肠球菌感染的治疗

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Languages 帮助 欢迎, 重庆医科大学附属第一医院 登录 返回搜索结果 检索所有专题 肠球菌 专题分类 , , 药物相互作用 , 计算器 , PCUs , 重要更新 , 患者信息 查找患者 肠球菌感染的治疗 Official reprint from UpToDate? www.uptodate.com ?2015 UpToDate? 肠球菌感染的治疗 Author Barbara E Murray, MD Section Editor Daniel J Sexton, MD Deputy Editor Elinor L Baron, MD, DTMH 翻译 朱振华, 主治医师 Disclosures: Barbara E Murray, MD Grant/Research/Clinical Trial Support: Cubist [Evaluation Of The Impact Of The Inoculum Effect On Efficacy Of Cefazolin In Staphylococcal Experimental Endocarditis And A Comparison To Daptomycin (Cefazolin)]; Theravance [Efficacy Of Televancin In The Treatment Of E. Faecalis Experimental Endocarditis In A Rat Model (Televancin)]; Forest [Efficacy Of Ceftaroline In A Rat Model Of Endocarditis Against Mssa That Hydrolyze Cefazolin (Ceftaroline)]. Consultant/Advisory Boards: Rib-X [Abx Resistance]; GSK [Abx Resistance]; Theravance [Abx Resistance]. Patent Holder: Ace [Adhesin To Collagen Of E. Faecalis]. Employment: The University Of Texas Health Science Center At Houston. Daniel J Sexton, MD Grant/Research/Clinical Trail Support: Cubist [C. difficile infection (Fidaxomycin)]. Consultant/Advisory Boards: Johnson & Johnson [Pelvic mesh-related infection]; Sterilis [Medical waste disposal systems]; Magnolia Medical Technologies [Intravenous devices]. Other Financial Interest: National Football League [Infection control program]. Equity Ownership/Stock Options: Magnolia Medical Technologies [Intravenous devices]. Elinor L Baron, MD, DTMH Nothing to disclose. 公开性原则: 朱振华, 主治医师 没有透露。 编辑组会认真审核作者的声明。之间的利益冲突将会通过编辑组对文章以及参考文献的多级审评来解决。 所有的作者 都必须提供与文章相关的文献，文章以及文献须严格依循UpToDate 的相关的标准。 利益矛盾的解决 方案 气瓶 现场处置方案 .pdf气瓶 现场处置方案 .doc见习基地管理方案.doc关于群访事件的化解方案建筑工地扬尘治理专项方案下载 我们的所有专题都会依据新发表的证据和同行评议过程而更新。 文献评审有效期至: 2015-06 . | 专题最后更新日期: 2014-09-03. There is a newer version of this topic available in English. 该主题有一个新的 英文版本。 引言 — 肠球菌可引起多种感染，包括泌尿道感染(urinary tract infection, UTI)、菌血症、心内膜炎及脑膜炎。可用于治疗肠球菌感染的抗菌药物将 总结 初级经济法重点总结下载党员个人总结TXt高中句型全总结.doc高中句型全总结.doc理论力学知识点总结pdf 在此，之后是肠球菌导致的临床综合征的治疗 方法 快递客服问题件处理详细方法山木方法pdf计算方法pdf华与华方法下载八字理论方法下载 。与肠球菌相关的其他问题将会单独详细讨论。 (参见“肠球菌中抗生素耐药性的机制”和“耐万古霉素肠球菌的流行病学、预防和控制”和“肠球菌的微生物学”) 临床治疗方法 敏感菌株的治疗方法 — 与大多数链球菌相比，肠球菌对青霉素和氨苄西林相对耐药;甚至当这些具有破坏细胞壁作用的药物抑制肠球菌时，往往也不能杀灭它们，而万古霉素的杀菌效果甚至更差。屎肠球菌分离株与粪肠球菌相比，前者对青霉素的耐药性更强[屎肠球菌分离株的最低抑菌浓度(minimal inhibitory concentration, MIC)90>16mg/mL vs 粪肠球菌分离株的MIC90为2-4μg/mL];氨苄西林的MIC通常比青霉素的低一个稀释度。哌拉西林的活性与青霉素相似，而亚胺培南具有一定的抗粪肠球菌活性。具有破坏细胞壁作用但抗肠球菌活性有限或无抗肠球菌活性的药物，包括萘夫西林、苯唑西林、替卡西林、厄他培南、氨曲南和大多数头孢菌素类。 氨基糖苷类抗生素也相对不能渗透进入肠球菌，且氨基糖苷类抗生素要达到杀菌活性所需的血清浓度，大大超过其在人体内的安全药物浓度。因此，需要同时使用具有破坏细菌细胞壁作用的药物来提高细胞的渗透性，以便在不产生过度毒性的情况下，能够达到细胞内氨基糖苷类的杀菌浓度[1]。在存在危及生命感染的临床情况下，需要保证杀菌活性。 (参见下文„临床感染?) 通常会对肠球菌分离株进行氨苄西林、青霉素和万古霉素药敏试验。在使用青霉素或氨苄西林治疗心内膜炎或其他危及生命的肠球菌感染(如脑膜炎)之前，即使分离株对氨苄西林敏感，也应该用头孢硝噻吩(一种显色头孢菌素)筛查分离株是否会生成β-内酰胺酶。虽然仅很少发现，但是当存在大量微生物时(如心内膜炎赘生物)，即使采用标准实验室接种可能检测出微生物对药物敏感，存在β-内酰胺酶仍然会使肠球菌对青霉素和氨苄西林产生耐药性。 也应该检测危及生命的感染中的肠球菌分离株是否对庆大霉素和链霉素有高水平耐药性。如果结果报告肠球菌对一种高水平氨基糖苷类药物敏感[“SYN-S”代表“对抗菌药物的协同作用敏感(susceptible to synergism)”]，那么可推测，采用该药物将会达到协同作用。对高水平庆大霉素耐药的菌株对妥布霉素、奈替米星和阿米卡星及庆大霉素的协同作用耐药，但其中某些菌株对链霉素并没有高水平耐药性，将证实该药物具有协同作用[2,3]。 (参见下文„临床感染?) 甚至是对庆大霉素并无高水平耐药性的菌株，也应避免使用妥布霉素和特别是阿米卡星。一种菌株特异性氨基糖苷转移酶导致所有屎肠球菌都对妥布霉素的协同作用具有耐药性，并且对大多数屎肠球菌和粪肠球菌，未显示出阿米卡星具有协同作用。 优选的具有破坏细胞壁作用的药物为氨苄西林或青霉素;仅在对β-内酰胺类耐药或发生超敏反应的情况下，用万古霉素替代[4]。氨苄西林或青霉素与庆大霉素或链霉素联合用药，优于万古霉素-氨基糖苷类联合用药，因为后者发生肾毒性的风险更高。与链霉素相比，更易测定血清中庆大霉素的浓度，故使用庆大霉素更方便。如上文所述，通常避免使用阿米卡星与妥布霉素，实验室也不会检测这些氨基糖苷类抗生素。 对于粪肠球菌心内膜炎，氨苄西林与头孢曲松联用的临床治愈率与氨苄西林加庆大霉素的相当，许多粪肠球菌性心内膜炎并不对氨基糖苷类高水平耐药[5]。如果其他研究也证实这一结果，那么这可能是一种在治疗严重肠球菌感染的同时可避免氨基糖苷类毒性的具有吸引力的联合用药方案。 (参见“Antimicrobial therapy of native valve endocarditis”, section on „High-level aminoglycoside or vancomycin resistance?) 敏感菌株的抗菌药物治疗方案及剂量概述见下表(图表 1)。 耐药菌株的治疗方法 — 耐药肠球菌的主要类别包括对高水平青霉素耐药、对高水平氨基糖苷类耐药和对万古霉素耐药的肠球菌[6]。 高水平青霉素耐药 — 青霉素/氨苄西林耐药性(MIC?16μg/mL)可能由青霉素结合蛋白(penicillin binding protein, PBP)的改变，或极少情况下由产生β-内酰胺酶所致。在这类微生物导致感染的情况下，万古霉素是首选的具有破坏细胞壁作用的药物，除非产生β-内酰胺酶导致耐药;而在这种耐药情况下，氨苄西林-舒巴坦可用作破坏细胞壁作用的药物。在一些病例报告(对于不产生β-内酰胺酶的耐氨苄西林菌株)中，采用大剂量氨苄西林和大剂量氨苄西林-舒巴坦(联合氨基糖苷类抗生素)治疗获得成功[7,8]。 对高水平青霉素耐药的肠球菌引起感染的治疗方案和剂量概述见下表(图表 2)。 高水平氨基糖苷类耐药 — 当需要协同杀菌治疗时(例如，存在心内膜炎的情况下)，肠球菌的检测应该包括对庆大霉素和链霉素进行高水平氨基糖苷类耐药试验，因为当这两种药物中的一种无活性时，另一种药物也可能有活性。对于“协同敏感”的微生物，应该决不采用氨基糖苷类单药治疗，而是应该将具有破坏细胞壁作用的药物与氨基糖苷类药物合用。不应使用报告为“对协同耐 药(resistant to synergism, SYN-R)” 的氨基糖苷类抗生素(或者庆大霉素MIC?500μg/mL或链霉素MIC?2000μg/mL)进行治疗;一般应该避免使用其他氨基糖苷类抗生素。 对庆大霉素及链霉素有高水平氨基糖苷类耐药性的粪肠球菌导致的感染性心内膜炎，β-内酰胺类联合治疗是一种选择。