革兰阳性球菌耐药与治疗课件

革兰阳性球菌耐药与治疗,倪语星 上海交通大学医学院 附属瑞金医院,MDR细菌已成为全球关注的焦点,在全球范围内，“ESKAPE”耐药已成为导致患者发病及死亡的重要原因1,“ESKAPE”耐药现象日益严重，但当前新型抗菌药物的研发逐渐减缓，未来可能面临无药可用的局面3,新药数量,1983-1987,1988-1992,1993-1997,1998-2002,2003-2007,1. Rice LB et al. The Journal of Infectious Diseases 2008; 197:107981 2. http:/www.who.int/world-health-day/zh/ 3. Boucher HW et al. Clinical Infectious Diseases 2009; 48:112,我国主要的MDR致病菌,我国，“ESKAPE”耐药菌株检出率高,检出率(%),产ESBL大肠埃希菌,MRSA,产ESBL肺炎克雷伯菌属,不动杆菌属*,铜绿假单胞菌*,耐万古霉素屎肠球菌,*在G-菌中的检出率,朱德妹等.中国感染与化疗杂志.2011;11(5):321-329,13967株,5380株,431株,1733株,1623株,汪复, 等. 中国感染与化疗杂志. 2010;10(5):325-334.,各类标本中的主要病原菌？,血培养排名前10位的临床致病菌,一、药敏监测数据,R.N. Jones et al. Diagnostic Microbiology and Infectious Disease. 2009;64:191201.,ZAAPS监测项目简介,R.N. Jones et al. Diagnostic Microbiology and Infectious Disease. 2009;64:191201.,近6年ZAAPS监测共分离到G+菌34170株,不同国家MRSA耐药率,加拿大：55.7% 拉丁美洲：平均为50.1%(29.0% - 64.1%) 欧洲：平均为28.2%(1.7% - 56.2%) 亚太地区：平均为44.2%(25.3% - 68.0%),R.N. Jones et al. Diagnostic Microbiology and Infectious Disease. 2009;64:191201.,常用抗菌药物对金黄色葡萄球菌抗菌活性,R.N. Jones et al. Diagnostic Microbiology and Infectious Disease. 2009;64:191201.,2007年ZAAPS项目对3000株金黄色葡萄球菌药敏监测结果,常用抗菌药物对CoNS的抗菌活性,R.N. Jones et al. Diagnostic Microbiology and Infectious Disease. 2009;64:191201.,2007年ZAAPS项目对716株CoNS药敏监测结果,2008年CHINET监测网各医院金葡菌MR菌株检出率,2008年CHINET监测网各医院凝固酶(-)葡萄球菌MR菌株检出率,MSSA(1495株)与MRSA(1916株)的耐药率（%）,MRSA的耐药率MSSA 仍有75，67菌株对SMZ/TMP、磷霉素敏感 MSSA对内酰胺类、氟喹诺酮类、 SMZ/TMP、利福平、磷霉素的耐药率10 无万古、替考拉宁、利奈唑胺耐药株,MSCNS(555株)和MRCNS(1723株)的耐药率（%）,MRCNS的耐药率MSCNS MRCNS耐药率MRSA，但仍有约90、65菌株对利福平、磷霉素敏感。 无万古、替考拉宁、利奈唑胺耐药株,2006-2010年监测数据 耐万古霉素的粪肠球菌与屎肠球菌发生率极少,汪复. 2006年中国CHINET细菌耐药性监测. 中国感染与化疗杂志 2008; 8(1):1-9. 汪复等. 2007年中国CHINET细菌耐药性监测. 中国感染与化疗杂志 2008; 8(5):325-333. 肖永红等. 2006-2007年Mohnarin细菌耐药检测. 中华医院感染学杂志 2008; 18(8):1051-1056. 汪复等. 2008年中国CHINET细菌耐药性监测. 中国感染与化疗杂志 2009; 9(5):321-329. 汪复等. 2009年中国CHINET细菌耐药性监测. 中国感染与化疗杂志 2010; 10(5):325-334. 朱德妹, 汪复, 胡付品等. 2010年中国CHINET细菌耐药性监测. 中国感染与化疗杂志 2011; 11(5):321-329.,二、S. aureus and MRSA,Methicillin resistant S. aureus Presence of a mecA gene Carried in a mobile genetic element (SCCmec) Most routine testing antibiotic sensitivity (MRSA id agar),CLSI药敏指南,“金黄色葡萄球菌或所有凝固酶阴性葡萄球菌 如对苯唑西林(或甲氧西林)耐药，则对青霉素类、 头孢菌素类、碳青霉烯类和含酶抑制剂的复方制剂 均应报告耐药，而不考虑其体外药敏结果”。,Cefoxitin Disk Test for mecA-mediated Resistance in Staphylococci Breakpoints (mm),* Report as oxacillin resistant * Report as oxacillin susceptible CoNS, coagulase-negative staphylococci,OX-R=mecA=MRSA?,Discovery of the new MRSA strains (LGA251),We found S. aureus that were highly resistant on one farm (ST425) (Oxacilin MIC=16mg/l, cefoxitin MIC=32mg/l) Looked for mecA gene negative results Sequenced whole genome to look for the reason Found a divergent mecA gene inside a new SCCmec,Importance of the new MRSA,Molecular tests (PCR & slide agglutination test) designed to detect MRSA give a negative result when tested on the new strain The new MRSA is moving between people and cattle Old MRSA was not found in dairy cows Divergent MRSA is found in S. aureus strains thought to be restricted to animals Geographical clustering of human and cow strains of the new MRSA Divergent MRSA mecA gene has not been found in human strains Isolations of divergent MRSA appear to be increasing,New MRSA isolates by year,三、对糖肽类的耐药机制,VRSA,vanA gene positive Change of D-alanyl-D-alanyl-D-lactate 1000 fold decrease in affinity to vancomycin Typical MIC16mg/L to vancomycin,VRSA,USA 12 cases http:/www.cdc.gov/HAI/settings/lab/vrsa_lab_search_containment.html First discovered in 2002 8 from Michigan! 2 most reccent from Delaware (2010) Iran - 1 case THE-2, 2005 India 6 cases From intensive care units in 2 tertiary hospitals in Hydrabad - 2008,VISA isolates,Not a single mutation or acquisition of a single gene Complex! Involves a series of changes! Increased cell wall thickening, increased number of free D-alanyl-D-alanin residues, reduced autolytic activity, mutations in regulators of cell wall synthesis (i.e. graRS, vraSR), change in transcription profile Typical MIC 4-8mg/L,hVISA,isolates susceptible by standard MIC testing but have subpopulations expressing reduced susceptibility Same types of resistance mechanisms as VISA isolates Typical MIC 1-2mg/L,Population profile of initial isolate (6000) and after persistant bacteremia / vancomycin therapy (6001),Howden, AAC, 2006,Prevalence of VISA/hVISA,Highly variable prevalences are reported in the literature including within countries Illustrated by data from Australia Melbourne (Austin) 117 MRSA VISA 2 isolates (2%) Sydney 401 MRSA BSI hVISA 46 (11.5%) (almost all ST239) VISA 2 (0.5%) Australia general 532 SAB / 202 MRSA hVISA 2 isolates 0.4% / 1% VISA 0 isolates,Horne AAC, 2009. Val Hal, Plosone. Homes, JID 2011.,Summary,The prevalence of VRSA and VISA isolates are still low in most part of the world The prevalance of hVISA varies in general relatively low but can locally be up 50% of MRSA isolates There are increasing evidence that strains with MIC1mg/L are associated with poo