1、MRSA感染诊治进展,刘又宁 2014年6月7日,content,2013年卫生部监测网血培养结果(155940),前十位细菌分布,2000-2013中国抗生素耐药的变化,Drug Resistance Updates 14 (2011) 236 250 Mohnarin data 2010 to 2013,亚洲地区社区获得MRSA流行情况（占金葡菌百分比）国内的CA-MRSA发生率低,ANSORP Surveillance in Asia-2005-6,%,Song JH, Hsueh PR et al. ANSORP 2006 data,HAP流调显示：金黄色葡萄球菌感染所占病例数达12.
2、85%,致病原构成：VAP vs 非VAP,致病原分离情况：APACHE II =20,49株金黄色葡萄球菌的抗生素敏感性,ORSA,content,如何早期识别及时治疗G+球菌感染,MRSA高危因素基础疾病和症状影像学特点MRSA、MSSA、肺炎链球菌,MRSA感染的危险因素,多变量模型测试中与MRSA相关的危险因素：入住长期医疗照护机构通过医院药房处方抗生素类药物治疗年龄55岁年龄15-54岁DDD计算的抗生素用量,多中心、回顾性队列研究，对比利时国内确诊微生物感染的患者进行了研究。研究者们利用多变量分析法进行分析，以明确与MRSA定植/感染相关的风险因素。,Risk Factors fo
3、r Methicillin Resistant Staphylococcusaureus: A Multi-Laboratory StudyCatry B, et al.PLoS One. 2014 Feb 26;9(2):e89579.,变量 例数 校正OR 95%置信区间 P值,2014年2月发表在 临床微生物和感染杂志上欧洲十年在应用利奈唑胺治疗MRSA cssti启示,MRSA cSSTIs 感染的一般危险因素,MRSA感染/定值病史之前使用抗菌药物治疗高龄慢性开放性伤口（褥疮/压力性溃疡）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免疫抑制反复就诊于医疗体系（包括医院、长
4、期护理、护士家庭、家庭护理、血透中心和医生办公室）入住ICU侵入性操作（如透析、中心静脉导管 24h）注射用药物使用,European perspective and update on the management of complicated skin and soft tissue infections due to methicillin-resistant Staphylococcus aureus after more than 10 years of experience with linezolid Bassetti M, et al. Clin Microbiol Infec
5、t.2014 Apr;20 Suppl 4:3-18.,2014年2月 临床微生物与感染杂志：欧洲十年应用利奈唑胺治疗MRSA 肺炎十年的启示,MRSA肺炎感染的危险因素,有手术史过去12个月内有住院史长期住院使用左氧氟沙星使用大环内酯类药物肠道喂养VAP发生前的机械通气时间使用抗菌药物入住ICU时APACHE 评分高,胸腔积液有MRSA感染病史从疗养院转入晚发性感染鼻咽部发现MRSA慢性阻塞性肺病（COPD）病史,European perspective and update on the management of nosocomial pneumonia due to methicill
6、in-resistant Staphylococcus aureus after more than 10 years of experience with linezolid Chastre J, et al. Clin Microbiol Infect.2014 Apr;20 Suppl 4:19-36.,2-3个高危因素联合有很高的敏感性,INT: intubation气管插管OW: open wound开放伤口TA: treatment with ntibiotics抗生素治疗ST: steroid administration类固醇治疗,Assessment of risk fact
7、ors related to healthcareassociated methicillin-resistant Staphylococcus aureus infection at patient admission to an intensive care unit in Japan BMC Infectious Diseases 2011, 11:303,MRSA鼻部定植是未来发生MRSA感染重要危险因素,项回顾性队列研究，其目的是评估住院患者1年内的MRSA感染风险。分组情况：1组：鼻部样本PCR检测MRSA阳性，且MRSA培养也呈阳性2组：鼻部样本PCR检测MRSA阳性，但MRSA
8、培养呈阴性3组：鼻部样本PCR检测MRSA阴性,Ridgway JP, Peterson LR, Brown EC, Du H, et al. (2013) Clinical Significance of Methicillin-Resistant Staphylococcus aureus Colonization on Hospital Admission: One-Year Infection Risk. PLoS ONE 8(11): e79716. doi:10.1371/journal.pone.0079716,如何早期识别及时治疗G+球菌感染,MRSA高危因素基础疾病和症状影像
9、学特点MRSA、MSSA、肺炎链球菌,发表在2012年6月英国放射杂志,G+菌感染的基础疾病及症状最常见基础疾病为心血管疾病与恶性肿瘤,Meticillin-resistant Staphylococcus aureus and meticillinsusceptible S. aureus pneumonia: comparison of clinical and thin-section CT findingsThe British Journal of Radiology, 85 (2012), e168e175,MRSA肺炎感染CT表现：毛玻璃样影、实变&小叶中心结节、胸腔积液,74岁
