上海交通大学医学院新华儿童儿童医学中心儿科学之CAMRSA0910.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),Wang H et al. Diagn Microbiol Infect Dis 2008;62:226-9.,Prevalence of

4、 MRSA in China,798 isolates, 2005, 12 Cities, China,CHINET 2007, China MRSA 58% (1963/3384),MRSA,MRSA infections in hospitals from 127,000 in 1999 to 278,000 in 2005 annual deaths increased from 11,000 to more than 17,000 at the same time MRSA responsible for 94,360 serious infections and associated

5、 with 18,650 hospital stay-related deaths in the United States in 2005,Emerg Infect Dis. (2007). 13 (12): 18406. JAMA, 2007, Oct, 298: 1803,MRSA deaths AIDS in the U.S. each year,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 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M

6、RSA（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和37.3 1.3的社区人群有MRSA定殖,CA-MRSA,2001 - 2002 surveillan

7、ce 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 Post. Retrieved on 2007-10-19,Community-acquired MRSA

8、 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

9、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 lesions are also a common presentation and are often i

10、ncorrectly 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Necrotizing fasciitis USA300, SCCmec IV 危险因素: pre MRSA, Hep

11、 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 previously healthy children in whom episodes of bac

12、terial 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 pneumonia) 15 cases of MRSA CAP from 9 states (CDC),

13、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 S aureus infection in children were reported, 2 CA-

14、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, sinusitis, 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

15、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-

16、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 analysis of fragments of seven S. aureus housekeeping

17、 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 disadvantages that it is expensive, laborious and time

18、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) But two different nomenclature systems,金黄色葡萄球菌蛋白A

19、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 presence of the different ccr genes a multiplex PCR assay

20、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MRSA有 4090%携带PVL基因,而SCCmec IIII 型MRSA则5% 与CA-MRSA感染严重程度

21、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M