上海交通大学医学院新华儿童儿童医学中心儿科学之CA-MRSA-09.10.ppt

1、MRSA感染趋势和治疗进展,上海市儿童医院 上海交通大学附属儿童医院 呼吸科 陆敏,上海市儿童医院,Shanghai Childrens,STAPHYLOCOCCUS staphyle - a bunch of grapes kokkus - berry,金黄色葡萄球菌Staphylococcus Aureus,1928 所有葡萄球菌对青霉素敏感 1942 首次从病人分离耐青霉素的葡萄球菌 1950s医院内耐青霉素葡萄球菌大流行 头孢霉素、红霉素、万古霉素 1960 甲氧西林 耐青霉素酶 1961 首次在伦敦出现MRSA,金黄色葡萄球菌耐药,Methicillin-resistant Stap

2、hylococcus aureus (MRSA),difficult-to-treat infections multidrug-resistant SA or oxacillin-resistant SA (ORSA) resistant to a large group of antibiotics called the beta-lactams penicillins cephalosporins,Europe MRSA 28% VRE (E. faecium) 8 (22)% SP/penicillin 15%,Jones, RN. Personal Communications, F

3、ebruary 2008,United States MRSA 54% VRE (E.faecium) 27 (72)% SP/penicillin 15%,Asia Pacific MRSA 42% VRE (E. faecium) 5 (10)% SP/penicillin 32%,Latin America MRSA 38% VRE (E. faecium) 9 (36)% SP/penicillin 13%,G+全球耐药状况 （2005-2006),80年代初，首次报道从静脉吸毒者或经常接触护理机构的高危人群种分离出MRSA 80年代后期，首次报道从经常接触护理所的儿童中分离到MRSA

4、 1990s中期，芝加哥大学报道住院病人MRSA增加25倍 1999年报道4例儿童死于致死性社区获得性MRSA（CA-MRSA）感染，这些儿童并无MRSA易感因素,CA-MRSA出现,美国CDC将CA-MRSA 定义： 门诊或住院后48小时内分离到MRSA菌株 一年内无养老院、护理院或医院住院史， 无透析或手术史、无永久性经皮留置体内的导管或医疗装置， 无MRSA感染史和定殖史的患者，,CA-MRSA定义,多中心监测显示：社区获得MRSA为12 美国郊区74MRSA感染是社区获得的，提示在这一地区MRSA已取代了MSSA mata分析显示：总CA-MRSA发生率分别占住院MRSA病人的30.2

5、和37.3 1.3的社区人群有MRSA定殖,CA-MRSA,2001 - 2002 surveillance in US,1647 CA-MRSA infection 8-20% were not associated with traditional risk factors - CA-MRSA Most were associated with clinically relevant infections that required treatment Many patients were children who required hospitalization,Washington P

6、ost. Retrieved on 2007-10-19,Community-acquired MRSA in Asia,ANSORP Surveillance in Asia-2005-6,%,部分亚洲国家MRSA发病率高于西方国家,占院内金黄色葡萄球菌标本的70 台湾北部儿童CA-MRSA占CA-SA感染的74。新加坡CA-MRSA非常少见 我国MRSA占SA的60以上 上海儿童CA-MRSA占MRSA 17%，占SA1%,CA-MRSA,CA-MRSA引起皮肤和软组织感染、肺炎、中耳炎、败血症和尿路感染 传统使用头孢菌素治疗社区获得性皮肤和软组织感染可能会失败，导致致死性感染 体外敏感试

7、验显示：CA-MRSA通常耐内酰胺类抗生素，但对其他抗生素敏感，而多数HA-MRSA对多种抗生素耐药 致死性感染的CA-MRSA含有Panlon-Valentine 基因（pvl）和肠毒素C和H基因（sec和seh）,CA-MRSA特征,CA-MRSA: What it does,CA-MRSA：比MSSA引起更深、更侵袭性 感染，尤其是坏死性肺炎 CA-MRSA：比MSSA更多坏死性筋膜炎 CA-MRSA：引起菌血症并不很多 CA-MRSA：更多引起反复感染,皮肤软组织感染 SSTIs,80% of CA-MRSA infections are SSTIs, Necrotic skin le

8、sions are also a common presentation and are often incorrectly attributed to bites by brown recluse spiders or other insects. Generally, CA-MRSA SSTIs are not life-threatening invasive infection (eg, bacteremia, necrotizing fasciitis) can become difficult to treat and even cause death.,坏死性筋膜炎Necroti

9、zing fasciitis USA300, SCCmec IV 危险因素: pre MRSA, Hep C virus infection, diabetes, current or past injection drug use, cancer, and HIV,皮肤软组织感染 SSTIs,CA-MRSA,7天婴儿，激惹和迅速增多皮疹,CA-MRSA,MRSA坏死性筋膜炎,MRSA坏死性筋膜炎,蜂窝织炎（短箭） 脂膜炎 （长箭） 筋膜炎（箭头） 革兰氏阳性球菌,植皮后2周,MRSA坏死性筋膜炎,常见于热带地区，温带地区也有增加，尤其HIV CA-MRSA 可能成为化脓性肌炎常见的病原 45