两种β-内酰胺类药物联合用药的益处，可能归因于不同PBP靶点的饱和。已经证实，氨苄西林与头孢曲松联合用药对高度耐氨基糖苷类抗生素的粪肠球菌菌株所致实验性心内膜炎的有效性，以及治疗粪肠球菌性心内膜炎患者的有效性[5,9-11]。 对高水平氨基糖苷类抗生素耐药的肠球菌引起的心内膜炎和其他感染的治疗方案及用药剂量，将单独详细讨论[5]。 (参见“Antimicrobial therapy of native valve endocarditis”, section on „High-level aminoglycoside or vancomycin resistance?) 耐万古霉素 — 尚不明确耐万古霉素屎肠球菌(Vancomycin-resistant E. faecium, VRE)所致肠球菌感染的最佳治疗方法。虽然有两种药物(利奈唑胺和奎奴普丁/达福普汀)已被批准用于治疗VRE所致的感染，但是尚不确定这些药物对于严重感染(如心内膜炎)的效用。当针对此类微生物感染选择适当治疗时，应结合感染性疾病的专业知识，仔细评估耐万古霉素肠球菌分离株的耐药谱。此外，应针对每个病例评估是否需要治疗此类分离株。 (参见下文„临床感染?) VRE分离株往往同时有高水平β-内酰胺类和氨基糖苷类抗生素耐药性。相反，耐万古霉素粪肠球菌通常对β-内酰胺类药物敏感，鹑鸡肠球菌和铅黄肠球菌[本质上对万古霉素耐药(vancomycin resistant, VR)]也通常对β-内酰胺类药物敏感。更新的药物(利奈唑胺、达托霉素和替加环素)均有抗耐万古霉素粪肠球菌和屎肠球菌的活性，而奎奴普丁-达福普汀仅有抗屎肠球菌活性。 耐万古霉素肠球菌的治疗方案概述见下表(图表 3)。 抗菌药物 有抗VRE活性的肠胃外药物 利奈唑胺 — 利奈唑胺是一种合成的噁唑烷酮类抗菌药物，具有抑菌作用，与50S核糖体肽基转移酶中心结合，阻止肽键形成，从而增加了新的氨基酸[12]。一种移动基因(cfr)可编码修饰23S rRNA的甲基转移酶，这种基因会引起对氯霉素、克林霉素、截短侧耳素、链霉杀阳菌素A及利奈唑胺的耐药性，已在葡萄球菌中发现这种基因[13,14]，而最近更常在肠球菌中发现[15]。利奈唑胺可口服或肠胃外给药。口服给药后生物利用度较高，且在大多数组织中能达到治疗水平。 利奈唑胺的早期数据在同情使用方案的情况下获得。一项报告称，在大约500例VRE感染者中，同情使用利奈唑胺的治愈率为81%[16]。另一项报告称，在85例有VRE感染的实体器官移植受者中(43例有菌血症)，同情使用利奈唑胺治疗后，63%的患者出现感染消退[17]。然而，也有利奈唑胺治疗失败或产生耐药的报道[18,19]。 对利奈唑胺安全性的考虑限制了其使用，特别是在长时间用药的情况下。不良反应包括血小板减少、贫血、乳酸酸中毒、周围神经病和眼毒性。当给予5-羟色胺能药物时(特别是选择性5-羟色胺再摄取抑制剂)时，由于利奈唑胺对单胺氧化酶的抑制，可诱发5-羟色胺综合征[20,21](参见“5-羟色胺综合征”)。 在存在终末期肾病的情况下，似乎更常出现与使用利奈唑胺相关的血小板减少，且通常在停药后消退[22]。神经病变(周围神经病和较少见的视神经病变)及乳酸酸中毒并不常见，但都是利奈唑胺的重要副作用。据报道，这些副作用常发生于长期使用利奈唑胺的情况下。周围神经病可能比较严重，停药后可能不会缓解[23-25]。 适当的利奈唑胺给药方式为每12小时600mg，口服或静脉给药。在利奈唑胺治疗期间，应至少每周监测1次血细胞计数及血清化学检查。 达托霉素 — 达托霉素是一种环脂肽类抗菌药物，具有杀菌作用，可引起细菌细胞膜去极化[26]。它已被美国食品药品监督管理局(United States Food and Drug Administration, FDA)批准用于治疗皮肤及皮肤结构感染，包括对万古霉素敏感的粪肠球菌感染的治疗。虽然支持批准将达托霉素用于治疗VR粪肠球菌感染的数据不足，但其很可能对这些微生物同样有效。 虽然FDA尚未批准将达托霉素用于治疗屎肠球菌感染，但是有人赞成对在体外对批准的抗菌药物耐药的屎肠球菌感染，使用达托霉素治疗[27-29]。达托霉素对屎肠球菌的MIC高于粪肠球菌。目前尚无FDA批准的达托霉素治疗屎肠球菌的MIC临界点，但是美国临床和实验室标准协会(Clinical and Laboratory Standards Institute, CLSI)提示:当MIC大于4时，达托霉素治疗屎肠球菌不敏感。 对于复杂性皮肤及皮肤结构感染(complicated skin and skin structure infection, cSSSI)，批准的达托霉素给药方式为一次4mg/kg，一日1次，静脉给药。治疗血流感染的最低剂量为一次6mg/kg，一日1次，静脉给药;在存在血流感染的情况下，一些人则偏好给予一次8mg/kg，一日1次，静脉给药，或者更大剂量。在少量志愿者中，高达12mg/kg的剂量似乎是安全的，因此可考虑将这一剂量的达托霉素用于治疗MIC相对较高且危及生命的VRE感染[30]。 对于接受达托霉素治疗的患者，应定期评估其是否存在肌病的临床证据[31]。应该至少每周监测1次血清肌酸激酶的系列测量值;对于肌酸磷酸激酶(creatine phosphokinase, CPK)不低于5倍正常上限(upper limit of normal, ULN)且有症状性肌病患者，或者是CPK不低于10倍ULN的无症状患者，应该停止用药。 替加环素 — 替加环素是一种衍生自米诺环素的甘氨酰环素类抗菌药物，在体外具有抗多种革兰阳性病原体[包括耐甲氧西林金黄色葡萄球菌(Methicillin-resistant Staphylococcus aureus, MRSA)、耐万古霉素肠球菌和耐青霉素肺炎链球菌]、许多革兰阴性菌(重要的例外包括假单胞菌属、变形杆菌属、普罗维登斯菌属和摩根菌属)、厌氧菌及非典型性菌种的活性。 尽管替加环素已被美国FDA批准用于治疗cSSSI及腹腔内感染，包括检出对万古霉素敏感的粪肠球菌的感染，但是其尚未被批准用于治疗VRE。基于体外和动物模型数据，VRE似乎也对替加环素敏感[32-34]。替加环素对屎肠球菌的MIC通常低于对粪肠球菌或葡萄球菌。 鉴于对达到足够替加环素血清药物浓度的担忧，在治疗菌血症患者时，应谨慎使用替加环素[35]。合适的替加环素给药方式为一次100mg，静脉给药，随后每12小时50mg，静脉给药[36,37]。主要不良反应包括恶心和呕吐。由于替加环素静脉制剂存在不稳定性，所以难以用于治疗门诊患者。 对于不能耐受其他药物的VRE感染者，或者同时存在VRE与其他对替加环素敏感的病原体时，替加环素可能有效。在肾功能不全的情况下，其也可能有效。有个案报道已联合替加环素和达托霉素来治疗VRE感染[38-40]。 奎奴普丁-达福普汀 — 奎奴普丁-达福普汀是一种混合型的链霉杀阳菌素类抗菌药物，FDA批准将其用于治疗VRE感染[41]。由于物种特异性的三磷酸腺苷(adenosine triphosphate, ATP)结合蛋白的存在，其抗粪肠球菌的活性较差[42,43]。需要建立中心静脉通路及不良反应限制了奎奴普丁-达福普汀的使用;不良反应包括代谢相互作用、严重肌痛、关节痛、恶心和高胆红素血症。 (参见“肠球菌中抗生素耐药性的机制”) 一项研究纳入396例采用奎奴普丁-达福普汀治疗VRE感染的患者(包括菌血症、腹腔内感染、UTI和皮肤感染)，结果显示，奎奴普丁-达福普汀的总体有效率(临床上和细菌学均成功)为66%[44]。奎奴普丁-达福普汀的临床疗效与利奈唑胺相当[45]。 替考拉宁 — 替考拉宁是一种糖肽类抗菌药物，未在美国上市[46]。该药在体外具有抗鹑鸡肠球菌和铅黄肠球菌(VanC型VRE)及大多数VanB型VRE的活性，但其抗VanA型VRE的活性很 小。部分VanB型VRE突变菌株对替考拉宁有固有耐药性，或者在体内或体外接触药物后出现[47,48]。 (参见“肠球菌中抗生素耐药性的机制”) 在可使用替考拉宁的国家，该药可能用于治疗敏感肠球菌导致的感染。对于肾功能正常的患者，应给予替考拉宁负荷剂量，一次6mg/kg(严重感染者为12mg/kg)，每12小时1次，共3剂;之后每24小时给予6mg/kg(严重感染者为12mg/kg)。应考虑增加一种氨基糖苷类药物(庆大霉素或链霉素，在不对其中一种药物有高水平耐药的情况下)，以减少耐替考拉宁的VanB突变菌株的出现。 泰拉万星 — 泰拉万星是一种脂糖肽类抗菌药物，已被批准用于治疗敏感革兰阳性菌(包括金黄色葡萄球菌)引起的cSSSI。尚无使用泰拉万星治疗肠球菌感染的临床数据，但其抗肠球菌的作用强度为万古霉素的4倍(例如，MIC90为0.12μg/mL)[49-51]，而抗VanB菌株的MIC增加很少或没有增加;据报道，不同的研究中抗VanA菌株的MIC90范围为4-16μg/mL(而万古霉素的MIC90大于256μg/mL)。对于有多重耐药的VRE感染(例如，耐利奈唑胺、耐达托霉素及高度耐氨苄西林)，泰拉万星加另外一种药物，如庆大霉素(如果不是高度耐药)或奎奴普丁/达福普汀，将是一种合理的考虑。 联合治疗 — 针对VRE感染的其他治疗性联合用药的数据有限。基于敏感性的方案包括: ?达托霉素联合庆大霉素和/或氨苄西林[15] ?达托霉素加替加环素[38] ?达托霉素、庆大霉素和利福平[52] ?氨苄西林加奎奴普丁-达福普汀[53,54] ?奎奴普丁-达福普汀加多西环素和利福平[55] ?奎奴普丁-达福普汀加米诺环素(每12小时100mg)[56] ?氨苄西林加氟喹诺酮类药物[57] 米诺环素加氯霉素[58] 替代药物 — 在某些情况下，氟喹诺酮类药物可能有助于治疗肠球菌UTI(参见下文„泌尿道感染?)。虽然证据显示四环素和氯霉素在体外具有抗某些肠球菌的活性，但是仅有抑菌作用[59,60]。已有氯霉素在临床应用中的成功和失败的报道，但是其毒性作用限制了其有效性[61-63]。 在美国，大多数肠球菌对红霉素及相关的大环内酯类抗生素耐药。此外，虽然一些肠球菌分离株在体外显示出对复方磺胺甲噁唑(trimethoprim-sulfamethoxazole, TMP/SMX)敏感，但是体内的肠球菌可利用外源性叶酸，并绕过TMP/SMX诱导的叶酸合成阻断[64]。