mrsa肺炎的診治進(jìn)展

1、MRSA肺炎的診治進(jìn)展,,中山大學(xué)孫逸仙紀(jì)念醫(yī)院呼吸內(nèi)科江山平,MRSA肺炎的危險(xiǎn)因素MRSA肺炎的臨床表現(xiàn)與X線特征MRSA肺炎與腎小球腎炎利奈唑胺治療MRSA肺炎的優(yōu)勢(shì),MRSA肺炎的危險(xiǎn)因素,MRSA 肺炎的危險(xiǎn)因素,MRSA定值MRSA感染病史高齡慢性開放性傷口（褥瘡/壓力性潰瘍）入住ICU時(shí)APACHE Ⅱ評(píng)分高存在以下疾病或情況慢性腎臟病糖尿病外周血管疾病心血管疾病惡性腫瘤COPD胸腔積液免

2、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(1

3、1): e79716.,反復(fù)就診于醫(yī)療體系（包括醫(yī)院、長(zhǎng)期護(hù)理、護(hù)士家庭、家庭護(hù)理、血透中心和醫(yī)生辦公室）氣管插管之前使用抗菌藥物治療(DDD)VAP發(fā)生前的機(jī)械通氣時(shí)間手術(shù)侵入性操作（如透析、中心靜脈導(dǎo)管 >24h）注射用藥物使用腸道喂養(yǎng)糖皮質(zhì)激素治療,宿主因素,醫(yī)療保健相關(guān)因素,,,,MRSA肺炎的臨床與X線特征,,MRSA肺炎的基礎(chǔ)疾病及癥狀,Meticillin-resistant Staphylococc

4、us aureus and meticillinsusceptible S. aureus pneumonia: comparison of clinical and thin-section CT findings. The British Journal of Radiology, 2012: 85; e168–e175,,MRSA肺炎的常見影像學(xué)表現(xiàn),Meticillin-resistant Staphylococcus aure

5、us and meticillinsusceptible S. aureus pneumonia: comparison of clinical and thin-section CT findings. The British Journal of Radiology, 2012: 85; e168–e175,,,,,肺氣囊,,,,,金黃色葡萄球菌肺炎X線表現(xiàn)以毛玻璃征最常見。其他依次為支氣管壁增厚、小葉中心結(jié)節(jié)（樹呀征或邊界不清的

6、小結(jié)節(jié)）、實(shí)變、網(wǎng)狀斑塊、支氣管擴(kuò)張、小葉間隔增厚、空洞、結(jié)節(jié)和胸積液。但最特征的影像學(xué)表現(xiàn)為肺氣囊。,Meticillin-resistant Staphylococcus aureus and meticillinsusceptible S. aureus pneumonia: comparison of clinical and thin-section CT findings. The British Journal of R

7、adiology, 2012: 85; e168–e175,,金黃色葡萄球菌肺炎與腎小球腎炎,胸部HRCT,2012-9-25,姓名：劉## 性別：男 年齡：28歲 職業(yè)：無業(yè)入院時(shí)間：2012-9-25 病案號(hào)：697941主訴：反復(fù)發(fā)熱伴腰痛、雙下肢浮腫10日，氣促1天。靜脈藥隱；左右手對(duì)稱部位血培養(yǎng)，支氣管分泌物培養(yǎng)均為金黃色葡萄球菌,治療經(jīng)過,患者入院后（9-25）予無創(chuàng)呼吸機(jī)輔助呼吸， 萬古霉素

8、抗感染治療；患者腎功能進(jìn)行性惡化，尿量進(jìn)行性減少，24小時(shí)尿量100ml，行CRT治療；9-26改氣管插管呼吸機(jī)輔助呼吸，利奈唑胺抗感染治療輸注丙種球蛋白、白蛋白、輸血等支持治療；患者癥狀、血?dú)饧靶貎?nèi)影像學(xué)好轉(zhuǎn)，2012-10-7拔除氣管插管。,利奈唑胺治療前后胸片對(duì)比,2012-10-7,2012-9-25,出院時(shí)情況,神情，低流量吸氧(2L/min)無氣促，少許咳嗽，咳少量白色粘稠痰，無胸痛、腹痛，無惡心、嘔吐，24小時(shí)尿量

