引言
嗜麥芽窄食單胞菌(Stenotrophomonas maltophilia </12；曾命名爲嗜麥芽黃單胞菌(Xanthomonas maltophilia)是一種機會性致病的耐多藥革蘭陰性桿菌[1-4]，特別是在住院患者中。免疫功能嚴重受損或日常活動能力嚴重衰弱者若感染這種病原體，可造成嚴重病況和高死亡率。
本文將討論嗜麥芽窄食單胞菌感染的臨牀表現和治療。革蘭陰性桿菌菌血症、導管相關血流感染和醫院獲得性肺炎詳見其他專題。(參見“成人革蘭陰性桿菌菌血症”和“血管內導管相關感染的治療”和“成人醫院獲得性肺炎和呼吸機相關肺炎的治療”)
微生物學
嗜麥芽窄食單胞菌是一種廣泛存在、需氧的非發酵革蘭陰性桿菌，與假單胞菌(Pseudomonas)關係密切[5]。該菌的名稱Stenotrophomonas是由希臘語詞根stenos(狹窄)、trophos(以……爲食者)及monas(單元)組成的，表示“攝食極少種類營養物質的單元”；Maltophilia表示“嗜麥芽”，來源於希臘語詞根maltum(麥芽)和philia(親和)。
嗜麥芽窄食單胞菌專性需氧，用實驗室常用的培養基就能長得很好，包括血瓊脂和MacConkey瓊脂培養基。該菌不能發酵乳糖，爲氧化酶陰性、過氧化氫酶陽性，通過實驗室用標準生化檢測就能可靠鑑定。此外，市售的自動鑑定系統也能準確鑑別該菌[4]。許多微生物學實驗室尚未配置窄食單胞菌(Stenotrophomonas)的基質輔助激光解吸/電離(matrix-assisted laser desorption/ionization, MALDI)鑑定技術。
嗜麥芽窄食單胞菌於1943年首次被分離，當時命名爲bookeri菌(Bacterium bookeri)。之後歸爲假單胞菌屬，而後又歸入黃單胞菌屬(Xanthomonas)，最終於1993年歸爲窄食單胞菌[4,6,7]。嗜麥芽窄食單胞菌是唯一已知可感染人類的窄食單胞菌[7]，與其遺傳學關係最近的是植物病原體[7,8]。常可從土壤、水、動物、植物及醫院設備中分離出該菌[4,9-21]。嗜麥芽窄食單胞菌本來就能附着於外物並形成生物膜，從而抵抗宿主防禦和抗生素[18,19,22-26]。其促進因素包括：菌體表面帶正電，且菌毛具有黏附作用[7,22-24,26-28]。
此外，嗜麥芽窄食單胞菌對幾種抗生素表現出天然或獲得性耐藥。其對β-內酰胺類抗生素的耐藥性來自於兩種誘導性β-內酰胺酶：一種含鋅青黴素酶(L1)和一種頭孢菌素酶(L2)[21,29-32]。其對氨基糖苷類抗生素的耐藥性來自於一種氨基糖苷類乙酰轉移酶[33-39]。外膜脂多糖(lipopolysaccharide, LPS)結構的溫度依賴性變化也增加了細菌對氨基糖苷類抗生素的耐藥性[18,40-43]。此外，許多嗜麥芽窄食單胞菌株具有主動外排泵，導致其對多種抗生素進一步耐藥[39,44-47]。(參見下文‘各種抗生素治療方案的效果’)