10、女性，急性MRSA肺炎、吸烟、心血管疾病、上颌骨肿瘤。发热、咳嗽&呼吸困难3天后。CT显示有毛玻璃影（箭头处）、实变和不清楚的小叶中心结节（楔形处） 。右胸腔积液。,Meticillin-resistant Staphylococcus aureus and meticillinsusceptible S. aureus pneumonia: comparison of clinical and thin-section CT findingsThe British Journal of Radiology, 85 (2012), e168e175,女性，15岁。于2013-1-14晚突然发热
11、，体温最高达39.1。于安阳市第六人民医院给予静滴大环内酯、地塞米松等治疗，用药后体温降至正常。 2013-1-16夜体温骤升至41，伴寒战，意识不清，于安阳市地区医院急诊监护室给予静滴阿奇霉素+更昔洛韦（2天）、头孢哌酮舒巴坦钠（舒普深，1天）抗感染治疗，效果不佳，并出现明显胸闷、喘息。2013-1-19入我院RICU。,病例分享,血气分析(2013-1-19)：PH7.411, PO2 84.4mmHg,PCO2 32.9mmHg，BE-3.2mmol/L,SO2 96.9%血常规(2013-1-19) ：WBC 10.1109/L, N0.873,CRP8.62mg/dl2013-1-1
12、9经验性给予注射用替加环素(惠氏) 50mg 静滴 1/12小时抗感染,病例分享,2013年1月19日,病例分享,1-20 痰培养：MRSA,病例分享,1-20 痰培养及药敏：MRSA,1-20 痰培养药敏：MRSA,病例分享,1-23 胸水培养：MRSA,1-29 金葡菌耐药基因检测：阳性,病例分享,1-23 胸水培养及药敏：MRSA,1-23 胸水培养药敏：MRSA,病例分享,1-28 胸部CT,病例分享,白细胞变化趋势及抗感染治疗方案,2-11始，替考拉宁 0.4g 静滴 1/日,病例分享,2-21 胸部CT,MRSA肺炎CT特点：,Meticillin-resistant Staphy
13、lococcus aureus and meticillinsusceptible S. aureus pneumonia: comparison of clinical and thin-section CT findingsThe British Journal of Radiology, 85 (2012), e168e175,70.6%发现胸腔积液（48/68)51.5%双侧病灶（36/68）70.6%实质异常呈外周分布（48/68)。MRSA小叶中心结节树芽征高于MSSA。,发表在2012年8月英国放射杂志,363例患者基础疾病和症状,Thin-section CT findings
14、 of patients with acute Streptococcus pneumoniae pneumonia with and without concurrent infectionThe British Journal of Radiology, August 2012,混合感染较单一肺链感染组：吸烟、酗酒、恶性肿瘤、心血管疾病、酗酒、哮喘和胶原病多。合并感染的基础疾病较单一感染的多常见症状：咳嗽、痰&发热 呼吸困难相对少,肺炎链球菌肺炎CT表现： 实变、毛玻璃样影、支气管壁增厚&小叶中心结节,65岁男性，单纯急性肺炎链球菌肺炎。发热、咳嗽&呼吸困难3天后。CT显示右肺上叶实变。,
15、Thin-section CT findings of patients with acute Streptococcus pneumoniae pneumonia with and without concurrent infectionThe British Journal of Radiology, August 2012,单纯肺炎链球菌感染毛玻璃样影和实变是最常见的，其次是支气管壁增厚和小叶中心结节。,content,斯沃的毒性抑制作用可能是早期退热的原因,Yoshizawa S, et al. Antimicrob Agents Chemother,2012, 56(4):1744-
16、1748.,一个临床现象引发的研究,Yoshizawa S等人临床观察到斯沃起效迅速。而后回顾52例使用斯沃治疗的重症MRSA感染的患者。发现64%的患者在3天内退热。退热中位天数为3天。,2004年1月至2009年4月间，共有52例MRSA所致脓毒症并使用LZD治疗的患者入选研究。回顾性分析了LZD对发热患者的治疗作用。52名患者中，发热定义为体温大于38（100F）。比较了他们至培养阴性的时间和退热时间。体温下降超过1/1.8定义为明显退热。,Virulence-Suppressing Effects of Linezolid on Methicillin-Resistant Staphy
17、lococcus aureus: Possible Contribution to Early DefervescenceYoshizawa S, et al. Antimicrob Agents Chemother,2012, 56(4):1744-1748.,利奈唑胺抑制MRSA肺部感染诱导产生炎症因子,利奈唑胺明显降低肺部IL-6、IL-12和TNF-水平，而万古霉素组却没有相似的效果,使用6周龄雌性BALB/c小鼠。 鼻腔接种MRSA悬液(30g/小鼠；约 106 至107 CFU/小鼠)后，立即皮下(s.c.)给予LZD (0.4 mg/小鼠；12 mg/kg 体重) 或万古霉素(V
18、CM)(1 mg/小鼠； 40 mg/kg) 。采用较既往文献报道低的LZD剂量来评价与杀菌作用无关的抗炎作用。使用1/2, 1/4, 和1/8 LZD亚抑菌(sub-MIC)浓度溶液来检测毒力因子表达是否能被药物这些药物浓度抑制。亚抑菌浓度LZD溶液加入MRSA菌液过夜震荡培养。过夜培养菌液使用0.22m孔径滤器过滤后给小鼠皮下注射。为检测抗菌药物对宿主介导的免疫反应可能的抑制作用，LZD在滤器过滤除菌的MRSA菌液给药前1h给药。炎症细胞因子水平采用三明治ELISA法测定，抗体对购自R&D Systems, Inc.,按照公司说明书操作。重复进行动物模型试验以保证可重复性。,Virulen
19、ce-Suppressing Effects of Linezolid on Methicillin-Resistant Staphylococcus aureus: Possible Contribution to Early DefervescenceYoshizawa S, et al. Antimicrob Agents Chemother,2012, 56(4):1744-1748.,利奈唑胺抑制肺产生炎性细胞因子呈剂量相关性,利奈唑胺呈剂量依赖性显著抑制MRSA肺部感染TNF-和 IL-6产生，但万古霉素无这一作用,注：此时利奈唑胺组和万古霉素组在肺部的菌量无差异,Virulenc