9、1120ml；查體：T 37.5℃，P 96次/分，R 17次/分，BP119/77 mmHg，雙肺呼吸音粗，可聞及少量濕性啰音，心率96次/分，律齊，未聞及雜音，腹軟，無壓痛，雙下肢無水腫。輔助檢查：血常規(guī)： WBC 20.24×109/L，NEU 79.3 %，HGB 66 g/L，PLT 205×109/L；生化：AST 38 U/L，ALT 32 U/L，TBIL 11.2 umol/L，ALB 27

10、.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 c

11、ell receptor (TCR). They bind only to Vβ 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 specul

12、ated 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 kidn

13、ey injuries including tubulointerstitial nephritis. The cytokines also cause polyclonal B cell activation that leads to the formation of immunecomplex, resulting in glomerulonephritis . Most cases

14、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 ass

15、ociated with glomerulonephritis have been reported: bacteremia associated with infected ventriculoatrial shunt , bacteremia associated with endocarditis, and glomerular lesion associated with visceral abcesses.

16、 In these cases, the level of complement is low, cryoglobulins are frequent, and the elevated immunoglobulin type is IgG but not IgA.,,,,,,,,,,,,,,,,,,,,金黃色葡萄球菌,腸毒素(超抗原),抗原呈遞細(xì)胞,T 細(xì)胞,細(xì)胞因子,小管間質(zhì)腎炎,過敏性紫癜,B 細(xì)胞,抗體形成,抗原抗體復(fù)合物,腎

17、小球腎炎,ANCA,血管炎,細(xì)胞膜抗原,腎小球基底膜,贅生物脫落,血流感染,腹主動(dòng)脈營(yíng)養(yǎng)血管受累,腎動(dòng)脈栓塞,腎實(shí)質(zhì)膿腫,壞死性動(dòng)脈炎,腎功能受損,假性主動(dòng)脈瘤,腎動(dòng)脈受累,IgA腎病,,,,,金黃色葡萄球菌肺炎的臨床表現(xiàn)復(fù)雜多樣，可以通過多種機(jī)制導(dǎo)致急性腎功能受損。對(duì)此，臨床醫(yī)生必須予以高度重視。,,利奈唑胺治療MRSA肺炎的優(yōu)勢(shì),利奈唑胺與萬古霉素在粒缺伴發(fā)熱腫瘤患者中療效和安全性：隨機(jī)、雙盲&對(duì)照實(shí)驗(yàn),一個(gè)新研究,Eff

18、icacy and Safety of Linezolid Compared with Vancomycin in a Randomized, Double-Blind Study of Febrile Neutropenic Patients with CancerClinical Infectious Diseases 2006; 42:597–607 2006 by the Infectious Diseases Societ

19、y of America. All rights reserved.1058-4838/2006/4205-0003$15.00,2000年4月18日：FDA批準(zhǔn)利奈唑胺上市,,隨機(jī)、雙盲、多中心研究，共入組611例病人,,粒缺伴發(fā)熱患者中利奈唑胺組較萬古霉素組退熱更快,ME微生物可評(píng)估組,MITT修正意向治療組,P=0.04,P=0.01,,,萬古霉素,利奈唑胺,單位：天,Efficacy and Safety of Lin

20、ezolid Compared with Vancomycin in a Randomized, Double-Blind Study of Febrile Neutropenic Patients with CancerClinical Infectious Diseases 2006; 42:597–607 2006 by the Infectious Diseases Society of America. All right

21、s reserved. 1058-4838/2006/4205-0003$15.00,Yoshizawa S, et al. Antimicrob Agents Chemother, 2012; 56(4):1744-1748.,臨床回顧性分析結(jié)果： 28例發(fā)熱患者中64%在3天內(nèi)退熱，退熱中位時(shí)間為3天； MRSA培養(yǎng)轉(zhuǎn)陰中位時(shí)間為8天。,日本： 利奈唑胺治療MRSA膿毒癥可早期退熱,日本：利奈唑胺治療MRSA膿毒癥可早期退熱,

22、,,,,,,,,,,利奈唑胺對(duì)MRSA的毒性抑制作用 可能是其治療MRSA感染早期退熱的原因,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：

23、比較利奈唑胺與萬古霉素的抗菌作用,實(shí)驗(yàn)設(shè)計(jì),實(shí)驗(yàn)結(jié)果,MRSA感染后2小時(shí)及6小時(shí)時(shí)肺內(nèi)細(xì)菌數(shù)在LZD組和VCM組間無差異。,動(dòng)物實(shí)驗(yàn),Yoshizawa S, et al. Antimicrob Agents Chemother, 2012; 56(4):1744-1748.,第二步：證實(shí)利奈唑胺抑制MRSA肺炎細(xì)胞因子的產(chǎn)生,實(shí)驗(yàn)設(shè)計(jì),實(shí)驗(yàn)結(jié)果,動(dòng)物實(shí)驗(yàn),,,第三步：證實(shí)利奈唑胺抑制MRSA肺炎細(xì)胞因子產(chǎn)生的作用呈量效相關(guān),Yosh

