大动脉炎图文课件_1

耐药机理及治疗,Staphylococcus aureus 刘肇杰主任医师,Staphylococcus aureus,Staphylococcus aureus is a highly succeeful opportunistic pathogen. It is a frequent colonizer of the skin and mucosa of humans and animals (it is present in the anterior nares of up to 30% of the healthy human population) and can produce a wide variety of diseases.,These diseases encompass relatively benign skin infectons,such as folliculitis and furunculosis,and life-threateninconditions, including enysipelas, deep-seated abscesses, osteomyelitis, pneumonice,sepsis, and endocarditis,In addition to infections in which the organism is physically present at the infected site , S.aureus is also capable of producing “distant”disease , which are mediated by the secretion of toxins,这些疾病包括相对良性的皮肤感染，如毛囊炎、疖,The toxins can be produced directly by bacteria that colonize the skin or mucosa or indirectly by microorganisms that colonize food or beverages=drink . The former is exemplified by staphylococcal scalded skin Syndrome(SSSS) ,which is the result of mucsal or wound colonization by S.aureus-producing exfoliative toxin A or B (ETA or ETB) and by staphylococcal toxic shock syndrome (TSS), which is the result of the production of toxic shock syndrome toxin I(TSST1) or exotoxinB or C.,The later is exemplified by S. aureus food intoxication , in?hick the toxin is ingested with the contaminated dish and disease follows shortly thereafter in the form of vomiting and diarrhea . Food intoxication are heat stable . Cooking may kill the contaminants but dose not denaturate the toxins .,Definition: .Gram-possitive pathogen responsible for superficial and deep-seated infections. .frequent colonizer of asymptomatic carriers. .responsible for both pyogenic and taxin-related diseases .Primary cause of community-and hospital acquired bloodstream infections .First cause of invasive infections, including infective endocarditis and osteomyelitis .First cause of invasive infections , including infective endocarditi osteomyelitisserre,.Frequently resistant to methicillin (MRSA) and all -Lactam drugs (in up to 50% of hospital isolates) .often co-resistant to many clinically available antibiotics,Epidemiology:,.Colonizer of an anterior nostrils in 20% to 40% of the normal population .Human one public health problem in drug resistant nosocomial infections .Clonal spread of MRSA from health care(HA-MRSA) and other permissive enviroments .Superantigne producer responsible for toxic shock syndrome and food poisoning microbiology .Most virulent species of more than 40 staphylococcus spp.taxa .Conserred core genome of approximately 2.8 million bp.,.Multiple mobile genetic elements (MGEs) ：pathogenic and genomic islands ,transposans ,and