20、e-Suppressing Effects of Linezolid on Methicillin-Resistant Staphylococcus aureus: Possible Contribution to Early DefervescenceYoshizawa S, et al. Antimicrob Agents Chemother,2012, 56(4):1744-1748.,亚抑制浓度利奈唑胺显著抑制MRSA的毒力因子产生,利奈唑胺抑制炎症因子的作用可能基于其能够抑制MRSA毒力因子。,Yoshizawa S, et al. Antimicrob Agents Chemoth
21、er,2012, 56(4):1744-1748.,为排除抗生素作用导致炎性因子减少，统计了各组间的细菌数量。各组间无显著差异。,亚抑菌浓度的没有减少细菌数量，说明利奈唑胺抑制MRSA毒力因子能力很强。也反映了毒力因子减少不是因细菌数量减少导致的。,研究小结,在抗生素抗菌作用外，抗生素的免疫调节对破坏性的局部炎症反应可能有保护作用。研究的数据表明利奈唑胺的毒力因子抑制作用可以减少炎性因子的产生。而这些可能和退热迅速有关。,LZD：利奈唑胺,The immunoregulatory activities of antimicrobial agents may, in addition to th
22、eir antimicrobial effects, have a protective effect against the destructive local inflammatory response in areas ofinfection. The present data suggest potent virulence factor-suppressing activity of LZD, which results in a reduction of inflammatory cytokine production. Since these effects were obser
23、ved at LZD concentrations that are achievable in human serum with the conventional dosing, they may explain at least in part early defervescenceobserved in patients treated with LZD, despite the presence of positive cultures of MRSA from normally sterile sites.,Virulence-Suppressing Effects of Linez
24、olid on Methicillin-Resistant Staphylococcus aureus: Possible Contribution to Early DefervescenceYoshizawa S, et al. Antimicrob Agents Chemother,2012, 56(4):1744-1748.,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
25、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 o
26、n 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升,百分比,感染1.5小时后, 早期阶段：
27、在发生急性肺损伤和肺部炎症之前。感染4 小时后，中间阶段：发生了显著的肺水肿和炎症反应。感染9小时后，终末阶段：大量的细胞因子释放，中性粒细胞涌入， 肺部水肿，肺泡出血并且重度的肺坏死已经开始发生。,利奈唑胺提高生存率的作用与其抗菌作用无关,利奈唑胺治疗MRSA感染的肺部菌落数与万古霉素相当，提示利奈唑胺提高生存率的作用与其抗菌作用无关,*P0.05,*P0.05,Effects of Linezolid on Suppressing In Vivo Production of Staphylococcal Toxins and Improving Survival Outcomes in a
28、 Rabbit Model of Methicillin-Resistant Staphylococcus aureus Necrotizing Pneumonia Diep BA, et al.J Infect Dis. 2013 Jul;208(1):75-82.,利奈唑胺减轻MRSA肺炎中性粒介导的炎症反应同时避免肺相关损伤,一个新研究,Journal of Infectious Diseases Advance Access published April 10, 2014 The Author 2014. Published by Oxford University Press on
29、 behalf of the Infectious Diseases Society of America,利奈唑胺有效减轻MRSA所致肺损伤，而万古霉素无此作用,Linezolid Dampens Neutrophil-Mediated Inflammation in Methicillin-Resistant Staphylococcus aureusInduced Pneumonia and Protects the Lung of Associated Damages Journal of Infectious Diseases Advance Access published Apr
30、il 10, 2014,未感染未治疗,感染未治疗,感染利奈唑胺治疗,感染万古霉素治疗,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
31、Society of America. All rights reserved.1058-4838/2006/4205-0003$15.00,影响因子： 9.374 (2013),进行了随机、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 Neutr