不同的體外藥敏試驗方法在結果上存在差異，故最佳藥敏法尚未確定[48-51]。美國臨牀和實驗室標準協會(Clinical and Laboratory Standards Institute, CLSI)發佈了複方磺胺甲噁唑(trimethoprim-sulfamethoxazole, TMP-SMX)、米諾環素和左氧氟沙星對嗜麥芽窄食單胞菌的紙片擴散法最低抑菌濃度(minimal inhibitory concentration, MIC)折點，以及替卡西林-克拉維酸、頭孢他啶、米諾環素、左氧氟沙星和氯黴素對該菌的肉湯稀釋法MIC折點[18,49,52,53]。Etest法可用於評估細菌對頭孢他啶、米諾環素和氯黴素的敏感性。四環素或替加環素對嗜麥芽窄食單胞菌的MIC值暫無判讀標準，不過對替加環素的敏感性可利用針對腸桿菌科細菌的判讀標準來假設[54]。相較之下，歐洲抗菌藥物藥敏試驗委員會(European Committee on Antimicrobial Susceptibility Testing, EUCAST)僅發佈了TMP-SMX的折點[55]。
流行病學
據報道，嗜麥芽窄食單胞菌感染的發病率爲7.1-37.7例/10,000例出院[4,39,48,56]。隨着有風險的患者羣體日漸龐大，發病率似乎也在增加[1,4,49,57-59]。這種增加可能歸因於惡性腫瘤的治療進步、侵入性裝置的運用增加和廣譜抗生素的廣泛應用。
與嗜麥芽窄食單胞菌感染相關的危險因素包括：收入ICU、HIV感染、惡性腫瘤、囊性纖維化、中性粒細胞減少、機械通氣、中心靜脈置管、近期手術、創傷和曾用過廣譜抗生素[1,2,4,20,21,48,57,58,60]。嗜麥芽窄食單胞菌感染通常爲醫院獲得性，即使爲社區獲得性，患者大多也時常就醫，或者有致其易感的共存病況，比如既往創傷、致免疫功能低下的疾病和體內有留置裝置[61]。
目前已出現過許多次嗜麥芽窄食單胞菌感染暴發，涉及的人羣包括ICU成人患者[62-64]、血液系統惡性腫瘤患者和骨髓移植受者[65,66]、血液透析患者[67]和新生兒[68,69]。懷疑有多次暴發的病因都是患者使用了受污染的自來水[64,66,68]。此外，一些暴發和假暴發與內鏡再處理失敗有關[70-74]。
與疾病的關聯
肺炎和菌血症是感染的最常見表現[2,4,39,49,50,75-78]。
肺部感染 — 嗜麥芽窄食單胞菌肺炎通常爲醫院獲得性，最常發生於機械通氣患者。相較於肺部定植，感染與基礎性免疫抑制有關[79]。臨牀和影像學表現與其他感染性病因所致醫院獲得性肺炎相似。血液系統惡性腫瘤患者可出現一種與嗜麥芽窄食單胞菌感染有關的綜合徵，表現爲快速進展且常致死的出血性肺炎，相關報道越來越多[9,80,81]。
在美國，已明確嗜麥芽窄食單胞菌是囊性纖維化的一種病原體，在囊性纖維化患者中的總體檢出率與非結核分枝桿菌相近[82]。嗜麥芽窄食單胞菌感染與成人和兒童囊性纖維化患者的肺功能下降有關，但尚未確定因果關係[83,84]。(參見“囊性纖維化：肺病的抗生素治療”，關於‘其他病原體’一節)
菌血症 — 大多數嗜麥芽窄食單胞菌菌血症病例都與留置導管有關[3,85,86]。例如，一項研究納入腫瘤科207例有中心靜脈置管且出現嗜麥芽窄食單胞菌血流感染的患者，結果顯示，73%的感染與導管相關，22%爲繼發性(主要源於肺部)，5%爲原發性、與導管無關[85]。許多導管相關嗜麥芽窄食單胞菌血流感染都爲多重性。還有導管相關菌血症復發的病例，最晚甚至在初始感染得到治療後200日復發，這與長時間中性粒細胞減少和導管留置有關[87]。
在嚴重中性粒細胞減少患者中，菌血症的其他來源包括胃腸道或重度黏膜炎[85,88]。
其他表現 — 嗜麥芽窄食單胞菌感染的較少見臨牀表現包括：心內膜炎、乳突炎、腹膜炎、腦膜炎、軟組織感染、傷口感染、泌尿道感染和眼部感染[2,4,39,49,50,76-78,89]。窄食單胞菌也可引起皮膚表現，這可能反映轉移性感染或局部浸潤[90,91]。已有報道的皮膚表現包括蜂窩織炎、感染性潰瘍和壞疽性深膿皰。
