MRSA肺炎的诊治进展

MRSA肺炎的诊治进展,中山大学孙逸仙纪念医院呼吸内科江山平,MRSA肺炎的危险因素MRSA肺炎的临床表现与X线特征MRSA肺炎与肾小球肾炎利奈唑胺治疗MRSA肺炎的优势,MRSA肺炎的危险因素,MRSA 肺炎的危险因素,MRSA定值MRSA感染病史高龄慢性开放性伤口（褥疮/压力性溃疡）入住ICU时APACHE 评分高存在以下疾病或情况慢性肾脏病糖尿病外周血管疾病心血管疾病恶性肿瘤COPD胸腔积液免疫抑制,1：Clin Microbiol Infect.2014 Apr;20 Suppl 4:3-18. 2：Clin Microbiol Infect.2014 Apr;20 Suppl 4:19-36.,3：PLoS One. 2014 Feb 26;9(2):e89579.4:. BMC Infectious Diseases 2011, 11:3035: . PLoS ONE.2013; 8(11): e79716.,反复就诊于医疗体系（包括医院、长期护理、护士家庭、家庭护理、血透中心和医生办公室）气管插管之前使用抗菌药物治疗(DDD)VAP发生前的机械通气时间手术侵入性操作（如透析、中心静脉导管 24h）注射用药物使用肠道喂养糖皮质激素治疗,宿主因素,医疗保健相关因素,MRSA肺炎的临床与X线特征,MRSA肺炎的基础疾病及症状,Meticillin-resistant Staphylococcus aureus and meticillinsusceptible S. aureus pneumonia: comparison of clinical and thin-section CT findings. The British Journal of Radiology, 2012: 85; e168e175,MRSA肺炎的常见影像学表现,Meticillin-resistant Staphylococcus aureus and meticillinsusceptible S. aureus pneumonia: comparison of clinical and thin-section CT findings. The British Journal of Radiology, 2012: 85; e168e175,肺气囊,金黄色葡萄球菌肺炎X线表现以毛玻璃征最常见。其他依次为支气管壁增厚、小叶中心结节（树呀征或边界不清的小结节）、实变、网状斑块、支气管扩张、小叶间隔增厚、空洞、结节和胸积液。但最特征的影像学表现为肺气囊。,Meticillin-resistant Staphylococcus aureus and meticillinsusceptible S. aureus pneumonia: comparison of clinical and thin-section CT findings. The British Journal of Radiology, 2012: 85; e168e175,金黄色葡萄球菌肺炎与肾小球肾炎,胸部HRCT,2012-9-25,姓名：刘# 性别：男 年龄：28岁 职业：无业入院时间：2012-9-25 病案号：697941主诉：反复发热伴腰痛、双下肢浮肿10日，气促1天。静脉药隐；左右手对称部位血培养，支气管分泌物培养均为金黄色葡萄球菌,治疗经过,患者入院后（9-25）予无创呼吸机辅助呼吸， 万古霉素抗感染治疗；患者肾功能进行性恶化，尿量进行性减少，24小时尿量100ml，行CRT治疗；9-26改气管插管呼吸机辅助呼吸，利奈唑胺抗感染治疗输注丙种球蛋白、白蛋白、输血等支持治疗；患者症状、血气及胸内影像学好转，2012-10-7拔除气管插管。,利奈唑胺治疗前后胸片对比,2012-10-7,2012-9-25,出院时情况,神情，低流量吸氧(2L/min)无气促，少许咳嗽，咳少量白色粘稠痰，无胸痛、腹痛，无恶心、呕吐，24小时尿量1120ml；查体：T 37.5，P 96次/分，R 17次/分，BP119/77 mmHg，双肺呼吸音粗，可闻及少量湿性啰音，心率96次/分，律齐，未闻及杂音，腹软，无压痛，双下肢无水肿。辅助检查：血常规： WBC 20.24109/L，NEU 79.3 %，HGB 66 g/L，PLT 205109/L；生化：AST 38 U/L，ALT 32 U/L，TBIL 11.2 umol/L，ALB 27.8g/L， Cr 469 umol/L,Staphylococcal enterotoxins are known to act as superantigens. Superantigens can bind directly to major histocompatibility complex class II on antigen-presenting cells and are recognized by T cell receptor (TCR). They bind only to V chain on the TCR,and cause massive activation of T cells and subsequent release of T cell-derived cytokines, such as IL-2, TNF and INF-y.,The pathogenesis of MRSA-GN is speculated as follows; long-term infection of MRSA leads to the production of Staphylococcal enterotoxins and these substances act as superantigens. That causes massive T cell activation and released cytokines induce kidney injuries including tubulointerstitial nephritis. The cytokines also cause polyclonal B cell activation