引言
嗜麦芽窄食单胞菌(Stenotrophomonas maltophilia
本文将讨论嗜麦芽窄食单胞菌感染的临床表现和治疗。革兰阴性杆菌菌血症、导管相关血流感染和医院获得性肺炎详见其他专题。(参见“成人革兰阴性杆菌菌血症”和“血管内导管相关感染的治疗”和“成人医院获得性肺炎和呼吸机相关肺炎的治疗”)
微生物学
嗜麦芽窄食单胞菌是一种广泛存在、需氧的非发酵革兰阴性杆菌，与假单胞菌(Pseudomonas)关系密切[5]。该菌的名称Stenotrophomonas是由希腊语词根stenos(狭窄)、trophos(以……为食者)及monas(单元)组成的，表示“摄食极少种类营养物质的单元”；Maltophilia表示“嗜麦芽”，来源于希腊语词根maltum(麦芽)和philia(亲和)。
嗜麦芽窄食单胞菌专性需氧，用实验室常用的培养基就能长得很好，包括血琼脂和MacConkey琼脂培养基。该菌不能发酵乳糖，为氧化酶阴性、过氧化氢酶阳性，通过实验室用标准生化检测就能可靠鉴定。此外，市售的自动鉴定系统也能准确鉴别该菌[4]。许多微生物学实验室尚未配置窄食单胞菌(Stenotrophomonas)的基质辅助激光解吸/电离(matrix-assisted laser desorption/ionization, MALDI)鉴定技术。
嗜麦芽窄食单胞菌于1943年首次被分离，当时命名为bookeri菌(Bacterium bookeri)。之后归为假单胞菌属，而后又归入黄单胞菌属(Xanthomonas)，最终于1993年归为窄食单胞菌[4,6,7]。嗜麦芽窄食单胞菌是唯一已知可感染人类的窄食单胞菌[7]，与其遗传学关系最近的是植物病原体[7,8]。常可从土壤、水、动物、植物及医院设备中分离出该菌[4,9-21]。嗜麦芽窄食单胞菌本来就能附着于外物并形成生物膜，从而抵抗宿主防御和抗生素[18,19,22-26]。其促进因素包括：菌体表面带正电，且菌毛具有黏附作用[7,22-24,26-28]。
此外，嗜麦芽窄食单胞菌对几种抗生素表现出天然或获得性耐药。其对β-内酰胺类抗生素的耐药性来自于两种诱导性β-内酰胺酶：一种含锌青霉素酶(L1)和一种头孢菌素酶(L2)[21,29-32]。其对氨基糖苷类抗生素的耐药性来自于一种氨基糖苷类乙酰转移酶[33-39]。外膜脂多糖(lipopolysaccharide, LPS)结构的温度依赖性变化也增加了细菌对氨基糖苷类抗生素的耐药性[18,40-43]。此外，许多嗜麦芽窄食单胞菌株具有主动外排泵，导致其对多种抗生素进一步耐药[39,44-47]。(参见下文‘各种抗生素治疗方案的效果’)
不同的体外药敏试验方法在结果上存在差异，故最佳药敏法尚未确定[48-51]。美国临床和实验室标准协会(Clinical and Laboratory Standards Institute, CLSI)发布了复方磺胺甲噁唑(trimethoprim-sulfamethoxazole, TMP-SMX)、米诺环素和左氧氟沙星对嗜麦芽窄食单胞菌的纸片扩散法最低抑菌浓度(minimal inhibitory concentration, MIC)折点，以及替卡西林-克拉维酸、头孢他啶、米诺环素、左氧氟沙星和氯霉素对该菌的肉汤稀释法MIC折点[18,49,52,53]。Etest法可用于评估细菌对头孢他啶、米诺环素和氯霉素的敏感性。四环素或替加环素对嗜麦芽窄食单胞菌的MIC值暂无判读标准，不过对替加环素的敏感性可利用针对肠杆菌科细菌的判读标准来假设[54]。相较之下，欧洲抗菌药物药敏试验委员会(European Committee on Antimicrobial Susceptibility Testing, EUCAST)仅发布了TMP-SMX的折点[55]。