prophages endcoding virulence and antibiotic-resistance genes .Evolution of successful dones via mutations and acquisition of MGEs .Methicillin resistant conferred by a polymorph family of SCC mer cassettes,Therapy,.First choice:ponicillinasse-resistant Lactams . Vancomycin and daptomycin .alternatives:clindamycin . trimethoprimsulfamethoxazole , Linezolid and newer quinolones .Partner drug for combinations :rifampin .Benefie of aminoglycosides not well demonstrated,本菌是毒性强的细菌，产生多种毒素 Staphylococcal enrerotoxins SEs 从A-E，可产生呕吐，腹泻 ， hemolysin 可破坏免疫细胞 PVL Panton-Valentine lenkocidin 杀白细胞毒素，可破坏白细胞 Exfoliative toxin 表皮剥脱毒素，可导致新生儿剥脱性皮炎，葡萄球菌性皮肤剥脱症。SSSS等。 超抗原：引起DIC MOF TSS 等,MRSA:定义,有mecA 基因的S.aureus and/or Oxacillin 的MIC4ug/ml SCCmec,MRSA contains one resistance island called staphylococcal cassette chromosome (SCC 金黄色葡萄球菌盒式染色体)mec,where mec is the genetic element that confers resistance to methicillin. 故含有SCCmec基因即可获得对甲氧苯青霉素耐药.mecA(在mec中的一种)可编码对-Lactams亲和性低的PBP2导致耐药。,SCCmec 目前发现有-，HA-MRSA(hospital-acquired MRSA)多为-型。CA-MRSA(Community-acquired MRSA)多为IV-V型。故HA-MRSA为高度耐药，CA-MRSA，对内酰胺外抗生素敏感。,Vancomycin.作用机理，属糖肽类抗生素是MRSA第一线药物，通过与菌体细胞壁上murein mononer 末端的Acyl-D-Ala-D-Ala结合，阻止细胞壁合成。 杀菌：要考虑：A loading dose of 25-30mg/kg must be considered.肾功能损害 二、Tigecycline and Ouinupristin-dalfopristin (喹效普丁-达福普汀) 替加环素属四环素家族，喹效普丁-达福普汀是链霉杀阳毒素A和B的混合物。,三、替考拉宁与万古是一类，目前发现它与-Lactams合用有很好前景。 四、ABK，氨基糖甙类，阻止细菌蛋白质合成，在抗MRSA药中与达托霉素一样具有强力短时间杀菌药。对有峰热样的MRSA败血症最合适。与 -Lactams有相加作用。 五、LID，该药与23核糖体V区结合，阻止细菌生长，肺炎疗效好。,六、Daptomycin,它独特的杀菌作用，它与Ca结合后形成Ca-达托霉素混合体，通过细胞膜把Ca排出体外，杀死细菌，这个杀菌最大特征是对静止期细菌也有作用，几乎所有抗生素是作用在增殖期，那么处于静止期可形成生物膜（心内膜炎、骨髓炎、导管感染等），以及处于厌氧状态的细菌也可杀灭。因Daptomycin结合在磷脂，故也可结合到肺泡表面活性物质，可在肺泡上失活不能用于肺炎。其他部位感染特别是无肾损害，它用于除肺感染外，肾功能低者的感染。 七、minocycline,rifampin.ST Rifampin易出现耐药，为抑制叶酸合成同时应用sulfamethoxazole-trimethoprim。故rifampin+Smzco.,Streptococcus pneumonia,Long recognized for causing asymptomatic colonization and as a prominent cause of pneumonia ,bacteremia ,meningitis ,sinusitis,and otitis media,Streplococcus pneumonia is likely the most common woldwide cause of serious bacterial respiratory infection in both children and asults,Antimicrobials and vaccines have substantially reduced the of ,and morbid outcomes from ,pneu-mococcal infection,but acquisition of amtibiotic resistance and the more limited impact of vaccines on mucosal disease,including pneumonia and otitis media as well as the emergence of nonvaccine serotypes,provide challenges for ongoing control of this prevalent and invasive pathogen.,History:,Streptococcus pneumonide has played a prominent role in the history of microbiology,Identified concurrently in 1881 in France by Pasteur and in the United States by Sternberg ,this bacterium was soon recognized as the