因此，即使体外药敏试验表明具有敏感性，也不应该将TMP/SMX用于治疗肠球菌感染[65-67]。 临床感染 — 肠球菌所致的重要临床感染包括UTI、伤口感染、菌血症、心内膜炎及脑膜炎。UTI一般无需杀菌治疗，细菌尿常在拔除尿管后消失消退。当需要针对肠球菌泌尿道分离株进行治疗时，单药治疗即已足够。在存在侵袭性感染的情况下，例如心内膜炎、脑膜炎及菌血症(在存在心脏瓣膜病和/或危重疾病的情况下)，需要保证杀菌活性。在这种情况下，通常需要具有破坏细胞壁作用的药物联合庆大霉素或链霉素的协同活性。当需要联合治疗时，应检测是否对庆大霉素及链霉素具有高水平耐药(参见上文„敏感菌株的治疗方法?)。 一般而言，对于从患者中检出的肠球菌属的临床作用，应视患者的个体情况判断，因为分离出肠球菌并不一定需要进行靶向治疗。肠球菌属可能是一种定植菌(例如，呼吸道样本或导尿管)，也可能是混合感染的一部分(例如，在腹腔内手术或创伤性伤口的情况下培养出多种微生物)，后一种情况下给予的治疗往往针对致病性更强的微生物。相较于屎肠球菌感染，粪肠球菌感染的致病性往往更强，当对细菌培养数据的临床意义存在疑问时，我们应给予更多的关注。 VRE导致的急性感染可能经治疗而消退，但在某些情况下，这种定植可能无限期持续，这取决于临床疾病的性质。 泌尿道感染 — 泌尿道是最常检出肠球菌的部位;临床表现包括尿路定植、单纯性膀胱炎、肾盂肾炎、肾周脓肿或前列腺炎[64]。大多数肠球菌UTI是医院感染和/或与梗阻、输尿管插管或器械操作有关[68-70]。在肠球菌UTI情况下的菌血症相对少见[71]。 治疗应该包括移除导尿管(如果可能);据观察，在某些情况下，仅采取此项干预 措施 《全国民用建筑工程设计技术措施》规划•建筑•景观全国民用建筑工程设计技术措施》规划•建筑•景观软件质量保证措施下载工地伤害及预防措施下载关于贯彻落实的具体措施 就解决了导 72]。如果确定对药物敏感，口服药物治疗肠球菌下UTI的尿管相关的肠球菌泌尿道感染/定植[ 最佳选择为阿莫西林、呋喃妥因或磷霉素;给药方法如下表所示(图表 4)[73]。呋喃妥因在尿液和肾实质中能达到极佳的治疗浓度，但不足以治疗其他部位的感染。FDA已批准将磷霉素用于治疗由粪肠球菌和/或大肠埃希菌导致的单纯性UTI，但许多屎肠球菌菌株也对磷霉素敏感[74,75]。也可考虑静脉给予氨苄西林(见下文) 其他的口服药物包括利奈唑胺或一种氟喹诺酮类，尽管关于它们治疗肠球菌UTI有效性的数据有限;在存在全身性感染的情况下，不应使用氟喹诺酮类药物进行单药治疗，因为氟喹诺酮类药物可达到的血清浓度常常接近MIC[76-83]。 与较早的氟喹诺酮类药物(如环丙沙星)相比，莫西沙星的体外活性更好，但莫西沙星达到的尿药浓度较低。与较新的氟喹诺酮类药物相比，耐环丙沙星的分离株往往具有相对较高的MIC[84]。 对于复杂性UTI患者以及无法耐受口服治疗的患者，氨苄西林是首选药物。即使对于氨苄西林MIC大于64μg/mL的菌株，由于该药浓集于尿液中，所以可能仍然有效。如果细菌敏感，万古霉素是一个合适的替代选择。对于由耐氨苄西林和耐万古霉素菌株引起的UTI，可考虑使用利奈唑胺。 菌血症 — 肠球菌性菌血症的入侵途径包括胃肠道、泌尿道、血管内导管及伤口(如溃疡或烧伤)[64,85-89]。大多数由粪肠球菌外的其他菌种引起的肠球菌性菌血症的病例，不会出现心内膜炎[68,85,87,90-93]。粪肠球菌性菌血症患者，发生心内膜炎的相对风险更高，但仍相对较低。在出现肠球菌性菌血症的情况下，脓毒性休克很少见;但如果出现，应怀疑存在伴革兰阴性杆菌感染的多种微生物感染。 (参见“血管内导管相关感染的治疗”，关于„肠球菌属?一节) 需要抗菌药物治疗肠球菌性菌血症的情况包括以下:2次或以上血培养阳性、单次血培养阳性且伴有脓毒症征象，或者单次血培养阳性加上其他通常无菌部位的肠球菌培养阳性。对于既往有人工心脏瓣膜的患者，在出现单次一种肠球菌(特别是粪肠球菌)血培养阳性结果的情况下，一些人赞成在等待更多的血培养结果的同时开始治疗;其他人则赞成在等待更多血培养结果时暂不治疗。尚不明确治疗的最佳持续时间;1-2周或许合适。 在单次血培养阳性且无脓毒症临床证据的情况下，或者对有多种微生物感染并且正在接受针对致病性更强微生物的恰当治疗的患者，许多专家赞成推迟使用抗菌药物治疗肠球菌性菌血症[94,95]。在菌血症很有可能归因于血管内导管的情况下，仅移除导管可能就足以治愈感染。然而，对于大多数发热的患者在发现肠球菌感染并且进行培养后，应给予经验性抗菌药物治疗;如果症状已消退且无瓣膜异常，一般在5-7日后停药。 关于肠球菌性菌血症的最佳治疗是包括单药治疗还是联合治疗，尚未达成共识。尽管许多研究表明，联合疗法较单药治疗并无优势，但一些人赞成在有心脏瓣膜病和/或危重疾病的情况下进行联合治疗[88,94,96]。 单药治疗和联合治疗的选择概述见下表(图表 1)。单药治疗时，氨苄西林是针对敏感菌株的首选药物。在β-内酰胺类耐药或对其过敏的情况下，可给予万古霉素。在有人工瓣膜和/或长期菌血症的情况下，应给予联合治疗;联合治疗时，应增加一种氨基糖苷类药物(庆大霉素，或在耐药的情况下使用链霉素)或头孢曲松。耐药性肠球菌的治疗选择概述见下表(图表 2 and 图表 3)。关于β-内酰胺类联合用药方案治疗肠球菌性心内膜炎的数据，将单独详细介绍(参见“Antimicrobial therapy of native valve endocarditis”, section on „Enterococci?)。 尚不明确抗菌药物治疗肠球菌性菌血症的最佳持续时间。对于单纯性感染，很可能治疗5-7日即足够。存在持续性重度菌血症的情况下和存在人工心脏瓣膜的情况下，甚至在超声心动图未显示有赘生物时，也应该延长治疗持续时间。治疗的持续时间应该反映假定的心内膜炎，将单独概述。 (参见“人工瓣膜心内膜炎的抗生素治疗”) 心内膜炎 — 肠球菌性心内膜炎的治疗将单独详细讨论(参见“Antimicrobial therapy of native valve endocarditis”和“人工瓣膜心内膜炎的抗生素治疗”)。 脑膜炎 — 对于正常成人，肠球菌很少引起脑膜炎[97]。大多数肠球菌性脑膜炎病例发生在有头部创伤、行神经外科手术、存在脑室内或鞘内导管，或者有中枢神经系统(central nervous system, CNS)解剖缺陷的患者中[98,99]。极少数情况下，肠球菌性脑膜炎可能是肠球菌性心内膜炎或有免疫缺陷[例如，获得性免疫缺陷综合征(acquired immune deficiency syndrome, AIDS)或血液系统恶性肿瘤]患者的重度菌血症的一种并发症[97,98]。肠球菌性脑膜炎还可出现于新生儿脓毒症的情况下，且已被描述与类圆线虫属高度感染相关[100,101]。 虽然大多数人赞成联合治疗优于单药治疗，但尚不明确治疗肠球菌性脑膜炎的最佳方案[97,98,102]。脑膜炎的联合治疗方案选择概述见下表(图表 5)。对于全身性抗菌药物治疗无效的患者，脑室内给予万古霉素、庆大霉素或奎奴普丁-达福普汀(如果为屎肠球菌)可能有效。达托霉素对CNS渗透性较差[103]。 (参见“Infections of central nervous system shunts and other devices”) 由耐青霉素、氨基糖苷类抗生素和万古霉素的屎肠球菌株引起的肠球菌性脑膜炎的治疗是一项困难的挑战;虽然静脉给予利奈唑胺，或静脉加上脑室内给予奎奴普丁-达福普汀是合理的抗菌药物选择，但脑室内给药的经验有限[104-112];达托霉素也可通过脑室内途径给药[40,103]。利福平(如果敏感)可能也是一种有用的辅助药物;不应该使用氯霉素治疗肠球菌性脑膜炎[113-115]。 患者教育 — UpToDate提供两种类型的患者教育资料:“基础篇”和“高级篇”。基础篇通俗易懂，相当于5-6级阅读水平(美国)，可以解答关于某种疾病患者可能想了解的4-5个关键问题。基础 篇更适合想了解疾病概况且喜欢阅读简短易读资料的患者。高级篇篇幅较长，内容更深入详尽;相当于10-12级阅读水平(美国)，适合想深入了解并且能接受一些医学术语的患者。 以下是与此专题相关的患者教育资料。我们建议您以打印或电子邮件的方式给予患者。(您也可以通过检索“患者教育”和关键词找到更多相关专题内容。) ?基础篇(参见“Patient information: Vancomycin-resistant enterococci (The Basics)”) 总结与推荐 ?肠球菌对具有破坏细胞壁作用的药物(青霉素、氨苄西林和万古霉素)的杀灭作用相对耐 药，氨基糖苷类抗生素也不能渗透进入肠球菌。因此，为了达到对侵袭性感染(例如，心内 膜炎、很可能的脑膜炎及某些情况下的菌血症)的最佳治愈率，需要采用两种药物的联合治 疗方案:一种具有破坏细胞壁作用的药物联合一种具有协同作用的氨基糖苷类抗生素，或 是氨苄西林联合头孢曲松。敏感菌株的抗菌药物治疗方案及剂量概述见下表(图表 1)。 (参 见上文„临床治疗方法?) ?耐药肠球菌的主要类型，包括高水平氨苄西林和/或万古霉素耐药的肠球菌。抗菌药物方 案的概述见下表(图表 2 and 图表 3)[6]。 (参见上文„耐药菌株的治疗方法?) ?口服治疗肠球菌性泌尿道感染(UTI)的选择概述见下表(图表 4)。对于敏感菌株，我们建议 使用阿莫西林、磷霉素或呋喃妥因(Grade 2B)。对于复杂性泌尿道感染(UTI)患者，以及无 法耐受口服治疗的患者，我们建议胃肠外给予氨苄西林(Grade 2B)。 (参见上文„泌尿道感 染?) ?我们推荐在出现情况时给予抗菌药物治疗:两次及以上血培养阳性、单次血培养阳性且伴 有脓毒症征象，或者单次血培养阳性加上其他通常无菌部位的肠球菌培养阳性(Grade 1B)。 单药治疗和联合治疗的选择概述见下表(图表 2 and 图表 3)。对于单纯性感染，通常治疗 ?)5-7日即足够。 (参见上文„菌血症 ?肠球菌性心内膜炎的治疗将单独详细讨论(参见“Antimicrobial therapy of native valve endocarditis”和“人工瓣膜心内膜炎的抗生素治疗”)。 ?我们建议采用联合用药方案治疗肠球菌性脑膜炎(Grade 2C)。脑膜炎的联合治疗选择的概 述见下表(图表 5)。 (参见上文„脑膜炎?) 使用UpToDate临床顾问须遵循用户 协议 离婚协议模板下载合伙人协议 下载渠道分销协议免费下载敬业协议下载授课协议下载 。 参考文献 1. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation 2005; 111:e394. 2. Caballero-Granado FJ, Cisneros JM, Luque R, et al. Comparative study of bacteremias caused by Enterococcus spp. with and without high-level resistance to gentamicin. The Grupo Andaluz para el estudio de las Enfermedades Infecciosas. J Clin Microbiol 1998; 36:520. 3. Antalek MD, Mylotte JM, Lesse AJ, Sellick JA Jr. Clinical and molecular epidemiology of Enterococcus faecalis bacteremia, with special reference to strains with high-level resistance to gentamicin. Clin Infect Dis 1995; 20:103. 4. Treatment Guidelines. Med Lett 2007; 57:33. 5. Fernández-Hidalgo N, Almirante B, Gavaldà J, et al. Ampicillin plus ceftriaxone is as effective as ampicillin plus gentamicin for treating enterococcus faecalis infective endocarditis. Clin Infect Dis 2013; 56:1261. Murray BE. Vancomycin-resistant enterococcal infections. N Engl J Med 2000; 342:710. 6. 7. Mekonen ET, Noskin GA, Hacek DM, Peterson LR. Successful treatment of persistent bacteremia due to vancomycin-resistant, ampicillin-resistant Enterococcus faecium. Microb Drug Resist 1995; 1:249. 8. Dodge RA, Daly JS, Davaro R, Glew RH. High-dose ampicillin plus streptomycin for treatment of a patient with severe infection due to multiresistant enterococci. Clin Infect Dis 1997; 25:1269. 9. Gavaldà J, Torres C, Tenorio C, et al. Efficacy of ampicillin plus ceftriaxone in treatment of experimental endocarditis due to Enterococcus faecalis strains highly resistant to aminoglycosides. Antimicrob Agents Chemother 1999; 43:639. 10. Gavaldà J, Len O, Miró JM, et al. Brief communication: treatment of Enterococcus faecalis endocarditis with ampicillin plus ceftriaxone. Ann Intern Med 2007; 146:574. 11. Jones BL, Ludlam HA, Brown DF. High dose ampicillin for the treatment of high-level aminoglycoside resistant enterococcal endocarditis. J Antimicrob Chemother 1994; 33:891. 12. Wilson DN, Schluenzen F, Harms JM, et al. The oxazolidinone antibiotics perturb the ribosomal peptidyl-transferase center and effect tRNA positioning. Proc Natl Acad Sci U S A 2008; 105:13339. 13. Long KS, Poehlsgaard J, Kehrenberg C, et al. The Cfr rRNA methyltransferase confers resistance to Phenicols, Lincosamides, Oxazolidinones, Pleuromutilins, and Streptogramin A antibiotics. Antimicrob Agents Chemother 2006; 50:2500. 14. Toh SM, Xiong L, Arias CA, et al. Acquisition of a natural resistance gene renders a clinical strain of methicillin-resistant Staphylococcus aureus resistant to the synthetic antibiotic linezolid. Mol Microbiol 2007; 64:1506. 15. Arias CA, Torres HA, Singh KV, et al. Failure of daptomycin monotherapy for endocarditis caused by an Enterococcus faecium strain with vancomycin-resistant and vancomycin-susceptible subpopulations and evidence of in vivo loss of the vanA gene cluster. Clin Infect Dis 2007; 45:1343. 16. Birmingham MC, Rayner CR, Meagher AK, et al. Linezolid for the treatment of multidrug-resistant, gram-positive infections: experience from a compassionate-use program. Clin Infect Dis 2003; 36:159. 17. El-Khoury J, Fishman JA. Linezolid in the treatment of vancomycin-resistant Enterococcus faecium in solid organ transplant recipients: report of a multicenter compassionate-use trial. Transpl Infect Dis 2003; 5:121. 18. Zimmer SM, Caliendo AM, Thigpen MC, Somani J. Failure of linezolid treatment for enterococcal endocarditis. Clin Infect Dis 2003; 37:e29. 19. Meka VG, Gold HS. Antimicrobial resistance to linezolid. Clin Infect Dis 2004; 39:1010. 20. Lawrence KR, Adra M, Gillman PK. Serotonin toxicity associated with the use of linezolid: a review of postmarketing data. Clin Infect Dis 2006; 42:1578. 21. Taylor JJ, Wilson JW, Estes LL. Linezolid and serotonergic drug interactions: a retrospective survey. Clin Infect Dis 2006; 43:180. 22. Wu VC, Wang YT, Wang CY, et al. High frequency of linezolid-associated thrombocytopenia and anemia among patients with end-stage renal disease. Clin Infect Dis 2006; 42:66. 23. Senneville E, Legout L, Valette M, et al. Effectiveness and tolerability of prolonged linezolid treatment for chronic osteomyelitis: a retrospective study. Clin Ther 2006; 28:1155. 24. Palenzuela L, Hahn NM, Nelson RP Jr, et al. Does linezolid cause lactic acidosis by inhibiting mitochondrial protein synthesis? Clin Infect Dis 2005; 40:e113. 