流行病学
据报道，嗜麦芽窄食单胞菌感染的发病率为7.1-37.7例/10,000例出院[4,39,48,56]。随着有风险的患者群体日渐庞大，发病率似乎也在增加[1,4,49,57-59]。这种增加可能归因于恶性肿瘤的治疗进步、侵入性装置的运用增加和广谱抗生素的广泛应用。
与嗜麦芽窄食单胞菌感染相关的危险因素包括：收入ICU、HIV感染、恶性肿瘤、囊性纤维化、中性粒细胞减少、机械通气、中心静脉置管、近期手术、创伤和曾用过广谱抗生素[1,2,4,20,21,48,57,58,60]。嗜麦芽窄食单胞菌感染通常为医院获得性，即使为社区获得性，患者大多也时常就医，或者有致其易感的共存病况，比如既往创伤、致免疫功能低下的疾病和体内有留置装置[61]。
目前已出现过许多次嗜麦芽窄食单胞菌感染暴发，涉及的人群包括ICU成人患者[62-64]、血液系统恶性肿瘤患者和骨髓移植受者[65,66]、血液透析患者[67]和新生儿[68,69]。怀疑有多次暴发的病因都是患者使用了受污染的自来水[64,66,68]。此外，一些暴发和假暴发与内镜再处理失败有关[70-74]。
与疾病的关联
肺炎和菌血症是感染的最常见表现[2,4,39,49,50,75-78]。
肺部感染 — 嗜麦芽窄食单胞菌肺炎通常为医院获得性，最常发生于机械通气患者。相较于肺部定植，感染与基础性免疫抑制有关[79]。临床和影像学表现与其他感染性病因所致医院获得性肺炎相似。血液系统恶性肿瘤患者可出现一种与嗜麦芽窄食单胞菌感染有关的综合征，表现为快速进展且常致死的出血性肺炎，相关报道越来越多[9,80,81]。
在美国，已明确嗜麦芽窄食单胞菌是囊性纤维化的一种病原体，在囊性纤维化患者中的总体检出率与非结核分枝杆菌相近[82]。嗜麦芽窄食单胞菌感染与成人和儿童囊性纤维化患者的肺功能下降有关，但尚未确定因果关系[83,84]。(参见“囊性纤维化：肺病的抗生素治疗”，关于‘其他病原体’一节)
菌血症 — 大多数嗜麦芽窄食单胞菌菌血症病例都与留置导管有关[3,85,86]。例如，一项研究纳入肿瘤科207例有中心静脉置管且出现嗜麦芽窄食单胞菌血流感染的患者，结果显示，73%的感染与导管相关，22%为继发性(主要源于肺部)，5%为原发性、与导管无关[85]。许多导管相关嗜麦芽窄食单胞菌血流感染都为多重性。还有导管相关菌血症复发的病例，最晚甚至在初始感染得到治疗后200日复发，这与长时间中性粒细胞减少和导管留置有关[87]。
在严重中性粒细胞减少患者中，菌血症的其他来源包括胃肠道或重度黏膜炎[85,88]。
其他表现 — 嗜麦芽窄食单胞菌感染的较少见临床表现包括：心内膜炎、乳突炎、腹膜炎、脑膜炎、软组织感染、伤口感染、泌尿道感染和眼部感染[2,4,39,49,50,76-78,89]。窄食单胞菌也可引起皮肤表现，这可能反映转移性感染或局部浸润[90,91]。已有报道的皮肤表现包括蜂窝织炎、感染性溃疡和坏疽性深脓疱。
感染的诊断