most common cause of obor pneumonia and became known as the pneumococcus,.Based on its apperance in Gram-stained suptum ,the name Diplococcus pneumoniae was assigned in 1926 and finally streptococcus pneumoniae in 1974,based on its morphology during growth in liquid medium .,.Pneumo coccal infections were among the first to be treated with an antimicrobial agent,in this case optochin (奥普脱欣，ethyldrocupreine 乙基氢化卟啉)，a quinine derivative.The organism was dso the first to develop resistance to such therapy,resulting in failure of treatment both in experimental ymillions of animals and in humans.,These findings were premonitory for the remarksble resilience of bacteria ,and S,pneumeniae in particular ,that have evolved and adapted over many millions of years to subvert our efforts to contral and eradicatr them with antimicrobiols and vcccines developed in the last 100 year.,Microbiology：,S.pneumoniae is a gram-positive coccus that replicates in chains in liquid medium ,but appears as lancet - shaped diplococci in clinical specimans .The organism is catalase negative ,but generates hydrogen peroxide (H2O2) via a flavoenzyme system and therefore grows better in the presence of a source of the pneumococcal cell wall. More than 95 serotypes of S.pneumonae have been identified on the baasis of an tigenic difference in their caosular polysaccharides.,Epidemiology:,Penicillin A moxicilli Cetriaxone cetotaxime The spectrum of pneumococcal infections can range from asymptomatic colonization to mucosal disease (otitis media,sinusitis,pneumoniae )to invasive infections. Clinical syndromes: Otitis Media 2.Sinusitis 3.Meningitis 4.Acute exacerbation of chronic Bronchitis 5.pneumoniae 6.conplication 7.Other infection syndrome 8.noninfections syndromes Antiiotic susoeptibility,Penicillin - resistant streptococcus pneumoniae PRSP penicillin resistant S.pneumoniae PISP penicillin intermedia resistant S,pneumonine PSSP penicillin susceptible S.pneumoniae.,In the late 1970s,pneumococcal antimicrobial resistance was fint recognized and was associated with clinical failures of treatment ,particulary in the cases of meningitis. Isolates with a minimal inhibitory concentration (MIC) less than or equal to 0.06ug/ml,were called penicillin susceptible .Those with an MIC,less than or equral to 0.12 to 1.2ug/ml were considered to have reduced susceptibility or intermediate resistance ,and those with the MIC greater than or equal to 2.0ug/ml,were diefined as resistance.,对脑膜炎penicillin 的MIC 在0.06ug/ml以下为敏感，0.12ug/ml以上为耐药。除脑膜炎外使用静注时2ug/ml 敏感，4ug/ml 中间耐药 8ug/ml以上耐药。