25. Rucker JC, Hamilton SR, Bardenstein D, et al. Linezolid-associated toxic optic neuropathy. Neurology 2006; 66:595. 26. Boucher HW, Sakoulas G. Perspectives on Daptomycin resistance, with emphasis on resistance in Staphylococcus aureus. Clin Infect Dis 2007; 45:601. 27. Safdar N, Andes D, Craig WA. In vivo pharmacodynamic activity of daptomycin. Antimicrob Agents Chemother 2004; 48:63. 28. Vouillamoz J, Moreillon P, Giddey M, Entenza JM. Efficacy of daptomycin in the treatment of experimental endocarditis due to susceptible and multidrug-resistant enterococci. J Antimicrob Chemother 2006; 58:1208. 29. Caron F, Kitzis MD, Gutmann L, et al. Daptomycin or teicoplanin in combination with gentamicin for treatment of experimental endocarditis due to a highly glycopeptide-resistant isolate of Enterococcus faecium. Antimicrob Agents Chemother 1992; 36:2611. 30. Benvenuto M, Benziger DP, Yankelev S, Vigliani G. Pharmacokinetics and tolerability of daptomycin at doses up to 12 milligrams per kilogram of body weight once daily in healthy volunteers. Antimicrob Agents Chemother 2006; 50:3245. 31. Skiest DJ. Treatment failure resulting from resistance of Staphylococcus aureus to daptomycin. J Clin Microbiol 2006; 44:655. 32. Waites KB, Duffy LB, Dowzicky MJ. Antimicrobial susceptibility among pathogens collected from hospitalized patients in the United States and in vitro activity of tigecycline, a new glycylcycline antimicrobial. Antimicrob Agents Chemother 2006; 50:3479. 33. Lefort A, Lafaurie M, Massias L, et al. Activity and diffusion of tigecycline (GAR-936) in experimental enterococcal endocarditis. Antimicrob Agents Chemother 2003; 47:216. 34. Murphy TM, Deitz JM, Petersen PJ, et al. Therapeutic efficacy of GAR-936, a novel glycylcycline, in a rat model of experimental endocarditis. Antimicrob Agents Chemother 2000; 44:3022. 35. Rodvold KA, Gotfried MH, Cwik M, et al. Serum, tissue and body fluid concentrations of tigecycline after a single 100 mg dose. J Antimicrob Chemother 2006; 58:1221. 36. Ellis-Grosse EJ, Babinchak T, Dartois N, et al. The efficacy and safety of tigecycline in the treatment of skin and skin-structure infections: results of 2 double-blind phase 3 comparison studies with vancomycin-aztreonam. Clin Infect Dis 2005; 41 Suppl 5:S341. 37. Postier RG, Green SL, Klein SR, et al. Results of a multicenter, randomized, open-label efficacy and safety study of two doses of tigecycline for complicated skin and skin-structure infections in hospitalized patients. Clin Ther 2004; 26:704. 38. Jenkins I. Linezolid- and vancomycin-resistant Enterococcus faecium endocarditis: successful treatment with tigecycline and daptomycin. J Hosp Med 2007; 2:343. 39. Schutt AC, Bohm NM. Multidrug-resistant Enterococcus faecium endocarditis treated with combination tigecycline and high-dose daptomycin. Ann Pharmacother 2009; 43:2108. 40. Jaspan HB, Brothers AW, Campbell AJ, et al. Multidrug-resistant Enterococcus faecium meningitis in a toddler: characterization of the organism and successful treatment with intraventricular daptomycin and intravenous tigecycline. Pediatr Infect Dis J 2010; 29:379. 41. Batts DH, Lavin BS, Eliopoulos GM. Quinupristin/dalfopristin and linezolid: spectrum of activity and potential roles in therapy--a status report. Curr Clin Top Infect Dis 2001; 21:227. 42. Collins LA, Malanoski GJ, Eliopoulos GM, et al. In vitro activity of RP59500, an injectable streptogramin antibiotic, against vancomycin-resistant gram-positive organisms. Antimicrob Agents Chemother 1993; 37:598. 43. Singh KV, Weinstock GM, Murray BE. An Enterococcus faecalis ABC homologue (Lsa) is required for the resistance of this species to clindamycin and quinupristin-dalfopristin. Antimicrob Agents Chemother 2002; 46:1845. 44. Moellering RC, Linden PK, Reinhardt J, et al. The efficacy and safety of quinupristin/dalfopristin for the treatment of infections caused by vancomycin-resistant Enterococcus faecium. Synercid Emergency-Use Study Group. J Antimicrob Chemother 1999; 44:251. 45. Raad I, Hachem R, Hanna H, et al. Prospective, randomized study comparing quinupristin-dalfopristin with linezolid in the treatment of vancomycin-resistant Enterococcus faecium infections. J Antimicrob Chemother 2004; 53:646. 46. Finch RG, Eliopoulos GM. Safety and efficacy of glycopeptide antibiotics. J Antimicrob Chemother 2005; 55 Suppl 2:ii5. 