感染的診斷
對相關臨牀樣本進行培養很容易發現嗜麥芽窄食單胞菌。若從正常情況下無菌的部位(如血液或腹腔液)培養出該菌，應解讀爲真性感染。該細菌能附着於上氣道和大支氣管的黏膜表面，可能在其中定植而不引發感染，故區分是定植還是真性感染十分重要，呼吸道樣本培養所得分離株尤其需要注意這一點。
若患者有肺炎的臨牀證據，例如新發肺部浸潤、氧合下降和發熱和/或白細胞增多，則呼吸道樣本培養出嗜麥芽窄食單胞菌時(無論是否還培養出其他呼吸道病原體)，應解讀爲符合真性感染。
若胸片上無實變表現，也沒有肺部感染的其他臨牀徵象，則呼吸道窄食單胞菌分離結果陽性很可能僅代表定植，而非侵襲性病變。一項回顧性研究納入92例出現急性呼吸道症狀、隨後發現呼吸道窄食單胞菌分離結果呈陽性的患者，結果顯示在無胸片實變表現的情況下，予以抗生素治療未產生可量化的影響[92]。
此外，由於該菌有定植於外物的習性，臨牀醫生必須謹慎解讀非無菌部位[如留置尿管、外科引流管和血管導管接口部位(catheter hub)]的培養結果。在這些情況下，對感染的臨牀證據(如發熱、白細胞增多和局部疼痛)的評估至關重要。若沒有菌血症或者其他無菌部位(如胸膜液和腹腔液)沒有感染證據，可推測該培養結果反映定植，而非感染。
治療
治療指徵 — 鑑於延誤適當的治療可導致很高死亡率，對於嗜麥芽窄食單胞菌感染應立即用抗生素治療。需要仔細評估從臨牀樣本中分離出嗜麥芽窄食單胞菌代表真性感染還是定植，因爲對於定植不應該予以治療，不恰當地使用抗生素將導致不良反應增加，並選擇出耐藥菌。感染和定植的區別見上文。(參見上文‘感染的診斷’)
對於無法明確是感染還是定植的情況，例如已知氣道有嗜麥芽窄食單胞菌定植、後來又出現肺炎臨牀證據，我們推薦啓動針對嗜麥芽窄食單胞菌的治療，直到獲得進一步的臨牀信息。在48-72小時後，我們會重新評估是否需要繼續此治療。對於肺炎或者病情危重或免疫功能受損患者的膿毒症，若沒有嗜麥芽窄食單胞菌定植既往證據，我們在予以經驗性治療時通常不會覆蓋嗜麥芽窄食單胞菌。
各種抗生素治療方案的效果 — 嗜麥芽窄食單胞菌多重耐藥，因此抗生素選擇有限，關於最佳療法的臨牀數據也較少。TMP-SMX是首選療法，因其在體外對嗜麥芽窄食單胞菌的活性最可靠[93-95]。例如，監測2009-2012年間分離自因肺炎住院患者的革蘭陰性菌，發現美國醫院分離的302株嗜麥芽窄食單胞菌中有96%對TMP-SMX敏感，歐洲醫院分離的192株嗜麥芽窄食單胞菌中，敏感率爲98%[93]。另外，觀察性研究和病例系列研究顯示，TMP-SMX的臨牀結局良好[57,96]。但部分患者因爲超敏反應、藥物毒性或其他不良反應而無法耐受TMP-SMX。此外，已發現越來越多的對TMP-SMX體外耐藥的嗜麥芽窄食單胞菌分離株，尤其在囊性纖維化患者中[49,75,97,98]。
氟喹諾酮類，特別是左氧氟沙星，是TMP-SMX的潛在替代藥物[94]。在上文討論過的監測研究中，75%-84%的嗜麥芽窄食單胞菌肺部分離株對左氧氟沙星敏感[93]。此外，小型回顧性研究顯示，對於嗜麥芽窄食單胞菌感染，採用氟喹諾酮和TMP-SMX單藥治療的臨牀結局(微生物學治癒率、臨牀成功率和短期死亡率)相似[96,99]。但體外研究指出，氟喹諾酮治療期間可能選擇出耐藥突變株[100,101]。數據顯示，莫西沙星對嗜麥芽窄食單胞菌的體外活性可能與左氧氟沙星相似[102]，但CLSI沒有設定莫西沙星的折點。因此，我們通常優選左氧氟沙星而不是莫西沙星來治療嗜麥芽窄食單胞菌感染。