对相关临床样本进行培养很容易发现嗜麦芽窄食单胞菌。若从正常情况下无菌的部位(如血液或腹腔液)培养出该菌，应解读为真性感染。该细菌能附着于上气道和大支气管的黏膜表面，可能在其中定植而不引发感染，故区分是定植还是真性感染十分重要，呼吸道样本培养所得分离株尤其需要注意这一点。
若患者有肺炎的临床证据，例如新发肺部浸润、氧合下降和发热和/或白细胞增多，则呼吸道样本培养出嗜麦芽窄食单胞菌时(无论是否还培养出其他呼吸道病原体)，应解读为符合真性感染。
若胸片上无实变表现，也没有肺部感染的其他临床征象，则呼吸道窄食单胞菌分离结果阳性很可能仅代表定植，而非侵袭性病变。一项回顾性研究纳入92例出现急性呼吸道症状、随后发现呼吸道窄食单胞菌分离结果呈阳性的患者，结果显示在无胸片实变表现的情况下，予以抗生素治疗未产生可量化的影响[92]。
此外，由于该菌有定植于外物的习性，临床医生必须谨慎解读非无菌部位[如留置尿管、外科引流管和血管导管接口部位(catheter hub)]的培养结果。在这些情况下，对感染的临床证据(如发热、白细胞增多和局部疼痛)的评估至关重要。若没有菌血症或者其他无菌部位(如胸膜液和腹腔液)没有感染证据，可推测该培养结果反映定植，而非感染。
治疗
治疗指征 — 鉴于延误适当的治疗可导致很高死亡率，对于嗜麦芽窄食单胞菌感染应立即用抗生素治疗。需要仔细评估从临床样本中分离出嗜麦芽窄食单胞菌代表真性感染还是定植，因为对于定植不应该予以治疗，不恰当地使用抗生素将导致不良反应增加，并选择出耐药菌。感染和定植的区别见上文。(参见上文‘感染的诊断’)
对于无法明确是感染还是定植的情况，例如已知气道有嗜麦芽窄食单胞菌定植、后来又出现肺炎临床证据，我们推荐启动针对嗜麦芽窄食单胞菌的治疗，直到获得进一步的临床信息。在48-72小时后，我们会重新评估是否需要继续此治疗。对于肺炎或者病情危重或免疫功能受损患者的脓毒症，若没有嗜麦芽窄食单胞菌定植既往证据，我们在予以经验性治疗时通常不会覆盖嗜麦芽窄食单胞菌。
各种抗生素治疗方案的效果 — 嗜麦芽窄食单胞菌多重耐药，因此抗生素选择有限，关于最佳疗法的临床数据也较少。TMP-SMX是首选疗法，因其在体外对嗜麦芽窄食单胞菌的活性最可靠[93-95]。例如，监测2009-2012年间分离自因肺炎住院患者的革兰阴性菌，发现美国医院分离的302株嗜麦芽窄食单胞菌中有96%对TMP-SMX敏感，欧洲医院分离的192株嗜麦芽窄食单胞菌中，敏感率为98%[93]。另外，观察性研究和病例系列研究显示，TMP-SMX的临床结局良好[57,96]。但部分患者因为超敏反应、药物毒性或其他不良反应而无法耐受TMP-SMX。此外，已发现越来越多的对TMP-SMX体外耐药的嗜麦芽窄食单胞菌分离株，尤其在囊性纤维化患者中[49,75,97,98]。
氟喹诺酮类，特别是左氧氟沙星，是TMP-SMX的潜在替代药物[94]。在上文讨论过的监测研究中，75%-84%的嗜麦芽窄食单胞菌肺部分离株对左氧氟沙星敏感[93]。此外，小型回顾性研究显示，对于嗜麦芽窄食单胞菌感染，采用氟喹诺酮和TMP-SMX单药治疗的临床结局(微生物学治愈率、临床成功率和短期死亡率)相似[96,99]。但体外研究指出，氟喹诺酮治疗期间可能选择出耐药突变株[100,101]。数据显示，莫西沙星对嗜麦芽窄食单胞菌的体外活性可能与左氧氟沙星相似[102]，但CLSI没有设定莫西沙星的折点。因此，我们通常优选左氧氟沙星而不是莫西沙星来治疗嗜麦芽窄食单胞菌感染。
