革兰阳性球菌耐药机制研究进展

革兰阳性球菌是下呼吸道感染的重要致病菌.近20多年来,革兰阳性菌的感染呈日益增加的趋势,而革兰阳性菌耐药现象的日趋严重给临床治疗带来了困难和挑战.了解耐甲氧西林金黄色葡萄球菌、耐药肺炎链球菌、耐万古霉素肠球菌等革兰阳性球菌的耐药机制对发展新的临床治疗手段具有重要意义.     

革兰阳性球菌治疗的优化策略

本文主要介绍葡萄球菌、链球菌和肠球菌这三种常见的革兰阳性球菌的分布及临床微生物学特性,并对这三种病原菌的耐药性进行分析,以指导目前抗生素的合理应用。此外,还介绍了部分新型抗革兰阳性球菌药物,提示耐药球菌的新型治疗药物仍处于研发阶段,更多的临床试验在逐步开展中。     

利奈唑胺在革兰阳性球菌肺炎中的临床应用

 革兰阳性（G⁺）球菌是医院和社区获得性肺炎的重要病原菌。以往认为,医院获得性G⁺菌肺炎以金黄色葡萄球菌（以下简称金葡菌）为主,而社区获得性G⁺菌肺炎以肺炎链球菌为主。然而,近年来随着全球抗菌药物的广泛应用,耐药G⁺球菌日益增多,尤其是甲氧西林耐药的金葡菌（MRSA）已成为医院获得性肺炎的重要致病菌之一,其在社区获得性肺炎中的比例也在不断上升^［1-2］。特别是在院内呼吸机相关性肺炎患者分离的金葡菌中, MRSA检出率可达40%～70%^［3］。而在亚洲8个国家和地区进行的一项调查显示,医院获得性MRSA和社区获得性MRSA的检出率分别为67.4%和25.5%^［4］。由于MRSA对多种抗菌药物耐药,医院获得性MRSA肺炎和社区获得性MRSA肺炎住院时间延长,治疗费用增加,且预后不佳,因此早期合理的经验性抗菌治疗显得尤为重要。长期以来,糖肽类的万古霉素一直是治疗MRSA感染的主要抗菌药物,但随着使用时间的延长和应用范围拓宽,糖肽类药物的最低抑菌浓度（MIC）值向上爬升。虽然目前万古霉素耐药的金葡菌（VRSA）较少,但万古霉素中介的金葡菌（VISA）、异质性万古霉素中介的金葡菌（hVISA）等的不断出现,仍然给临床MRSA肺炎治疗带来了新的挑战。     

利奈唑胺和万古霉素对革兰阳性球菌肺炎治疗效果的荟萃分析

目的 采用荟萃分析方法对现已发表的利奈唑胺和万古霉素治疗革兰阳性球菌肺炎的文献进行综合分析,评价利奈唑胺的疗效及其安全性是否优于万古霉素.方法 检索Medline数据库、Embase数据库、Ovid数据库、Cochrane图书馆及中文生物医学期刊数据库中的相关文献.检索年限均从建库到2009年2月,并查阅所有纳入文献的参考文献.外文检索词包括linezolid、glycopeptides、vancomycin、pneumonia、gram-positive cocci、saureus、MRSA、enterococcus及streptococci.限定语言为中文或英文,限定对象为"人".中文检索词为相应的主题词.纳入用英文或中文发表的比较利奈唑胺和万古霉素治疗革兰阳性球菌肺炎疗效的随机对照试验,由2名评价员独立筛查文献、评价质量和提取资料.采用Jadad量表及随机分配方案隐藏方法评估纳入研究的方法学质量;采用x2检验鉴定研究间的异质性,使用随机效应或固定效应模型合并研究;采用敏感性分析方法探讨研究结果的影响因素.结果共纳入7个随机对照研究,包括1425例革兰阳性球菌肺炎患者.荟萃分析结果显示,利奈唑胺治疗结束后在临床可评估患者的临床治愈率优于万古霉素(OR=2.16,95%CI为1.13～4.16,P<0.05);随访结束后,临床可评估患者(OR=1.11,95%CI为0.81～1.53,P>0.05)及意向性治疗患者(OR=1.01,95%CI为0.78～1.31,P>0.05)利奈唑胺的临床治愈率、微生物学总治愈率(OR=1.31,95%CI为0.85～2.04,P>0.05)、金黄色葡萄球菌清除率(OR=1.45,95%CI为0.84～2.51,P>0.05)、耐甲氧西林金黄色葡萄球菌清除率(OR=1.36,95%CI为0.51～3.61,P>0.05)、链球菌清除率(OR=4.27,95%CI为0.01～1365.87,P>0.05)及肠球菌清除率(OR=0.75,95%CI为0.03～17.51,P>0.05)与万古霉素相同.利条唑胺治疗组与万古霉素治疗组的病死率(OR=0.80,95%CI为0.59～1.07,P>0.05)及不良反应总体发生率(OR=1.06,95%CI为0.68～1.64,P>0.05)比较差异无统计学意义.结论 对革兰阳性球菌肺炎患者,利奈唑胺虽在治疗刚结束时的临床疗效优于万古霉素,但1～4周随访结束后,两组临床疗效无明显差异.     