32、openic 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,Efficacy and Safety of Linezolid Compared with Vancomycin in a Randomized, Double-Blind Study of Febrile Neutropenic Patient
33、s 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,利奈唑胺组退热随天数的累积百分比显著高于万古霉素组,天,病人累积百分比,病人累积百分比,天,常见抗阳性菌药物对比,小结,我国CA-MRSA比例低，HAP中MRSA排序第三。高龄、气管插管、住院、应用抗生素、使用激素、MRSA定植等是MRSA感染的高危因素。MRSA感染最常见基
34、础疾病为：心血管疾病&恶性肿瘤MRSA感染肺炎CT特点：支气管壁增厚、毛玻璃样影、实变&小叶中心结节、双侧肺炎伴胸水。利奈唑胺可显著降低细胞毒素分泌，从而调节机体免疫应答，进而减少组织水肿、破坏，保护器官，减少损伤。抗生素的临床疗效不仅取决于对应的杀菌或抑菌效果也可能与细菌毒性因子的抑制有关。利奈唑胺退热更快。,Thanks,引用文献,退热快 Effects of Linezolid on Suppressing In Vivo Production of Staphylococcal Toxins and Improving Survival Outcomes in a Rabbit Mod
35、el of Methicillin-Resistant Staphylococcus aureus Necrotizing Pneumonia Diep BA, et al.J Infect Dis. 2013 Jul;208(1):75-82. 高危因素1Risk Factors for Methicillin Resistant Staphylococcus aureus: A Multi-Laboratory Study Catry B, et al.PLoS One. 2014 Feb 26;9(2):e89579.2European perspective and update on
36、 the management of complicated skin and soft tissue infections due to methicillin-resistant Staphylococcus aureus after more than 10 years of experience with linezolid Bassetti M, et al. Clin Microbiol Infect.2014 Apr;20 Suppl 4:3-18. 3European perspective and update on the management of nosocomial
37、pneumonia due to methicillin-resistant Staphylococcus aureus after more than 10 years of experience with linezolid Chastre J, et al. Clin Microbiol Infect.2014 Apr;20 Suppl 4:19-36. 4Assessment of risk factors related to healthcareassociated methicillin-resistant Staphylococcus aureus infection at p
38、atient admission to an intensive care unit in Japan BMC Infectious Diseases 2011, 11:303临床体征基础疾病及影像1Meticillin-resistant Staphylococcus aureus and meticillinsusceptible S. aureus pneumonia: comparison of clinical and thin-section CT findings The British Journal of Radiology, 85 (2012), e168e1752Thin
39、-section CT findings of patients with acute Streptococcus pneumoniae pneumonia with and without concurrent infection The British Journal of Radiology, August 2012减轻炎症，保护器官1Linezolid Exerts Greater Bacterial Clearance but No Modification of Host Lung Gene Expression Profiling: A Mouse MRSA Pneumonia
40、Model June 2013 | Volume 8 | Issue 6 | e679942Linezolid Effects on Bacterial Toxin Production and Host Immune Response: Review of the Evidence Diep BA, et al.Curr Ther Res Clin Exp. 2012 Jun;73(3):86-102.3 Effects of Linezolid on Suppressing In Vivo Production of Staphylococcal Toxins and Improving
41、Survival Outcomes in a Rabbit Model of Methicillin-Resistant Staphylococcus aureus Necrotizing Pneumonia iep BA, et al.J Infect Dis. 2013 Jul;208(1):75-82. 4Linezolid Dampens Neutrophil-Mediated Inflammation in Methicillin-Resistant Staphylococcus aureusInduced Pneumonia and Protects the Lung of Associated Damages Journal of Infectious Diseases Advance Access published April 10, 2014,