,Penicillin inhibits the replication of S.pneumoniae by inding one or more enzymes needs to synthesize peptidoglycan,including higher-molecular weight transpeptidases and a lower-molecular weight carboxypeptidases ,resulting in bacterial autolysis,the binding is covalent,and a serine-ester-linked ,enzymatically inactive penicilloy complex is formed .Six such enzymes are identified ,1A,1B,2A,2B,2X an3,肺炎球菌对内酰胺药物敏感性低下，是它作用靶物质PBP的改变，（penicillin binding protein 青霉素结合蛋白）PBP是酶，合成细胞壁的酶。PBP发生改变：使细胞壁向长轴延长是PBP1A，细菌分裂时两个菌间的壁由PBP2X和PBP2A控制，而PBP2B控制细菌形成柳叶刀状； 影响敏感性下降的主要是PBP的氨基酸序列，即与内酰胺药物结合的STMK（Ser-Thr-Met-Lys）or SSN (Ser-Ser-Asp)及它们相邻氨基酸的置换。为区别生物敏感性结果，表示基因型g不是克而是genotype，penicillin-resistant streptococcus pneumoniae PRSP,基因型是gPRSP青霉素、碳青霉烯类抗生素结合在PBPIA和PBP2B上发挥作用,头孢类抗生素结合在PPB2X发挥作用。那么控制这PBP1A、PBP2X、PBP2B的基因是pbp1a、pbp2x、 pbp2b。此三种PBP中1-2个基因变异是轻度耐药用gPISP表示，（例gPISPphpla+php2x）无基因变异敏感菌则gPSSP。,二、大环内酯类抗生素耐药 macrolide耐药与2个基因相关，一个ermB基因控制的甲基化酶，此酶使核糖体50S上23srRNA第V区腺嘌呤甲基化，从而Macrolide不能与50S结合产生耐药。产生此酶的株对14元环（红霉素、克拉霉素）15元环阿奇，16元环交沙霉素、罗红及克林霉素全部耐药，即高度耐药。此种耐药分诱导型ermA，和构成型ermB。 mefA基因编码药物排出泵蛋白mefA。该蛋白存在于菌体膜上，是排出对菌体不利物质，当有mefA基因株时，对14元环和阿奇中毒耐药。,三、喹诺酮类：耐药是DNAgyrase（回旋酶），拓扑异构酶IV发生变异。 编码DNA回旋酶的基因有gyrA、gyrB两个，最常见的是GyrA中81号的serine被phenylalanine置换，此氨基酸被置换后new qunotone高度耐药。 编码拓扑异构酶IV的有ParC(parE)和ParE（parE），ParC的79号Ser被tylisin置换，产生轻度耐药。,S:serine T:threonine M:methionone K:lysine A:alanine F:Fenylalanine N:asparagine Y:tyrosine CTX:cetotaxine MIC Treatment: 可静脉panipenem meropenem vancomcin 口服：faropenem 法罗培南 cefditoren 头孢妥仑 tebipenem 替比培南,Prevention Two vaccines provide protection against invasive pneumococcal disease:a pneumococcal polyssaccharide protein conjugate vaccine(PCV13)with the 13 most common pediatric capsulr serotypes for children (90% protection)and a 23 valent polysaccharide vaccine for adults (PPSV 23)(54%to 81%protection) PCV13also prevents up to one third of childhood bacterial pneumoniae and some proportion of meningitis and otitis media.,The efficacy of the 23 valent polysaccharide vaccine against adult pneumoniae is less chear. Both PpsV23 and PCV13 are now approved indeoendently for use in old adults .for immunocompromised adults, vaccination with the 13 valent conjugate , is recommened . Widespread pneumococcal vaccination of children has reduced the overall incidence of invasve disease and hospitalization for pneumoniae. 本菌基因是变化的，一种疫苗不可能持续应用，故应根据流行的菌株和变异株进行调整，细菌已与时俱进，那么医师？,Mycoplasma pneumoniae,流行病学 上世纪1988年后每四年一次流行已被打破，曾经的奥林匹克肺炎，发生了改变，每四年流行消失与红霉素、米诺环素、克拉霉素应用相关。1990-2000年是既不流行也不耐药。2000年阿奇霉素进入市场后，迅速出现支原体肺炎耐药。阿奇霉素容易使大环内酯类药物作用靶点发生变异。大环内酯类药物作用在核糖体23sRNAV区，使支原体不能合成蛋白而死亡。阿奇霉素可使V区第2063位的腺嘌呤发生变异由鸟嘌呤替代，A2063G，而且作用强于克拉霉素4倍，那么产生了支原体对阿奇的耐药。由于可以说大环内酯类抗生素对支原体的流行、耐药产生重大影响。红霉素、克拉霉素打破4年的循环，阿奇产生广泛耐药。,支原体肺炎与气候：支原体肺炎发生率与平均气温正相关，气温每上升1，支原体肺炎发生率增加16.9%，湿度上升1%，发病率增加4.1%。季节以冬季为主，但近年夏季也有高峰。,二、快速诊断，目前有2种 支原体脂质体：以肺炎支原体脂质体（liosome）LT/L12为靶分子，用免疫色谱法快速诊断。