替考拉宁治疗革兰阳性球菌感染的临床研究

目的 观察替考拉宁在我国人群中治疗革兰阳性(G^ )球菌中、重度感染的疗效和安全性。方法 前瞻性、多中心、非对照、开放性Ⅳ期药物临床试验。结果 (1)156例诊断和高度怀疑中、重度G^ 球菌感染者入选,年龄9～93岁。感染诊断有下呼吸道感染(66．0％)、败血症(9．0％)、导管相关感染(5．1％)、心内膜炎(1．9％)、中性粒细胞减少伴发热(14．1％)、骨关节感染(1．3％)、皮肤软组织感染(7．7％)和其他(10．9％)。87．8％的患者合并严重基础疾病,其中免疫抑制占28．2％(44／156)。69．2％的患者先期接受过抗生素治疗,其中以头孢菌素类(57．4％)和碳青霉烯类(28．7％)药物应用最多。(2)123例(78．8％)患者分离到G^ 球菌130株;54株金黄色葡萄球菌中耐甲氧西林金黄色葡萄球菌占90．7％(49／54);34株凝固酶阴性葡萄球菌(CNS)中耐甲氧西林CNS占88．2％(30／34．)。105株替考拉宁药敏测试结果,葡萄球菌和肠球菌全部敏感(100％);121株万古霉素药敏测试结果,葡萄球菌全部敏感,23株肠球菌敏感率78．3％(18／23)。有16例患者同时分离到1～2种革兰阴性(G^-)杆菌,1例同时分离到白色念珠菌。(3)进入临床疗效ITF(意向治疗)分析156例,PP(符合方案)分析135例,细菌学疗效PP分析121例。临床总有效率ITT分析和PP分析分别为82．1％和85．2％,其中痊愈率分别为44．2％和45．2％,细菌学清除率(按菌株计)为87．7％。对33例细菌学阴性者经验性应用替考拉宁治疗PP分析总有效率为96．8％。不同类型感染疗效相似。(4)不良反应发生率为1.28％,表现为血细胞一过性减少和肝功能一过性异常。结论 替考拉宁治疗中、重度G^ 球菌感染疗效确凿,安全性高。对临床高度怀疑耐甲氧西林葡萄球菌或肠球菌感染时,可考虑初始经验性使用。     

达托霉素对2679株革兰阳性球菌外抗菌活性的研究

目的 研究达托霉素等抗菌药物对2679株革兰阳球菌的体外抗菌活性.方法 收集2010年1月-2011年12月9个城市17家教学医院临床分离的2679株非重复革兰阳性球菌.采用微量肉汤稀释法测定的达托霉素最低抑菌浓度(MIC),用琼脂稀释法测定其他抗菌药物的MIC值,用WHONET5.6软件进行药敏数据统计分析.结果 耐甲氧西林金黄色葡萄球菌(MRSA)和耐甲氧西林凝固酶阴性葡萄球菌(MRSCoN)检出率分别为45.8％和84.2％,MRSA对复方磺胺甲(噁)唑和氯霉素的敏感率分别为93.1％和85.5％,对红霉素、四环素、克林霉素和利福平的敏感率分别为13.8％、26.6％、63.2％、50.0％,对达托霉素、万古霉素和利奈唑胺的敏感率均为100.0％,MRSCoN对达托霉素、万古霉素和利奈唑胺的敏感率均为100.0％,达托霉素对于MRSA和MRSCoN的MIC50和MIC90均为0.5 mg/L.513株肠球菌对于高水平庆大霉素耐药率为56.9％,氯霉素和四环素的敏感率分别为76.0％和44.1％,对替加环素和达托霉素敏感率均达100.0％,达托霉素对于其中17株耐万古霉素肠球菌(V RE)的MIC50和MIC90均为2 mg/L.肺炎链球菌和β-溶血链球菌对于达托霉素的敏感率均为100.0％,按口服青霉素折点判读,青霉素不敏感的肺炎链球菌(PNSSP)的比例为63.1％.达托霉素对于PNSSP的MIC50和MIC90分别是0.125 mg/L和0.25 mg/L.达托霉素对于β-溶血链球菌MIC50和MIC90分别是0.008 mg/L和0.032 mg/L.结论 达托霉素对临床常见革兰阳性球菌具有较好的抗菌活性,包括多重耐药菌,是治疗革兰阳性菌特别是耐药菌感染的很好选择.     

