐药背景下的个体化治疗 理性回归/责任所在 经验性抗感染治疗的基本原则 -耐药背景下的个体化治疗 合理使用碳青霉烯类药物 -指南vs 临床实践 内 容 安 排 慢性咳嗽和黄痰-原因 哮喘 后鼻腔鼻漏 病毒感染后气道高反应性 胃酸返流 吸烟相关的慢性支气管炎 支气管扩张症 弥漫性泛细支气管炎 肺泡蛋白沉积症 急性发热 -wbc不高/淋巴增高（无感染灶）病毒！ -wbc增高/中性粒增高/核左移 可能细菌 ！ 部位/病原体？ 原发性菌血症？ 慢性发热 ie、布病、慢性感染灶？结核病？ 非感染性发热 药物热、风湿病、恶性肿瘤 正确诊断是正确治疗的前提 发热的诊断与鉴别诊断 27-year-old man with acute lymphocytic leukemia. 51-year-old man with chronic myelogenous leukemia. 22-year-old woman with adult t-cell leukemia. 67-year-old woman with adult t-cell leukemia. 61-year-old man with interstitial fibrosis; patient was receiving chlorambucil for chronic lymphocytic leukemia. cop rapid tests when available. gram stain! start adequate antibiotic coverage (within 1 hour?) tillou a et al. am surg 2004;70:841-4 drain purulent collection sampling including invasive procedures when needed (bal) 合格标本进行微生物学检查 开始经验性抗感染治疗 目标治疗 经验性治疗和目标治疗的统一 选择哪种抗菌药物 感染部位的常见病原学 选择能够覆盖病原体的抗感染药物 -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 考虑病人生理和病理生理状态 高龄/儿童/孕妇/哺乳 肾功不全/肝功不全/肝肾功能联合不全 其它因素 杀菌和抑菌/单药和联合/静脉和口服/ 疗程 经验性抗感染治疗合理选择药物 -considerations in choosing antibiotic for empiric therapy 评估病原体 -有的而放矢！ 评估耐药性 -到位不越位！ 病情严重性评估 + - 个体化评估-特殊修正因子 先期抗菌药物对细菌学及其耐药性影响 不同部位感染-病原体的流行病学 从病原学认识感染性疾病 mouth peptococcus peptostreptococcus actinomyces skin/soft tissue s. aureus s. pyogenes s. epidermidis pasteurella bone and joint s. aureus s. epidermidis streptococci n. gonorrhoeae gram-negative rods abdomen e. coli, proteus klebsiella enterococcus bacteroides sp. urinary tract e. coli, proteus klebsiella enterococcus staph saprophyticus upper respiratory s. pneumoniae h. influenzae m. catarrhalis s. pyogenes lower respiratory community s. pneumoniae h. influenzae k. pneumoniae legionella pneumophila mycoplasma, chlamydia lower respiratory hospital k. pneumoniae p. aeruginosa enterobacter sp. serratia sp. s. aureus meningitis s. pneumoniae n. meningitidis h. influenza group b strep e. coli listeria 抗菌谱(coverage) 组织穿透性(tissue penetration) 耐药性(resistance, specifically local resistance) 参考代表性资料/依靠当地资料 安全性(safety profile) 药物本身/制剂/工艺/杂质 费用/效益(cost/effectiveness) 失败或副作用致再治疗费用更高 经验性抗感染治疗药物选择的基本原则 评价病原体耐药可能？ 是否耐药菌？ -了解耐药病原体流行状况 参考代表性治疗/依靠当地资料 -个体化用药-合理用药的精髓 病人来源：社区、养老院、医院 高龄、基础疾病、近期抗菌药物、近期住院、侵袭性操作、晚发医院感染 s. aureus penicillin 1944 penicillin-resistant s. aureus 金黄色葡萄球菌耐药的发生发展过程 methicillin 1962 methicillin-resistant s. aureus (mrsa) vancomycin-resistant enterococci (vre) vancomycin 1990s 1997 vancomycin intermediate s. aureus (visa) 2002 vancomycin- resistant s. aureus cdc, mmwr 2002;51(26):565-567 1960 评价病原体耐药可能？ 是否耐药菌？ -了解耐药病原体流行状况 参考代表性治疗/依靠当地资料 -个体化用药-合理用药的精髓 病人来源：社区、养老院、医院 高龄、基础疾病、近期抗菌药物、近期住院、侵袭性操作、晚发医院感染 中国大陆中国大陆esblesbl的发生率的发生率 % year 细菌耐药监测结果如何解读？ wang h, chen m. diagnos microbiol infect dis, 2005, 51, 201-208cmss/seanir/cares. 实验室药物敏感性监测的解读 意义 -反映了耐药趋势/告诫要谨慎使用抗菌药物 -影响选择药物/考虑耐药性对疗效的影响 不足 -实验室收集菌株/大型教学医院/icu 抗生素选择压力导致耐药性高估！ -没有临床背景资料/不能用于指导个体化用药 （年龄、基础疾病、社区/医院感染、前期抗菌药物使用情况） no risk factors for mdros risk factors for mdr enterobacteriaceaea risk factors for mdr pseudomonas health care contact no yes! (eg, recent hospital admission, nursing home, dialysis) without invasive procedure yes, long hospitalization and/or infection following invasive procedures (5 days) recent abx no yes! (14 days in past 90 days) yes ! (14 days in past 90 days) patient characteristi cs young few comorbidities 65 yrs comorbidities such as tpn or renal insufficiency co-morbidities such as cf, structural lung disease, advanced aids, neutropenia, or other severe immunodeficiency drugs of choice amoxi/calv ampicillin/sulb 2nd or 3rd g fqs pip/tazo cefaperazone/sulbactam ertapenem ceftazidine cefepime pip/tazo cefperazone/sulbactam imipenem meropenem aexcept nonfermenters/non-pseudomonas species. adapted from carmeli y. predictive factors for multidrug-resistant organisms. in: role of ertapenem in the era of antimicrobial resistance newsletter. available at: www.invanz.co.il/secure/downloads/ivz_carmeli_nl_2006_w-226364-nl.pdf. accessed 7 april 2008; dimopoulos g, falagas me. eur infect dis. 2007;4951; ben-ami r, et al. clin infect dis. 2006;42(7):925934; pop-vicas ae, dagata emc. clin infect dis. 2005;40(12):17921798; shah pm. clin microbiol infect. 2008;14(suppl 1):175180. stratification for risk for mdr gram-negative pathogens 重症感染 耐药菌感染！ 重症感染 革兰阴性肠杆菌科细菌感染！ 肺炎链球菌、化脓性链球菌、军团 菌、肺孢子菌等均可致重症感染 pcp ld 对于选择抗菌药物-耐药性 vs 严重性哪个更重要？ pcp ld 耐药菌感染 vs 严重感染 -pcp和ld告诉我们什么？ 观点: -耐药性判断 对于合理选择抗菌药物更重要！ 包括重症感染 -即使重症感染,抗感染治疗方案 仍需根据病原体及其耐药性评估 来制定 经验性抗感染治疗的基本原则 -耐药背景下的个体化治疗 合理使用碳青霉烯类药物 -指南 vs 临床实践 内 容 安 排 cap 碳青霉烯 hap 碳青霉烯 cns感染 碳青霉烯 中性粒细胞减少性发热 碳青霉烯 外科感染 碳青霉烯 抗感染指南中碳青霉烯的地位 所有抗感染指南都推荐碳青霉烯作为治疗选择之一！ 如何恰到好处地个体化应用碳青霉烯？ effectiveness- role of carbapenem？-why？when？which？ nempiric therapy ucovers close to 100% of suspected pathogens ndirected therapy uclinical success safety profile nadverse events cost/effectiveness minimizing resistance nself resistance/resistance to other agents considerations in choosing antibiotic for optimal therapy change of paradigm we are living in an era of high resistance g- ves resistant to - penicillins/cephalosporins - quinolones - aminoglycosides - tmp/smx think mdr rather than resistance increasing proportion of mdr gnr dagata e. iche 2004 %mdr sppesblciprogentamicintmp/sulpip/tz klebsiella n=90 +49%16%30%40% klebsiella n=158 -97%97%91%99% e. coli n=70 +16%14%11%71% e. coli n=535 -93%96%71%99% susceptibilities esbl vs non-esbl schwaber m. aac 2005 esbl contribute most to mdr pathogens failure esbl vs non-esbl 0%20%40%60%80%100% schwaber, 2005* kim, 2002* patterson dl, 2001 arrifin h, 2000* non-esbl esbl failure * failure = mortality susceptibilities of 1030 esbl producing e. coli 37:14051433. vapmdr细菌感染的危险因素 135 次vap icu 变量 or p mv7 days 6.0 .009 先期abs 13.5 7 days / prior abs trouillet, et al. am j respir crit care med. 1998;157:531 effectiveness- role of carbapenem？-why？when？which？ nempiric therapy ucovers close to 100% of suspected pathogens ndirected therapy uclinical success safety profile nadverse events cost/effectiveness minimizing resistance nself resistance/resistance to other agents considerations in choosing antibiotic for optimal therapy ertapenem pharmacokinetics: minimal selectivity for resistant p aeruginosa under clinical conditions minimal resistance selection among p aeruginosa (mic90:16 mg/l) minimal resistance selection among enterobacteriaceae (mic90:0.03 mg/l) n=68 healthy volunteers mrsa=methicillin-resistant s aureus; mssa=methicillin-susceptible s aureus. adapted from nix de, et al. j antimicrob chemother. 2004;53(suppl s2):ii23ii28; friedland i, et al. j chemother. 2002;14(5):483491. plasma ertapenem concentration, mg/l total free 0.01 0.1 1000 1 10 100 04812162024 mic90, mg/l organism 16p aeruginosa, enterococci, mrsa 1.0 anaerobes 0.25 mssa, pneumococci 0.12group a streptococci 0.03enterobacteriaceae hours after 1 g intravenous dose of ertapenem summary effect of ertapenem on p aeruginosa, enterobacteriaceae, and other g-ve pathogens use of ertapenem not decrease susceptibilities of p aeruginosa, enterobacteriaceae, or other g-ve pathogens to carbapenems adapted from livermore dm, et al. j antimicrob chemother. 2005;55(3):306311; dinubile mj, et al. eur j clin microbiol infect dis. 2005;24: 443449; dinubile mj, et al. diagn microbiol infect dis. 2007;58:491494; dinubile mj, et al. antimicrob agents chemother. 2005;49(8): 32173221; crank c, et al. poster presented at: 44th annual meeting of the infectious diseases society of america (idsa); 1215 october 2006. toronto, ontario, canada; goff da, mangino je. poster presented at: 47th annual interscience conference on antimicrobial agents and chemotherapy (icaac); 1720 september 2007; chicago, illinois, usa; goldstein ejc, et al. poster presented at: 44th annual meeting of the infectious diseases society of america (idsa); 1215 october 2006; toronto, ontario, canada; carmeli y, et al. poster presented at: 47th annual interscience conference on antimicrobial agents and chemotherapy (icaac); 1720 september 2007; chicago, illinois, usa. clinical studies oasis i and oasis ii stitch crank goff goldstein carmeli basic science study livermore no risk factors for mdr pathogens risk factors for mdr enterobacteriaceaea risk factors for mdr pseudomonas health care contact no yes! (eg, recent hospital admission, nursing home, dialysis) without invasive procedure yes, long hospitalization and/or infection following invasive procedures (5 days) recent abx no yes! (14 days in past 90 days) yes ! (14 days in past 90 days) patient characteristics young few comorbidities 65 yrs comorbidities such as tpn or renal insufficiency co-morbidities such as cf, structural lung disease, advanced aids, neutropenia, or other severe immunodeficiency carbapenem? limited use of carbapenems ertapenem (group 1 carbapenem) imipenem, meropenem, dori