that leads to the formation of immunecomplex, resulting in glomerulonephritis . Most cases with MRSA-GN reveal rapidly progressive glomerulonephritis with various degrees of proteinuria and elevation of serum IgA and IgG,In addition to the superantigen-related glomerulonephritis,staphylococcal infections associated with glomerulonephritis have been reported: bacteremia associated with infected ventriculoatrial shunt , bacteremia associated with endocarditis, and glomerular lesion associated with visceral abcesses. In these cases, the level of complement is low, cryoglobulins are frequent, and the elevated immunoglobulin type is IgG but not IgA.,金黄色葡萄球菌,肠毒素(超抗原),抗原呈递细胞,T 细胞,细胞因子,小管间质肾炎,过敏性紫癜,B 细胞,抗体形成,抗原抗体复合物,肾小球肾炎,ANCA,血管炎,细胞膜抗原,肾小球基底膜,赘生物脱落,血流感染,腹主动脉营养血管受累,肾动脉栓塞,肾实质脓肿,坏死性动脉炎,肾功能受损,假性主动脉瘤,肾动脉受累,IgA肾病,金黄色葡萄球菌肺炎的临床表现复杂多样，可以通过多种机制导致急性肾功能受损。对此，临床医生必须予以高度重视。,利奈唑胺治疗MRSA肺炎的优势,利奈唑胺与万古霉素在粒缺伴发热肿瘤患者中疗效和安全性：随机、双盲&对照实验,一个新研究,Efficacy and Safety of Linezolid Compared with Vancomycin in a Randomized, Double-Blind Study of Febrile Neutropenic Patients with CancerClinical Infectious Diseases 2006; 42:597607 2006 by the Infectious Diseases Society of America. All rights reserved.1058-4838/2006/4205-0003$15.00,2000年4月18日：FDA批准利奈唑胺上市,随机、双盲、多中心研究，共入组611例病人,粒缺伴发热患者中利奈唑胺组较万古霉素组退热更快,ME微生物可评估组,MITT修正意向治疗组,P=0.04,P=0.01,万古霉素,利奈唑胺,单位：天,Efficacy and Safety of Linezolid Compared with Vancomycin in a Randomized, Double-Blind Study of Febrile Neutropenic Patients with CancerClinical Infectious Diseases 2006; 42:597607 2006 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2006/4205-0003$15.00,Yoshizawa S, et al. Antimicrob Agents Chemother, 2012; 56(4):1744-1748.,临床回顾性分析结果： 28例发热患者中64%在3天内退热，退热中位时间为3天； MRSA培养转阴中位时间为8天。,日本： 利奈唑胺治疗MRSA脓毒症可早期退热,日本：利奈唑胺治疗MRSA脓毒症可早期退热,利奈唑胺对MRSA的毒性抑制作用 可能是其治疗MRSA感染早期退热的原因,Yoshizawa S, et al. Antimicrob Agents Chemother, 2012; 56(4):1744-1748.,Yoshizawa S, et al. Antimicrob Agents Chemother, 2012; 56(4):1744-1748.,第一步：比较利奈唑胺与万古霉素的抗菌作用,实验设计,实验结果,MRSA感染后2小时及6小时时肺内细菌数在LZD组和VCM组间无差异。,动物实验,Yoshizawa S, et al. Antimicrob Agents Chemother, 2012; 56(4):1744-1748.,第二步：证实利奈唑胺抑制MRSA肺炎细胞因子的产生,实验设计,实验结果,动物实验,第三步：证实利奈唑胺抑制MRSA肺炎细胞因子产生的作用呈量效相关,Yoshizawa S, et al. Antimicrob Agents Chemother, 2012; 56(4):1744-1748.,第三步：证实利奈唑胺抑制MRSA肺炎细胞因子产生的作用呈量效相关,实验结果：不同组别TNF- 、IL-6水平比较,利奈唑胺显著抑制MRSA肺部感染后TNF-和 IL-6产生，且呈现剂量依赖性（* P 0.01， P 0.05）； 不同治疗组间肺内细菌数无显著性差异。,动物实验,Yoshizawa S, et al. Antimicrob Agents Chemother, 2012; 56(4):1744-1748.,第三步：证实利奈唑胺抑制MRSA肺炎细胞因子产生的作用呈量效相关,动物实验,Yoshizawa S, et al. Antimicrob Agents Chemother, 2012; 56(4):1744-1748.,第四步：证实Sub-MICs利奈唑胺抑制MRSA产生毒素,动物实验,Yoshizawa S, et al. Antimicrob Agents Chemother, 2012; 56(4):1744-1748.,第四步：证实Sub-MICs利奈唑胺抑制MRSA产生毒素,实验设计,* 利奈唑胺MIC：2mg/L；0.5MIC=1g/ml，0.25MIC=0.5g/ml，0.125MIC=0.25g/ml；* 进行细胞因子检测。