47. Baptista M, Depardieu F, Reynolds P, et al. Mutations leading to increased levels of resistance to glycopeptide antibiotics in VanB-type enterococci. Mol Microbiol 1997; 25:93. 48. Kawalec M, Gniadkowski M, Kedzierska J, et al. Selection of a teicoplanin-resistant Enterococcus faecium mutant during an outbreak caused by vancomycin-resistant enterococci with the vanB phenotype. J Clin Microbiol 2001; 39:4274. 49. Bérenger R, Bourdon N, Auzou M, et al. In vitro activity of new antimicrobial agents against glycopeptide-resistant Enterococcus faecium clinical isolates from France between 2006 and 2008. Med Mal Infect 2011; 41:405. 50. Draghi DC, Benton BM, Krause KM, et al. In vitro activity of telavancin against recent Gram-positive clinical isolates: results of the 2004-05 Prospective European Surveillance Initiative. J Antimicrob Chemother 2008; 62:116. 51. Krause KM, Renelli M, Difuntorum S, et al. In vitro activity of telavancin against resistant gram-positive bacteria. Antimicrob Agents Chemother 2008; 52:2647. 52. Stevens MP, Edmond MB. Endocarditis due to vancomycin-resistant enterococci: case report and review of the literature. Clin Infect Dis 2005; 41:1134. 53. Thompson RL, Lavin B, Talbot GH. Endocarditis due to vancomycin-resistant Enterococcus faecium in an immunocompromised patient: cure by administering combination therapy with quinupristin/dalfopristin and high-dose ampicillin. South Med J 2003; 96:818. 54. Bethea JA, Walko CM, Targos PA. Treatment of vancomycin-resistant enterococcus with quinupristin/dalfopristin and high-dose ampicillin. Ann Pharmacother 2004; 38:989. 55. Matsumura S, Simor AE. Treatment of endocarditis due to vancomycin-resistant Enterococcus faecium with quinupristin/dalfopristin, doxycycline, and rifampin: a synergistic drug combination. Clin Infect Dis 1998; 27:1554. 56. Raad I, Hachem R, Hanna H, et al. Treatment of vancomycin-resistant enterococcal infections in the immunocompromised host: quinupristin-dalfopristin in combination with minocycline. Antimicrob Agents Chemother 2001; 45:3202. 57. Tripodi MF, Locatelli A, Adinolfi LE, et al. Successful treatment with ampicillin and fluoroquinolones of human endocarditis due to high-level gentamicin-resistant enterococci. Eur J Clin Microbiol Infect Dis 1998; 17:734. 58. Safdar A, Bryan CS, Stinson S, Saunders DE. Prosthetic valve endocarditis due to vancomycin-resistant Enterococcus faecium: treatment with chloramphenicol plus minocycline. Clin Infect Dis 2002; 34:E61. 59. Moreno F, Jorgensen JH, Weiner MH. An old antibiotic for a new multiple-resistant Enterococcus faecium? Diagn Microbiol Infect Dis 1994; 20:41. 60. Howe RA, Robson M, Oakhill A, et al. Successful use of tetracycline as therapy of an immunocompromised patient with septicaemia caused by a vancomycin-resistant enterococcus. J Antimicrob Chemother 1997; 40:144. 61. Lautenbach E, Schuster MG, Bilker WB, Brennan PJ. The role of chloramphenicol in the treatment of bloodstream infection due to vancomycin-resistant Enterococcus. Clin Infect Dis 1998; 27:1259. 62. Norris AH, Reilly JP, Edelstein PH, et al. Chloramphenicol for the treatment of vancomycin-resistant enterococcal infections. Clin Infect Dis 1995; 20:1137. 63. Papanicolaou GA, Meyers BR, Meyers J, et al. Nosocomial infections with vancomycin-resistant Enterococcus faecium in liver transplant recipients: risk factors for acquisition and mortality. Clin Infect Dis 1996; 23:760. 64. Murray BE. The life and times of the Enterococcus. Clin Microbiol Rev 1990; 3:46. Hamilton-Miller JM. Reversal of activity of trimethoprim against gram-positive cocci by 65. thymidine, thymine and 'folates'. J Antimicrob Chemother 1988; 22:35. 66. Grayson ML, Thauvin-Eliopoulos C, Eliopoulos GM, et al. Failure of trimethoprim-sulfamethoxazole therapy in experimental enterococcal endocarditis. Antimicrob Agents Chemother 1990; 34:1792. 67. Goodhart GL. In vivo v in vitro susceptibility of enterococcus to trimethoprim-sulfamethoxazole. A pitfall. JAMA 1984; 252:2748. 68. Anonymous. National Nosocomial Infections Surveillance (NNIS) report, data summary from January 1990 to May 1999, Issued June 1999. Am J Infect Control 1999; 520:532. 69. National Nosocomial Infections Surveillance (NNIS) System report, data summary from October 1986-April 1998, issued June 1998. Am J Infect Control 1998; 26:522. 