24、izawa S, et al. Antimicrob Agents Chemother, 2012; 56(4):1744-1748.,第三步：證實(shí)利奈唑胺抑制MRSA肺炎細(xì)胞因子產(chǎn)生的作用呈量效相關(guān),實(shí)驗(yàn)結(jié)果：不同組別TNF-α 、IL-6水平比較,利奈唑胺顯著抑制MRSA肺部感染后TNF-α和 IL-6產(chǎn)生，且呈現(xiàn)劑量依賴性（* P ＜0.01， ◆ P ＜0.05）； 不同治療組間肺內(nèi)細(xì)菌數(shù)無顯著性差異。,動(dòng)物實(shí)驗(yàn),Yoshiz

25、awa S, et al. Antimicrob Agents Chemother, 2012; 56(4):1744-1748.,第三步：證實(shí)利奈唑胺抑制MRSA肺炎細(xì)胞因子產(chǎn)生的作用呈量效相關(guān),,,,,,動(dòng)物實(shí)驗(yàn),Yoshizawa S, et al. Antimicrob Agents Chemother, 2012; 56(4):1744-1748.,第四步：證實(shí)Sub-MICs利奈唑胺抑制MRSA產(chǎn)生毒素,動(dòng)物實(shí)驗(yàn),Yoshi

26、zawa S, et al. Antimicrob Agents Chemother, 2012; 56(4):1744-1748.,第四步：證實(shí)Sub-MICs利奈唑胺抑制MRSA產(chǎn)生毒素,實(shí)驗(yàn)設(shè)計(jì),* 利奈唑胺MIC：2mg/L；0.5MIC=1μg/ml，0.25MIC=0.5μg/ml，0.125MIC=0.25μg/ml；* 進(jìn)行細(xì)胞因子檢測(cè)。,動(dòng)物實(shí)驗(yàn),Yoshizawa S, et al. Antimicrob Agen

27、ts Chemother, 2012; 56(4):1744-1748.,第四步：證實(shí)Sub-MICs利奈唑胺抑制MRSA產(chǎn)生毒素,實(shí)驗(yàn)結(jié)果,亞抑菌濃度利奈唑胺能明顯抑制MRSA產(chǎn)生的IL-6，而感染前予以利奈唑胺并不未抑制IL-6的產(chǎn)生（* P ＜0.05， ◆ P ＜0.01） ； 0.5μg/ml（1/4MIC）組、0.25μg/ml （1/8MIC）組與對(duì)照組在細(xì)菌數(shù)量上無統(tǒng)計(jì)學(xué)差異。,動(dòng)物實(shí)驗(yàn),研究重要推論,The imm

28、unoregulatory 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 sug

29、gest 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

30、 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. An

31、timicrob Agents Chemother, 2012; 56(4):1744-1748.,利奈唑胺有抗感染和免疫調(diào)節(jié)作用，對(duì)感染部位的局部破壞性炎癥反應(yīng)有保護(hù)作用。利奈唑胺治療MRSA感染的早期退熱作用可能與其抑制MRSA毒性因子的產(chǎn)生有關(guān),,利奈唑胺減輕MRSA肺炎中性粒細(xì)胞介導(dǎo)的炎癥反應(yīng)同時(shí)避免相關(guān)肺損傷 背景：利奈唑胺除了直接抗細(xì)菌作用外，還具有抑制毒素產(chǎn)生及毒力因子表達(dá)的額外效應(yīng)。 目的：評(píng)價(jià)抗球菌藥物對(duì)MR

32、SA感染的療效以及免疫相關(guān)肺損傷情況。,Jacqueline C, et al. J Infect Dis. 2014;210(5):814-23.,Jacqueline C, et al. J Infect Dis. 2014;210(5):814-23.,實(shí)驗(yàn)設(shè)計(jì),* 取材后測(cè)定炎癥因子TNF- α、IL-1β、MIP-2及MPO活性，并進(jìn)行組織學(xué)和免疫組化分析。,Jacqueline C, et al. J I