米诺环素和替加环素对嗜麦芽窄食单胞菌分离株的MIC值也较低[93,94,103]，小型回顾性研究显示，它们的临床结局都与TMP-SMX相当[104,105]。然而，替加环素的血清药物浓度较低，这限制了它在血流感染中的应用，而且与其他用于治疗肺炎的药物相比，该药相关的死亡率更高，也削减了其临床应用。
有人提出将替卡西林-克拉维酸作为替代性治疗用药，但据报道该药的体外耐药率高达55%[18,39,106]。嗜麦芽窄食单胞菌对头孢他啶的耐药率也相对较高[94]。多粘菌素类(如硫酸粘菌素)对嗜麦芽窄食单胞菌的体外活性不一。
另外，嗜麦芽窄食单胞菌对其他β-内酰胺类药物、氨曲南、氨基糖苷类抗生素、磷霉素和碳青霉烯类的耐药率高，有的是天然耐药，有的是获得性耐药。无论药敏试验结果如何，均应假定该菌对碳青霉烯类耐药。
由于该菌对众多类别抗生素的耐药率都高，人们开始关注联合治疗方案具有协同作用的可能性。迄今为止，联合治疗有益的临床数据仍然有限，所以其作用待定。一项前瞻性研究纳入嗜麦芽窄食单胞菌菌血症患者，结果显示，TMP-SMX、第三代头孢菌素和超广谱青霉素这3类药物使用了2种或以上者，与仅使用1种者相比，死亡率更低[57]。联合治疗的证据主要来自体外研究。几项研究显示，一些抗生素组合具有体外协同作用，包括：TMP-SMX+头孢他啶，TMP-SMX+替卡西林-克拉维酸，以及替卡西林-克拉维酸+环丙沙星[107-109]。
如何选择抗生素 — TMP-SMX是首选治疗，剂量为TMP成分15mg/(kg·d)，分3次或4次给药，并根据肾功能调整剂量[7]；我们通常将其用于嗜麦芽窄食单胞菌感染的经验性治疗(即获得药敏结果之前)，若分离株对该药敏感则还用于针对性治疗。对于以下患者的嗜麦芽窄食单胞菌感染的经验性治疗，在获得药敏结果之前，我们建议再加一种有活性的药物(例如左氧氟沙星或头孢他啶，根据当地抗菌谱和患者因素如是否过敏决定)：病情严重的患者，中性粒细胞减少或有其他病况致免疫功能低下的患者，以及给予了看似适当的治疗但症状和体征仍持续的患者。
若患者因超敏反应或其他预期会出现的药物毒性而不能使用TMP-SMX，我们使用左氧氟沙星或头孢他啶进行经验性治疗，也是根据当地抗菌谱和患者特异性因素决定，后者包括过敏情况和/或是否需要覆盖其他病原体等。如果分离株对左氧氟沙星敏感，可继续使用左氧氟沙星进行嗜麦芽窄食单胞菌的针对性治疗，尤其是如果为多重感染且左氧氟沙星在治疗其他已得到识别的病原体。如果分离株对其他β-内酰胺类药物如替卡西林-克拉维酸或头孢他啶敏感，也可在不能使用TMP-SMX时用其作为替代。
若分离株对TMP-SMX敏感，但对氟喹诺酮类或β-内酰胺类药物都不敏感，并且TMP-SMX引起的超敏反应是由IgE介导，我们倾向于对患者进行快速脱敏(参见“药物速发型超敏反应的快速脱敏”)[7,110]。若患者因为IgE超敏反应以外原因无法使用TMP-SMX，并且对氟喹诺酮类或β-内酰胺类药物都不敏感，潜在替代药物包括米诺环素、替加环素和粘菌素，都各有特定的不良反应。建议请感染病专家会诊。
支持上述抗生素选择方法的证据见上文。(参见上文‘各种抗生素治疗方案的效果’)
疗程 — 疗程取决于感染部位，只要有临床改善的证据，菌血症治疗14日合适，对于免疫功能正常宿主的医院获得性肺炎，治疗7日合适。更长的疗程(10-14日)通常用于免疫功能受损宿主。(参见讨论具体感染疗程的相应专题)。