,动物实验,Yoshizawa S, et al. Antimicrob Agents Chemother, 2012; 56(4):1744-1748.,第四步：证实Sub-MICs利奈唑胺抑制MRSA产生毒素,实验结果,亚抑菌浓度利奈唑胺能明显抑制MRSA产生的IL-6，而感染前予以利奈唑胺并不未抑制IL-6的产生（* P 0.05， P 0.01） ； 0.5g/ml（1/4MIC）组、0.25g/ml （1/8MIC）组与对照组在细菌数量上无统计学差异。,动物实验,研究重要推论,The immunoregulatory activities of antimicrobial agents may, in addition to their antimicrobial effects, have a protective effect against the destructive local inflammatory response in areas of infection. The present data suggest potent virulence factor-suppressing activity of LZD, which results in a reduction of inflammatory cytokine production. Since these effects were observed at LZD concentrations that are achievable in human serum with the conventional dosing, they may explain at least in part early defervescence observed in patients treated with LZD, despite the presence of positive cultures of MRSA from normally sterile sites.,Yoshizawa S, et al. Antimicrob Agents Chemother, 2012; 56(4):1744-1748.,利奈唑胺有抗感染和免疫调节作用，对感染部位的局部破坏性炎症反应有保护作用。利奈唑胺治疗MRSA感染的早期退热作用可能与其抑制MRSA毒性因子的产生有关,利奈唑胺减轻MRSA肺炎中性粒细胞介导的炎症反应同时避免相关肺损伤 背景：利奈唑胺除了直接抗细菌作用外，还具有抑制毒素产生及毒力因子表达的额外效应。 目的：评价抗球菌药物对MRSA感染的疗效以及免疫相关肺损伤情况。,Jacqueline C, et al. J Infect Dis.2014;210(5):814-23.,Jacqueline C, et al. J Infect Dis.2014;210(5):814-23.,实验设计,* 取材后测定炎症因子TNF- 、IL-1、MIP-2及MPO活性，并进行组织学和免疫组化分析。,Jacqueline C, et al. J Infect Dis.2014;210(5):814-23.,实验结果,Jacqueline C, et al. J Infect Dis.2014;210(5):814-23.,实验结果,与对照组及万古霉素组相比，利奈唑胺组在MRSA感染8小时后TNF- 水平显著降低（ * P 0.05 ）。,*,Jacqueline C, et al. J Infect Dis.2014;210(5):814-23.,实验结果：利奈唑胺有效减轻MRSA所致肺损伤,不同组别MPO活性比较（sham 未感染未治疗；*P .001； *P .05 ）,与对照组及万古霉素组相比，利奈唑胺组在MRSA感染8小时、48小时后MPO活性显著下降； 相应的，MRSA感染8小时后利奈唑胺组小鼠肺组织病理显示中性粒细胞浸润减少，提示免疫相关肺损伤减轻。,Jacqueline C, et al. J Infect Dis.2014;210(5):814-23.,实验结果：利奈唑胺有效减轻MRSA所致肺损伤,Jacqueline C, et al. J Infect Dis.2014;210(5):814-23.,利奈唑胺抑制体内葡萄球菌毒素的产生并且改善兔子模型中坏死性MRSA肺炎的生存率,一个新研究,The Journal of Infectious Diseases 2013;208:7582 The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America,新西兰大耳白兔麻醉后菌液通过儿科气管内导管直接注射1.5mL含SF8300接种液入肺部（主支气管上部1cm）。感染的兔子被随机分为三组：未治疗对照组、万古霉素组、利奈唑胺组。在接种1.5、4、9小时后分别开始抗生素治疗。每3小时监测一次。存活下来的兔子36小时后安乐死。肺取出后切成0.5-cm 的块。三块肺在生理盐水中混合均匀，通过分层的血琼脂平板确定菌量。,早期应用利奈唑胺治疗显著提高MRSA感染的生存率,*P0.01*P0.001,Effects of Linezolid on Suppressing In Vivo Production of Staphylococcal Toxins and Improving Survival Outcomes in a Rabbit Model of Methicillin-Resistant Staphylococcus aureus Necrotizing Pneumonia. Diep BA, et al.J Infect Dis. 2013 Jul;208(1):75-82.,9小时,4小时,1.5小时,Vonco,linezolid,死亡率,利奈唑胺组存活率和存活时间显著提