临床革兰阳性细菌感染耐药情况分析

近年来,革兰阳性球菌感染比例增加是呼吸系统严重感染性疾病倍受临床关注的问题之一,其中葡萄球菌和肠球菌引起的肺部感染较其他革兰阳性菌严重,且极易造成心内膜炎和败血症。葡萄球菌中的耐甲氧西林金葡菌(MRSA)、耐甲氧西林表葡菌(MRSE)及肠球菌对多种β内酰胺类抗生素的耐药性已成为临床极为棘手的问题。现对葡萄球菌和肠球菌的耐药情况进行分析。     

达托霉素等抗菌药物对499株血流感染革兰阳性球菌的体外抗菌活性

目的 评价达托霉素、万古霉素、替考拉宁、替加环素、头孢吡普、利奈唑胺等抗菌药物对血培养分离革兰阳性球菌的体外抗菌活性.方法 用微最肉汤稀释法测定达托霉素对499株血培养分离革兰阳性球菌的最小抑菌浓度(MIC)值,用琼脂稀释法测定其余9种抗菌药物MIC值,WHONET 5.4软件分析药敏数据.结果 葡萄球菌对达托霉素、万古霉索、替考拉宁、替加环素、头孢吡普和利奈唑胺的敏感率均为100%.达托霉素在1 mg/L浓度下可抑制所有的葡萄球菌.对于甲氧西林耐药的金黄色葡萄球菌(MRSA)和甲氧西林耐药的凝固酶阴性葡萄球菌(MRSCoN),其MIC50和MIC90均为0.5 mg/L.达托霉素对肠球菌的最高MIC为4 mg/L,粪肠球菌的MIC50和MIC90均为2 mg/L;屎肠球菌的MIC50和MIC90分别为2 mg/L和4 mg/L.1株对利奈唑胺耐药(MIC为8 mg/L)的粪肠球菌对达托霉索敏感(MIC为1 mg/L).3株携带vanA基因的屎肠球菌(万古霉素的MIC均大于32 mg/L,替考拉宁的MIC均为32 mg/L)对达托霉素、替加环素、利奈唑胺均敏感.达托霉素对肺炎链球菌和草绿色链球菌的MIC范围分别为0.032～0.250 mg/L和0.125～1.000 mg/L.结论 达托霉素作为新型的抗菌药物,对血流感染常见的革兰阳性球菌均有很好的体外抗菌活性.可成为临床治疗革兰阳性球菌特别是耐药菌感染的很好选择.     

利奈唑胺在重症患者革兰阳性球菌感染治疗中的应用

 严重感染和感染性休克是以全身性感染导致器官功能障碍为特征的临床综合征,其发病率和病死率均很高。全世界每年大约1 000人中就有3人发生严重感染和感染性休克,呈现不断增长的趋势。革兰阳性（G+）球菌,如金黄色葡萄球菌、凝固酶阴性葡萄球菌、肠球菌等是ICU患者常见的病原菌。患者的基础疾病、器官功能障碍、广谱抗生素使用及临床侵入性操作等诸多因素,使得G+球菌感染及耐药性问题日益突出,临床治疗面临严峻挑战。近年来,尤其是甲氧西林耐药的金黄色葡萄球菌（MRSA）分离率不断上升,耐药性增加。由MRSA引起的院内感染病死率高,住院时间长,治疗费用高。早期恰当的经验性治疗对提高治疗成功率、改善预后具有重要意义。利奈唑胺（商品名斯沃）是首个应用于临床的新型噁唑烷酮类抗菌药物,具有作用机制独特,无交叉耐药,抗G+菌谱广,肝肾毒性等副作用较小等特点。现将重症患者院内G+球菌感染的临床特点及利奈唑胺治疗的疗效与安全性进行综述如下。     