米諾環素和替加環素對嗜麥芽窄食單胞菌分離株的MIC值也較低[93,94,103]，小型回顧性研究顯示，它們的臨牀結局都與TMP-SMX相當[104,105]。然而，替加環素的血清藥物濃度較低，這限制了它在血流感染中的應用，而且與其他用於治療肺炎的藥物相比，該藥相關的死亡率更高，也削減了其臨牀應用。
有人提出將替卡西林-克拉維酸作爲替代性治療用藥，但據報道該藥的體外耐藥率高達55%[18,39,106]。嗜麥芽窄食單胞菌對頭孢他啶的耐藥率也相對較高[94]。多粘菌素類(如硫酸粘菌素)對嗜麥芽窄食單胞菌的體外活性不一。
另外，嗜麥芽窄食單胞菌對其他β-內酰胺類藥物、氨曲南、氨基糖苷類抗生素、磷黴素和碳青黴烯類的耐藥率高，有的是天然耐藥，有的是獲得性耐藥。無論藥敏試驗結果如何，均應假定該菌對碳青黴烯類耐藥。
由於該菌對衆多類別抗生素的耐藥率都高，人們開始關注聯合治療方案具有協同作用的可能性。迄今爲止，聯合治療有益的臨牀數據仍然有限，所以其作用待定。一項前瞻性研究納入嗜麥芽窄食單胞菌菌血症患者，結果顯示，TMP-SMX、第三代頭孢菌素和超廣譜青黴素這3類藥物使用了2種或以上者，與僅使用1種者相比，死亡率更低[57]。聯合治療的證據主要來自體外研究。幾項研究顯示，一些抗生素組合具有體外協同作用，包括：TMP-SMX+頭孢他啶，TMP-SMX+替卡西林-克拉維酸，以及替卡西林-克拉維酸+環丙沙星[107-109]。
如何選擇抗生素 — TMP-SMX是首選治療，劑量爲TMP成分15mg/(kg·d)，分3次或4次給藥，並根據腎功能調整劑量[7]；我們通常將其用於嗜麥芽窄食單胞菌感染的經驗性治療(即獲得藥敏結果之前)，若分離株對該藥敏感則還用於針對性治療。對於以下患者的嗜麥芽窄食單胞菌感染的經驗性治療，在獲得藥敏結果之前，我們建議再加一種有活性的藥物(例如左氧氟沙星或頭孢他啶，根據當地抗菌譜和患者因素如是否過敏決定)：病情嚴重的患者，中性粒細胞減少或有其他病況致免疫功能低下的患者，以及給予了看似適當的治療但症狀和體徵仍持續的患者。
若患者因超敏反應或其他預期會出現的藥物毒性而不能使用TMP-SMX，我們使用左氧氟沙星或頭孢他啶進行經驗性治療，也是根據當地抗菌譜和患者特異性因素決定，後者包括過敏情況和/或是否需要覆蓋其他病原體等。如果分離株對左氧氟沙星敏感，可繼續使用左氧氟沙星進行嗜麥芽窄食單胞菌的針對性治療，尤其是如果爲多重感染且左氧氟沙星在治療其他已得到識別的病原體。如果分離株對其他β-內酰胺類藥物如替卡西林-克拉維酸或頭孢他啶敏感，也可在不能使用TMP-SMX時用其作爲替代。
若分離株對TMP-SMX敏感，但對氟喹諾酮類或β-內酰胺類藥物都不敏感，並且TMP-SMX引起的超敏反應是由IgE介導，我們傾向於對患者進行快速脫敏(參見“藥物速髮型超敏反應的快速脫敏”)[7,110]。若患者因爲IgE超敏反應以外原因無法使用TMP-SMX，並且對氟喹諾酮類或β-內酰胺類藥物都不敏感，潛在替代藥物包括米諾環素、替加環素和粘菌素，都各有特定的不良反應。建議請感染病專家會診。
支持上述抗生素選擇方法的證據見上文。(參見上文‘各種抗生素治療方案的效果’)