10、 previously healthy children in whom episodes of bacterial myositis or pyomyositis occurred, 26 of these children (57.8%) - SA 15 of these patients (57.7%) - CA-MRSA,化脓性肌炎 Pyomyositis.,MRSA Osteomyelitis,Necrotizing pneumonia (CAP),Postinfluenza virus infection Influenzalike illness (Postinfluenza p

11、neumonia) 15 cases of MRSA CAP from 9 states (CDC), 2003-2004 influenza season 4 deaths (fatality rate, 26.7%) 10 severe MRSA CAP, 6 deaths (fatality rate, 60%) 2006.12-2007.1,MRSA 肺炎,MRSA 肺炎后期,MRSA 肺炎后期,脓毒症 Sepsis,With or without Waterhouse-Friderichsen syndrome in 2005, 3 fatal cases attributed to

12、 S aureus infection in children were reported, 2 CA-MRSA 14 previously healthy children presented with severe sepsis, 12 had CA-MRSA sepsis,Other manifestations,Suppurative lymphadenitis, ophthalmic infections (preseptal cellulitis, lid abscess, conjunctivitis, corneal ulcers） otitis media, sinusiti

13、s, food-borne GI illness,分子生物学特征,SA对甲氧西林耐药是由于低亲和力青霉素结合蛋白（PBP2a 或PBP2） 编码PBP2a的mecA基因位于其调节基因mecI和mecR以及ccr元件组成的葡萄球菌染色体盒(SCCmec) 7种SCCmec（）基因型。 SCCmec、型中mecA复合体下游带有多个质粒和转座子，携带多种耐药基因，可产生多重耐药 SCCmec和SCCmec型基因盒中除mecA外不带任何其他耐药基因故仅对内酰胺类抗生素耐药，多见于CA-MRSA,所有MRSA含SCCmec 携带的mecA基因 mecA基因编码78 kDa 低亲和力PBP2 MRSA 7

14、种主要流行株大量地域性传播 SCCmec-(HA-MRSA) 伴其他耐药元件耐多药 SCCmec(CA-MRSA) 不伴其他耐药元件小而容易水平转移,SCCmec,SCCmec,Genetics and Evolution 8 (2008) 747763, ,Typing methods for S. aureus,Pulsed-field gel electrophoresis (PFGE) Multilocus sequence typing (MLST) spa typing SCCmec typing,Multilocus sequence typing MLST,Sequence a

15、nalysis of fragments of seven S. aureus housekeeping genes arcC, aroE, glpF, gmk, pta, tpi and yqiL An allelic profile of the 7 genes define the S. aureus lineage - sequence type (ST) The putative ancestor of a CC is the ST with the largest number of single locus variants (SLVs) In general, MLST dis

16、advantages that it is expensive, laborious and time consuming.,Typing of the spa locus,Single-locus sequence typing technique has become increasingly popular Determines the sequence variation of the polymorphic region X of the S. aureus protein A (spa) locus StaphType (Ridom GmbH, Wu rzburg, Germany

17、) But two different nomenclature systems,金黄色葡萄球菌蛋白A spa,葡萄球菌蛋白A是金黄色葡萄球菌细胞壁的一个组成部分，编码蛋白A的基因Spa有3个不同区域（Fc结合区、X区和C末端） X区215个重复序列，其数目、特征和排列顺序具有高度多态性，同时具有良好的重复性和稳定性，因此可用于对不同菌株分型,CA-MRSA,SCCmec typing,Multiplex PCR assay mecA and different loci on SCCmec I to IV structure of the mec complex and the presen

18、ce of the different ccr genes a multiplex PCR assay that is based on the amplification of six specific loci within the J1 region of SCCmec type IV variants,PantonValentine leukocidin PVL,PantonValentine leukocidin （PVL）是一种由lukS-PV和lukF-PV基因编码的具有破坏白细胞和介导组织坏死的微孔形成毒素（pore-forming toxin） 通常SCCmec IV型MRS

19、A有 4090%携带PVL基因,而SCCmec IIII 型MRSA则5% 与CA-MRSA感染严重程度和社区的传播有关。可引起健康儿童和年轻人皮肤和软组织感染以及坏死性肺炎,Panton-Valentine leukocidin(PVL),Boyle-Vavra and Daum. Lab Invest 2007,Survival of S. aureus PneumoniaCorrelation with Panton-Valentine Leukocidin (PVL) Gene,Rubinstein E et al. Clin Infect Dis 2008;46:S375-85.,CA-MRSA与HA-MRSA特征,CA-MRSA诊断,培养：对于所有疑似葡萄球菌感染都很重要，因为许多还是MSSA 敏感试验：自动，D试验 快速试验（已经培养的微生物）：被覆PBP2a单抗的乳胶颗粒 PCR：检测mecA甲氧西林耐药基因,CA-MRSA：治疗,治疗策略： 严重MRSA感染如菌血症和肺炎等需要尽早和恰当的初始经验治疗 4872小时后根据病原学诊断结果和临床治疗反应进行评估