其他治疗问题 — 除了抗菌治疗，某些感染可能需要额外干预，比如拔管或清创。例如，拔管对于降低导管相关血流感染复发率非常重要[87]。
预后
在免疫功能严重受损或日常活动能力严重衰弱者中，嗜麦芽窄食单胞菌感染可引起严重病况和高死亡率。
总体而言，估计死亡率介于21%-69%[58,111,112]。然而，在控制了其他变量的情况下，此类感染的真实死亡率尚不清楚。研究者试图通过回顾性分析确定与嗜麦芽窄食单胞菌感染患者死亡相关的独立危险因素，而一项回顾性队列研究发现，收入ICU和延误有效治疗是其中两种[2]。
预防
感染控制和抗生素管理措施，对于尽可能降低嗜麦芽窄食单胞菌感染发病率、减少耐药菌株的出现十分重要。这些措施包括：合理使用抗生素，避免长期或不必要地使用外物器械或设备，以及遵守手卫生习惯。可通过严格用手卫生和接触隔离措施来减少ICU内的菌株克隆播散[113]。(参见“感染预防：预防感染传播的措施”)
总结与推荐
嗜麦芽窄食单胞菌是一种机会性致病的多重耐药革兰阴性杆菌，可在免疫功能严重受损或日常活动能力严重衰弱者中引起严重病况和高死亡率。与窄食单胞菌感染相关的危险因素包括：收入ICU、HIV感染、恶性肿瘤、囊性纤维化、中性粒细胞减少、机械通气、中心静脉置管、近期手术、创伤和曾用过广谱抗生素(参见上文‘微生物学’和‘流行病学’)。
嗜麦芽窄食单胞菌感染最常见的表现是肺炎(通常为医院获得性)和菌血症(常与留置导管有关)。较少见表现包括：心内膜炎、乳突炎、腹膜炎、脑膜炎、软组织感染、伤口感染、泌尿道感染和眼部感染。(参见上文‘与疾病的关联’)
若从正常情况下无菌的部位(如血液或腹腔液)培养出嗜麦芽窄食单胞菌，应认为代表真性感染。对于有肺炎临床证据的患者，呼吸道样本培养出嗜麦芽窄食单胞菌应解读为符合感染，但若没有这种证据，可能反映定植而非侵袭性病变。同样，解读非无菌部位(如留置导管或引流管)的培养结果时，必须考虑到嗜麦芽窄食单胞菌有定植在外物而不引发感染的习性。(参见上文‘感染的诊断’)
对于嗜麦芽窄食单胞菌感染的经验性和针对性治疗，我们建议采用复方磺胺甲噁唑(TMP-SMX)(Grade 2C)。对于嗜麦芽窄食单胞菌感染病情严重、有致免疫功能低下病况或接受TMP-SMX治疗但症状持续的患者，我们还建议在经验性治疗中加用一种药物，例如左氧氟沙星或头孢他啶，直到获得药敏结果(Grade 2C)。若患者因为超敏反应或其他预期会出现的药物毒性而不能使用TMP-SMX，我们用左氧氟沙星或头孢他啶进行经验性治疗；这两种药物及替卡西林-克拉维酸在分离株敏感的情况下，也都可作为针对性治疗的备选。(参见上文‘如何选择抗生素’和‘各种抗生素治疗方案的效果’)
疗程取决于感染部位，对于菌血症，治疗14日合适，对于免疫功能正常宿主的医院获得性肺炎，通常治疗7日合适。某些感染可能需要额外干预，例如拔管或创面清创。(参见上文‘疗程’和‘其他治疗问题’)
有必要采取感染控制措施，以尽可能降低嗜麦芽窄食单胞菌感染的发病率、减少耐药菌株的出现，包括：合理使用抗生素，避免长期或不必要地使用外物设备，以及遵守手卫生(参见上文‘预防’和“感染预防：预防感染传播的措施”)。
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