Fluoroquinolone resistance among Gram-positive cocci

Resistance to fluoroquinolones among Gram-positive cocci has emerged as these antimicrobial agents have become extensively used in clinical medicine. Resistance is effected by changes in the bacterial target enzymes DNA gyrase and topoisomerase IV, which reduce drug binding, and by action of native bacterial membrane pumps that remove drug from the cell. In both cases, quinolone exposure selects for spontaneous mutants that are present in large bacterial populations, and which contain chromosomal mutations that alter the target protein or increase the level of pump expression. Resistance among clinical isolates has been greatest in Staphylococcus aureus and particularly among meticillin-resistant strains, in which both selection by quinolone exposure and transmission of clonal strains in health-care settings have contributed to high prevalence. Resistance in Streptococcus pneumoniae has also emerged in the community. Fluoroquinolone resistance has arisen in multidrug-resistant clones and its prevalence has been especially high in Hong Kong and Spain. Further spread and selection of such resistance could compromise the utility of a valuable class of antimicrobial agents, a point that emphasises the importance of the careful use of these agents in appropriate patients and doses, as well as careful infection-control practices.     

Antibacterial therapy of hospital-acquired pneumonia

Antibacterial therapy of hospital-acquired pneumonia
The committee for The Japanese Respiratory Society guidelines in management of respiratory infections. Respirology 2004; 9: S16–S24     

Gram-positive pneumonia

Gram-positive pneumonia is a leading cause of morbidity and mortality throughout the world. Of the gram-positive pathogens that cause pneumonia, Streptococcus pneumoniae and Staphylococcus aureus are the most common. The diagnosis of gram-positive pneumonia remains less than satisfactory, and newer diagnostic techniques such as antibody- and polymerase chain reaction-based antigen detection have yet to prove themselves. Drug resistance among gram-positive organisms is now endemic throughout the world and remains a serious therapeutic problem despite the availability of new antimicrobials. Efforts to control the spread of resistant strains include, in the case of S. aureus, stringent isolation policies and topical treatment to reduce carriage and, for S. pneumoniae, increased use of available vaccines and the development of more immunogenic vaccines.     

Re-evaluation of the therapy of severe pneumonia caused by Streptococcus pneumoniae

Pneumonia caused by Streptococcus pneumoniae is the most deadly form of community-acquired pneumonia. The death rate of bacteremic pneumococcal pneumonia has remained constant over the past 50 years. Several retrospective reviews of bacteremic pneumococcal pneumonia suggest that dual therapy with a beta-lactam and a macrolide antimicrobial agent is associated with a lower case fatality rate than therapy with a beta-lactam alone. These studies are reviewed, potential mechanisms are suggested, and future studies are discussed.     

Gram-positive cocci are associated with the formation of completely pure cholesterol stones

OBJECTIVES: Recently it has been reported that bacterial DNA has been detected in mixed cholesterol stones (cholesterol content < 95%), which were not previously believed to be related to bacteria, using the polymerase chain reaction (PCR). We examined bacterial DNA in pure cholesterol stones to clarify the mechanism of initiation or promotion of the formation of cholesterol gallstones. METHODS: We examined 69 gallstones (30 brown pigment stones, 21 pure cholesterol stones, and 18 mixed cholesterol stones). Bacterial DNA was extracted from the core of the gallstones and amplified by PCR. Bacteria species in gallstones were identified by DNA sequencing of the PCR products. RESULTS: Bacterial DNA was detected in 26/30 brown pigment stones (87%), in 12/21 pure cholesterol stones (57%) (cholesterol content = 100%), and in 12/18 mixed cholesterol stones (67%) (cholesterol content = 82-95%). Bacterial species in gallstones were identified by DNA sequencing of PCR products. Eighty percent of bacteria in brown pigment stones were gram-negative rods or anaerobes. In contrast, 100% of bacteria in pure cholesterol stones were gram-positive cocci. The bacteria in mixed cholesterol stones consisted of 40% gram-positive cocci, 50% gram-negative rods, and 10% anaerobes. CONCLUSIONS: It was strongly suggested that gram-positive cocci are associated with the formation of pure cholesterol stones.