70. Jones RN, Kugler KC, Pfaller MA, Winokur PL. Characteristics of pathogens causing urinary tract infections in hospitals in North America: results from the SENTRY Antimicrobial Surveillance Program, 1997. Diagn Microbiol Infect Dis 1999; 35:55. 71. Krieger JN, Kaiser DL, Wenzel RP. Urinary tract etiology of bloodstream infections in hospitalized patients. J Infect Dis 1983; 148:57. 72. Lai KK. Treatment of vancomycin-resistant Enterococcus faecium infections. Arch Intern Med 1996; 156:2579. 73. Minassian MA, Lewis DA, Chattopadhyay D, et al. A comparison between single-dose fosfomycin trometamol (Monuril) and a 5-day course of trimethoprim in the treatment of uncomplicated lower urinary tract infection in women. Int J Antimicrob Agents 1998; 10:39. 74. Patel SS, Balfour JA, Bryson HM. Fosfomycin tromethamine. A review of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy as a single-dose oral treatment for acute uncomplicated lower urinary tract infections. Drugs 1997; 53:637. 75. Allerberger F, Klare I. In-vitro activity of fosfomycin against vancomycin-resistant enterococci. J Antimicrob Chemother 1999; 43:211. 76. Onrust SV, Lamb HM, Balfour JA. Ofloxacin. A reappraisal of its use in the management of genitourinary tract infections. Drugs 1998; 56:895. 77. Malinverni R, Glauser MP. Comparative studies of fluoroquinolones in the treatment of urinary tract infections. Rev Infect Dis 1988; 10 Suppl 1:S153. 78. Corrado ML, Hesney M, Struble WE, et al. Norfloxacin versus trimethoprim-sulfamethoxazole in the treatment of urinary tract infections. Eur Urol 1990; 17 Suppl 1:34. 79. Zervos MJ, Bacon AE 3rd, Patterson JE, et al. Enterococcal superinfection in patients treated with ciprofloxacin. J Antimicrob Chemother 1988; 21:113. 80. Tice AD. Short-course therapy of acute cystitis: a brief review of therapeutic strategies. J Antimicrob Chemother 1999; 43 Suppl A:85. 81. Stannard AJ, Sharples SJ, Norman PM, Tillotson GS. Ciprofloxacin therapy of urinary tract infections in paraplegic and tetraplegic patients: a bacteriological assessment. J Antimicrob Chemother 1990; 26 Suppl F:13. 82. Malathum K, Singh KV, Murray BE. In vitro activity of moxifloxacin, a new 8-methoxyquinolone, against gram-positive bacteria. Diagn Microbiol Infect Dis 1999; 35:127. 83. Coque TM, Singh KV, Murray BE. Comparative in-vitro activity of the new fluoroquinolone trovafloxacin (CP-99,219) against gram-positive cocci. J Antimicrob Chemother 1996; 37:1011. 84. Martínez-Martínez L, Joyanes P, Pascual A, et al. Activity of eight fluoroquinolones against enterococci. Clin Microbiol Infect 1997; 3:497. 85. Gray J, Marsh PJ, Stewart D, Pedler SJ. Enterococcal bacteraemia: a prospective study of 125 episodes. J Hosp Infect 1994; 27:179. 86. Maki DG, Agger WA. Enterococcal bacteremia: clinical features, the risk of endocarditis, and management. Medicine (Baltimore) 1988; 67:248. 87. Patterson JE, Sweeney AH, Simms M, et al. An analysis of 110 serious enterococcal infections. Epidemiology, antibiotic susceptibility, and outcome. Medicine (Baltimore) 1995; 74:191. 88. Graninger W, Ragette R. Nosocomial bacteremia due to Enterococcus faecalis without endocarditis. Clin Infect Dis 1992; 15:49. 89. Shlaes DM, Levy J, Wolinsky E. Enterococcal bacteremia without endocarditis. Arch Intern Med 1981; 141:578. 90. Weinstein MP, Towns ML, Quartey SM, et al. The clinical significance of positive blood cultures in the 1990s: a prospective comprehensive evaluation of the microbiology, epidemiology, and outcome of bacteremia and fungemia in adults. Clin Infect Dis 1997; 24:584. 91. Edmond MB, Wallace SE, McClish DK, et al. Nosocomial bloodstream infections in United States hospitals: a three-year analysis. Clin Infect Dis 1999; 29:239. 92. Wisplinghoff H, Bischoff T, Tallent SM, et al. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 2004; 39:309. 93. Anderson DJ, Murdoch DR, Sexton DJ, et al. Risk factors for infective endocarditis in patients with enterococcal bacteremia: a case-control study. Infection 2004; 32:72. 94. Gullberg RM, Homann SR, Phair JP. Enterococcal bacteremia: analysis of 75 episodes. Rev Infect Dis 1989; 11:74. 95. Hoge CW, Adams J, Buchanan B, Sears SD. Enterococcal bacteremia: to treat or not to treat, a reappraisal. Rev Infect Dis 1991; 13:600. 