療程 — 療程取決於感染部位，只要有臨牀改善的證據，菌血症治療14日合適，對於免疫功能正常宿主的醫院獲得性肺炎，治療7日合適。更長的療程(10-14日)通常用於免疫功能受損宿主。(參見討論具體感染療程的相應專題)。
其他治療問題 — 除了抗菌治療，某些感染可能需要額外干預，比如拔管或清創。例如，拔管對於降低導管相關血流感染複發率非常重要[87]。
預後
在免疫功能嚴重受損或日常活動能力嚴重衰弱者中，嗜麥芽窄食單胞菌感染可引起嚴重病況和高死亡率。
總體而言，估計死亡率介於21%-69%[58,111,112]。然而，在控制了其他變量的情況下，此類感染的真實死亡率尚不清楚。研究者試圖通過回顧性分析確定與嗜麥芽窄食單胞菌感染患者死亡相關的獨立危險因素，而一項回顧性隊列研究發現，收入ICU和延誤有效治療是其中兩種[2]。
預防
感染控制和抗生素管理措施，對於儘可能降低嗜麥芽窄食單胞菌感染髮病率、減少耐藥菌株的出現十分重要。這些措施包括：合理使用抗生素，避免長期或不必要地使用外物器械或設備，以及遵守手衛生習慣。可通過嚴格用手衛生和接觸隔離措施來減少ICU內的菌株克隆播散[113]。(參見“感染預防：預防感染傳播的措施”)
總結與推薦
嗜麥芽窄食單胞菌是一種機會性致病的多重耐藥革蘭陰性桿菌，可在免疫功能嚴重受損或日常活動能力嚴重衰弱者中引起嚴重病況和高死亡率。與窄食單胞菌感染相關的危險因素包括：收入ICU、HIV感染、惡性腫瘤、囊性纖維化、中性粒細胞減少、機械通氣、中心靜脈置管、近期手術、創傷和曾用過廣譜抗生素(參見上文‘微生物學’和‘流行病學’)。
嗜麥芽窄食單胞菌感染最常見的表現是肺炎(通常爲醫院獲得性)和菌血症(常與留置導管有關)。較少見表現包括：心內膜炎、乳突炎、腹膜炎、腦膜炎、軟組織感染、傷口感染、泌尿道感染和眼部感染。(參見上文‘與疾病的關聯’)
若從正常情況下無菌的部位(如血液或腹腔液)培養出嗜麥芽窄食單胞菌，應認爲代表真性感染。對於有肺炎臨牀證據的患者，呼吸道樣本培養出嗜麥芽窄食單胞菌應解讀爲符合感染，但若沒有這種證據，可能反映定植而非侵襲性病變。同樣，解讀非無菌部位(如留置導管或引流管)的培養結果時，必須考慮到嗜麥芽窄食單胞菌有定植在外物而不引發感染的習性。(參見上文‘感染的診斷’)
對於嗜麥芽窄食單胞菌感染的經驗性和針對性治療，我們建議採用複方磺胺甲噁唑(TMP-SMX)(Grade 2C)。對於嗜麥芽窄食單胞菌感染病情嚴重、有致免疫功能低下病況或接受TMP-SMX治療但症狀持續的患者，我們還建議在經驗性治療中加用一種藥物，例如左氧氟沙星或頭孢他啶，直到獲得藥敏結果(Grade 2C)。若患者因爲超敏反應或其他預期會出現的藥物毒性而不能使用TMP-SMX，我們用左氧氟沙星或頭孢他啶進行經驗性治療；這兩種藥物及替卡西林-克拉維酸在分離株敏感的情況下，也都可作爲針對性治療的備選。(參見上文‘如何選擇抗生素’和‘各種抗生素治療方案的效果’)
療程取決於感染部位，對於菌血症，治療14日合適，對於免疫功能正常宿主的醫院獲得性肺炎，通常治療7日合適。某些感染可能需要額外干預，例如拔管或創面清創。(參見上文‘療程’和‘其他治療問題’)
有必要採取感染控制措施，以儘可能降低嗜麥芽窄食單胞菌感染的發病率、減少耐藥菌株的出現，包括：合理使用抗生素，避免長期或不必要地使用外物設備，以及遵守手衛生(參見上文‘預防’和“感染預防：預防感染傳播的措施”)。
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