LT/L12是全部细菌都含有，但每种菌各有不同，用来区别细菌感染。敏感度57.6%，特异度91.6%。 支原体蛋白：肺炎支原体的Dnak蛋白作为抗原，免疫色谱法快速诊断。 Dnak蛋白也称为heat shock protein ,细胞在热的刺激下产生，保护细胞的一群蛋白。敏感度44.9%特异度98%。 3.LAMP法：loop-mediated isothermal amplication。（环介导等温扩增）检查支原体DNA，2小时内出结果，可以咽试液or痰。敏感度96%，特异度100%。,三、耐药： 比率：中国63-97%，台湾23%，韩国8.7-62.9%,加拿大12.1%，德国3.6%，法国8.3%，日本30-50%。 从2000年开始出现对大环内酯类耐药（macrolide-resostant mycoplasma pneumoniae MRMP） 2.机理： macrolide（ML）作用部位是细菌合成蛋白的核糖体。核糖体由 小亚基：16srRNA和21种蛋白（S1-S2）构成30s。 大亚基：5srRNA,23srRNA及34种蛋白（L1-L34）构成50s。30s小亚基与mRNA结合，50s大亚基与tRNA转运氨基酸结合，形成多肽链。ML药物以50s大亚基的23srRNA为靶点，tetracycline TC药以30s小亚基为靶点。,ML与V区结合阻止转肽酶功能，结果蛋白质合成终止。如V区上重要的碱基发生变异时23srRNA立体构象发生变化，对ML药 结合率显著减低耐药。重要的变异点是2063位，2064位的腺嘌呤，其中一个变异既可产MRMP。而且这个点其他细菌是共用的。A2063G最多A2063T次之。orA2063C。A2064G A2064C C2617G C617A等。 23rsRNAV区临近的liposome中的L4和L2的变异也与MRMP相关。,3.临床如何判断 确诊支原体肺炎，ML敏感株81%2天内退热，持续3天以上83%MRMP，中国可以 几乎90% 以上耐药，重症肺炎100%耐药。 4.治疗： minocycline米诺环素 二甲胺四环素，duxyycline强力霉素，tosufloxacin 妥舒沙星。克拉霉素，克拉可抑制细胞因子产生，8岁以上可选用米诺or强力霉素。15岁以上可用喹诺酮类，高热则有支原体血症可用阿米卡星or红霉素、利福平等。 四、皮质激素有争议，但临床上可。,诊断治疗前3天加用地米停药。0.2-0.3mg/kg/日 支原体对人体损害不是直接而是它的细胞膜脂蛋白，具有强烈的细胞因子诱导作用，作用巨噬细胞，使它产生IL-18,IL-8为支原体肺炎感染后的司令部，机体的免疫反应不同，分别向Th1orTh2发展，日后则发生哮喘。激素可预防向Th2发展？ 严格的指征：L18 orLDH480 iu/L,用ML3天不退热，or大叶肺炎者。IL-18在重症支原体肺炎时。 ML+激素可能是最佳治疗方案，ML抑菌、调免疫，激素抑制免疫反应。,Haemophilus influenzae流感杆菌,Haemophilus influenzae is a small ,nonmotile ,non-spore-forming bacterium and a pathogen of humans found principally in the upper respiratory tract ,first sreported bypfeiffer in 1892.当时流感样疾病大流行，因从患者痰中分离到该菌，认为它是流感的病因。1933年流感病毒分离成功，流感杆菌为继发感染。,1974年，首次分离成功-Lactamase producing ampicillin resistant Haemophilus influenzae BLPAR,随后又分离-Lactamase nonproducing ampicillin resistant Haemophilus influenzae BLNAR。BLNAR耐药机理是PBP变异。在Haemophilus influenzae 上有8种PBP,与大肠杆菌有相同性，PBPIA,1B,2,3A,3B,4,5,6,2001年已确定ftsI基因上碱基发生变异，引起PBP3A,3B异常。变异的碱基数增加，耐药性增加。,BLNAR耐药的特征是对头孢类抗生素耐药，是因为头孢类抗生素作用在PBP3上，碳青霉烯类抗生素作用在PBP2上，故对碳青霉稀类耐药少。哌拉西林是青霉素中既对PBP3有高度亲和性，也对PBP2有亲和力，它是青霉素中唯一对BLNAR有效的药物。 治疗：哌拉西林，头孢曲松，美平,Vancomycin resistant Enterococcus VRE 耐万古霉素肠球菌,Enterococcus species,streptococcus gallolyticus Group,Leuconostoc species. The first time that the termenterocoquewas used appears to have been in an article in the French literature in 1899.The manuscript was referring to a diplococus found in the gastrointestinal troet that had the potential to be come pathogenic for human . Enterococcus are gram - positive facultatively anaerobic bacteria that usurally appear oval in shape and can be seen as single cells ,pairs ,short chains,or even very long chains.,Enterococcus are capable of growing in medium containing 6.5% sodium chloride and at temperature between 10 and 45 and are able to hydrolyze esculin in the presence of 40% bile salts Enterococcus faecalis and