96. Watanakunakorn C, Patel R. Comparison of patients with enterococcal bacteremia due to strains with and without high-level resistance to gentamicin. Clin Infect Dis 1993; 17:74. 97. Stevenson KB, Murray EW, Sarubbi FA. Enterococcal meningitis: report of four cases and review. Clin Infect Dis 1994; 18:233. 98. Bayer AS, Seidel JS, Yoshikawa TT, et al. Group D enterococcal meningitis. Clinical and therapeutic considerations with report of three cases and review of the literature. Arch Intern Med 1976; 136:883. 99. Kurup A, Tee WS, Loo LH, Lin R. Infection of central nervous system by motile Enterococcus: first case report. J Clin Microbiol 2001; 39:820. 100. Buchino JJ, Ciambarella E, Light I. Systemic group D streptococcal infection in newborn infants. Am J Dis Child 1979; 133:270. 101. Siegel JD, McCracken GH Jr. Group D streptococcal infections. J Pediatr 1978; 93:542. 102. Nagai K, Yuge K, Ono E, et al. Enterococcus faecium meningitis in a child. Pediatr Infect Dis J 1994; 13:1016. 103. Elvy J, Porter D, Brown E. Treatment of external ventricular drain-associated ventriculitis caused by Enterococcus faecalis with intraventricular daptomycin. J Antimicrob Chemother 2008; 61:461. 104. Williamson JC, Glazier SS, Peacock JE Jr. Successful treatment of ventriculostomy-related meningitis caused by vancomycin-resistant Enterococcus with intravenous and intraventricular quinupristin/dalfopristin. Clin Neurol Neurosurg 2002; 104:54. 105. Nachman SA, Verma R, Egnor M. Vancomycin-resistant Enterococcus faecium shunt infection in an infant: an antibiotic cure. Microb Drug Resist 1995; 1:95. 106. Tush GM, Huneycutt S, Phillips A, Ward JD. Intraventricular quinupristin/dalfopristin for the treatment of vancomycin-resistant Enterococcus faecium shunt infection. Clin Infect Dis 1998; 26:1460. 107. Garey KW, Tesoro E, Muggia V, et al. Cerebrospinal fluid concentrations of quinupristin-dalfopristin in a patient with vancomycin-resistant Enterococcus faecium [correction of faecalis] ventriculitis. Pharmacotherapy 2001; 21:748. 108. Shaikh ZH, Peloquin CA, Ericsson CD. Successful treatment of vancomycin-resistant Enterococcus faecium meningitis with linezolid: case report and literature review. Scand J Infect Dis 2001; 33:375. 109. Zeana C, Kubin CJ, Della-Latta P, Hammer SM. Vancomycin-resistant Enterococcus faecium meningitis successfully managed with linezolid: case report and review of the literature. Clin Infect Dis 2001; 33:477. 110. Graham PL, Ampofo K, Saiman L. Linezolid treatment of vancomycin-resistant Enterococcus faecium ventriculitis. Pediatr Infect Dis J 2002; 21:798. 111. Hachem R, Afif C, Gokaslan Z, Raad I. Successful treatment of vancomycin-resistant Enterococcus meningitis with linezolid. Eur J Clin Microbiol Infect Dis 2001; 20:432. 112. Steinmetz MP, Vogelbaum MA, De Georgia MA, et al. Successful treatment of vancomycin-resistant enterococcus meningitis with linezolid: case report and review of the literature. Crit Care Med 2001; 29:2383. 113. Ryan JL, Pachner A, Andriole VT, Root RK. Enterococcal meningitis: combined vancomycin and rifampin therapy. Am J Med 1980; 68:449. 114. Pérez Mato S, Robinson S, Bégué RE. Vancomycin-resistant Enterococcus faecium meningitis successfully treated with chloramphenicol. Pediatr Infect Dis J 1999; 18:483. 115. Venezio FR, Masters D, O'Keefe P. Enterococcal meningitis: failure of treatment with ampicillin and chloramphenicol. J Infect Dis 1984; 150:305. 专题 3163 版本 16.0.zh-Hans.2.0 专题提纲 , , 引言 , 临床治疗方法 , 敏感菌株的治疗方法 , 耐药菌株的治疗方法 , - 高水平青霉素耐药 , - 高水平氨基糖苷类耐药 , - 耐万古霉素 , 抗菌药物 , 有抗VRE活性的肠胃外药物 , - 利奈唑胺 , - 达托霉素 , - 替加环素 , - 奎奴普丁-达福普汀 , - 替考拉宁 , - 泰拉万星 , 联合治疗 , 替代药物 , 临床感染 , 泌尿道感染 , 菌血症 , 心内膜炎 , 脑膜炎 , 患者教育 , 总结与推荐 , 参考文献 图表 查看全部 , 图表 , , Parenteral rx enterococci , Rx EC amp resistance , Parenteral rx VRE , Rx enterococci UTI , Rx enterococci mening 相关专题 , 5-羟色胺综合征 , 人工瓣膜心内膜炎的抗生素治疗 , 耐万古霉素肠球菌的流行病学、预防和控制 , 肠球菌中抗生素耐药性的机制 , 肠球菌的微生物学 , 血管内导管相关感染的治疗 , Antimicrobial therapy of native valve endocarditis , Infections of central nervous system shunts and other devices , Patient information: Vancomycin-resistant enterococci (The Basics) 拖动此处调整窗口大小 用户协议 | 政策 | 支持标签 (网页)发布(版本):23.5 文献(版本): C23.131 授权于: 重庆医科大学附属第一医院 支持标签: [0605-218.207.2.100-6B44755E7E-I605869.14] 输入案例号 无案例参考编号? 联系我们 Wolters Kluwer Health 联系我们 帮助 关于我们 ? 2015 UpToDate, Inc. 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