33、nfect Dis. 2014;210(5):814-23.,實(shí)驗(yàn)結(jié)果,Jacqueline C, et al. J Infect Dis. 2014;210(5):814-23.,實(shí)驗(yàn)結(jié)果,與對(duì)照組及萬古霉素組相比，利奈唑胺組在MRSA感染8小時(shí)后TNF- α水平顯著降低（ * P ＜0.05 ）。,*,Jacqueline C, et al. J Infect Dis. 2014;210(5):814-

34、23.,實(shí)驗(yàn)結(jié)果：利奈唑胺有效減輕MRSA所致肺損傷,不同組別MPO活性比較（sham 未感染未治療；*P < .001； **P < .05 ）,與對(duì)照組及萬古霉素組相比，利奈唑胺組在MRSA感染8小時(shí)、48小時(shí)后MPO活性顯著下降； 相應(yīng)的，MRSA感染8小時(shí)后利奈唑胺組小鼠肺組織病理顯示中性粒細(xì)胞浸潤(rùn)減少，提示免疫相關(guān)肺損傷減輕。,Jacqueline C, et al. J Infect Dis. 20

35、14;210(5):814-23.,實(shí)驗(yàn)結(jié)果：利奈唑胺有效減輕MRSA所致肺損傷,,,Jacqueline C, et al. J Infect Dis. 2014;210(5):814-23.,利奈唑胺抑制體內(nèi)葡萄球菌毒素的產(chǎn)生并且改善兔子模型中壞死性MRSA肺炎的生存率,一個(gè)新研究,The Journal of Infectious Diseases 2013;208:75–82© The Author 20

36、13. Published by Oxford University Press on behalf of the Infectious Diseases Society of America,新西蘭大耳白兔麻醉后菌液通過兒科氣管內(nèi)導(dǎo)管直接注射1.5mL含SF8300接種液入肺部（主支氣管上部1cm）。感染的兔子被隨機(jī)分為三組：未治療對(duì)照組、萬古霉素組、利奈唑胺組。在接種1.5、4、9小時(shí)后分別開始抗生素治療。每3小時(shí)監(jiān)測(cè)一

37、次。存活下來的兔子36小時(shí)后安樂死。肺取出后切成<0.5-cm 的塊。三塊肺在生理鹽水中混合均勻，通過分層的血瓊脂平板確定菌量。,,,,,,早期應(yīng)用利奈唑胺治療顯著提高M(jìn)RSA感染的生存率,**P<0.01***P<0.001,Effects of Linezolid on Suppressing In Vivo Production of Staphylococcal Toxins and Improving Su

38、rvival 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小時(shí),4小時(shí),1.5小時(shí),,,Vonco,linezolid,死亡率,,,利奈唑胺組存活率和存活時(shí)間顯著提升,百分比,感染1.

39、5小時(shí)后, 早期階段：在發(fā)生急性肺損傷和肺部炎癥之前。 感染4 小時(shí)后，中間階段：發(fā)生了顯著的肺水腫和炎癥反應(yīng)。 感染9小時(shí)后，終末階段：大量的細(xì)胞因子釋放，中性粒細(xì)胞涌入， 肺部水腫，肺泡出血并且重度的肺壞死已經(jīng)開始發(fā)生。,利奈唑胺提高生存率的作用與其抗菌作用無關(guān),,**P<0.01,雖然與未治療組相比利奈唑胺組的細(xì)菌計(jì)數(shù)顯著降低，但與萬古霉素治療組相比卻沒有顯著差異。提示

40、利奈唑胺治療后生存率提高與其抗菌作用無關(guān)。,*P＜0.05,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 P

41、neumonia. Diep BA, et al.J Infect Dis. 2013 Jul;208(1):75-82.,利奈唑胺可明顯降低肺PVL、HLA和IL-8,*P<0.05**P<0.01,Effects of Linezolid on Suppressing In Vivo Production of Staphylococcal Toxins and Improving Survival Outcomes

42、in a Rabbit Model of Methicillin-Resistant Staphylococcus aureus Necrotizing Pneumonia. Diep BA, et al.J Infect Dis. 2013 Jul;208(1):75-82.,,,,抗生素的臨床療效不僅取決于對(duì)應(yīng)的殺菌或抑菌效果，也可能與細(xì)菌毒性因子的抑制有關(guān)。利奈唑胺可顯著降低細(xì)菌毒素分泌，從而調(diào)節(jié)機(jī)體免疫應(yīng)答，減少繼發(fā)性炎癥損傷，