Enterococcus fecium are the most clinicall relevant species. Most clinically relevant species of enterococci produce a leucine amino-prptidase and a pyrrolidonylarylamidase(吡咯烷酮酰-芳基酰胺酶),The leuconostoc genus comprises catalase - negative , gram - positive cocci,usually arranged in pairs or chains and are intrinsically resistant to vancomycin . Clinical presentations Enterococci are capable of causing bloodstream infactions,both in community and hospitial - associated clinical settings. infective endocarditis is one of the most serious and life - threatening infections caused by enterococci.,enterococci are one of the leading cause of nosocomial urinary tract infections. Enterococci have been described in soft tissue infestions,intra - abdoninal infections and meningitis. S.gallolyticus group of organisms have been associated with infective endocarditis. Leuconostoc causes opportunistic infections mainly in immunocompromised patients.,肠球菌常引起尿路感染、胆道感染、心内膜炎等。 肠球菌在G+菌中与葡萄球菌一样有多种耐药菌株，这是它的特点之一。不仅是天然耐药，还可通过获得各种耐药基因，从而导致多耐药。多耐药化的肠球菌可以是日常治疗中，也可特别是院内感染的病原菌。VRE的分型，目前有9个基因VanA、B 、C、D、E、G、L、M、N。主要耐药是A、B、C型。 治疗：利奈唑胺，对E、faecium有效。增强患者抵抗力和肠道菌丛中正常菌。,Extended spectrum -Lactamase(ESBL) producing orgnisms (超广谱内酰胺酶产生菌) 有内酰胺环骨架，青霉素类、头孢菌素、头霉素、碳青霉稀类统称为内酰胺类抗生素。内酰胺酶是加水分解这一类抗生素失去抗菌作用的酶，可以有多种细菌产生，（E.Coli ,klebsiella spp,proteus mirabilis,Salmonella spp,Shigella spp等）。,内酰胺酶根据基因序列or氨基酸序列分成A、B、C、D4类。ESBL，是起源于分解青霉素类ClassA，or Class D的 内酰胺酶。ClassA or Class D主要分解青霉素类，ClassC主要分解头孢霉素， ClassB主要分解青霉素、头孢霉素、碳青霉稀类。由于ClassA or Class D的内酰胺酶基因变异，不仅对青霉素类，第1、2、3、4代头孢霉素，单环类（氨曲南）都可分解，称为ESBL超广谱内酰胺酶。它可分解以上的抗生素，导致耐药。,目前，ESBL产生菌不仅存在于住院患者，即使健康成人、家畜、pet、环境中也可分离到。其原因之一是ESBL主要是肠道内细菌产生。因肠道内细菌是人、动物的肠内正常菌丛，ESBL产生菌一旦在体内定植，可长时间产生带菌状态。而且ESBL基因多存在于质粒上，有传递给其他菌株、菌种的可能性。即健康人可以是产生耐药菌株带菌者之一。 对内酰胺耐药机理，oxyimino 羟基胺基，氧基亚氨基,羟基胺基在内酰胺药中可阻止药物与内酰胺酶形成酰基结合，稳定内酰胺类药物的侧链。由于引入了羟基胺基使ClassA、C、D类内酰胺酶不能破坏内酰胺环，药物可发挥作用。,诊断： E.coli，K，pneumoniae，Proteus mirabilis， Salmonella SPP,Shigella spp.等细菌对cefpodoxime（头孢泊肟），ceftazidime（头孢他啶）cefotaxime（头孢噻肟），ceftrixone（头孢曲松）aztreonam（氨曲南）全部耐药。高度怀疑ESBL产生菌。 再进一步检查！,治疗： 碳青霉稀类，美平等 头霉素类：cefmetazole（头孢美唑） 氧头孢类：latamoxef（拉氧头孢）flomoxef（氟氧头孢） 内酰胺酶阻滞药：他唑巴坦等。,Carbapenem - resistant Enterobacteriaceae（CRE）耐碳青霉稀类肠杆菌,Point CRE的机理是细菌产生碳青霉烯酶，酶有各种各样。 CRE的菌种以klebsiella pneumoniae，Escherichia，coli等最多，（CRE）碳青霉烯酶的基因多通过质粒传递，传到其他肠内细菌，形成CRE化。 有碳青霉烯酶基因的株可不对碳青霉稀类耐药，相反不带有碳青霉烯酶基因的株可对碳青霉稀类耐药，临床检查很难。肠内细菌一般对碳青霉烯类抗生素敏感，近年对碳青霉稀类耐药株急剧增加。由CRE血行感染死亡率可达50%。,定义： CRE是指对碳青霉稀类及内酰胺类抗生素耐药的Klebsiella pneumonine Escherichia ，coli 等肠内杆菌。Klebsiella pneumonine 等肠内杆菌是正常的肠内杆菌，CRE可是带菌状态而不显示病原性。 但是这些CRE肠道外感染时，如尿路感染，创伤感染，呼吸道感染，血行感染等，以及其他重症感染时，抗生素治疗困难or不可能。一旦引起感染死亡率高达50%，特别是老龄，免疫缺陷，中心静脉导管，呼吸机等，CRE是重症感染的原因之一。,Carbapenemase 因（1）质粒。Carbapenemase gene 在菌株间，菌种间水平传播。（2）可移动基因传播Carbapene