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一、毒力機(jī)制 在過去的10年中，對鮑曼不動桿菌毒力機(jī)制的研究主要包括抗干燥性、抵抗消毒、生物膜形成和運(yùn)動能力，總體來說，鮑曼不動桿菌具有在不利條件下生存的顯著能力。最近發(fā)現(xiàn)的毒力因子，例如促進(jìn)鮑曼不動桿菌發(fā)病機(jī)制的分泌系統(tǒng)、表面糖綴合物和微量營養(yǎng)素獲取系統(tǒng)，可能決定了鮑曼不動桿菌菌株的毒力潛力。 抗干燥性即在干燥條件下保持活力的能力，因鮑曼不動桿菌的臨床分離株而異，有些分離株可存活近100天[6, 7]。雖然缺乏直接證據(jù)，但莢膜多糖很可能有助于鮑曼不動桿菌對干燥的抵抗力[8]。 消毒劑（如洗必泰）廣泛用于醫(yī)院和其他醫(yī)療衛(wèi)生機(jī)構(gòu)。鮑曼不動桿菌已被證實(shí)可以使用不動桿菌外排蛋白將洗必泰積極泵出細(xì)胞[9]，從而可能促進(jìn)細(xì)菌的存活。 微生物生物膜是包裹在細(xì)胞外基質(zhì)中的群落。鮑曼不動桿菌種群會在皮膚傷口、軟組織、封閉敷料、醫(yī)療器械（如氣管導(dǎo)管，以及聚碳酸酯和不銹鋼材質(zhì)的器材）上形成堅固的生物膜[10, 11]。 細(xì)菌運(yùn)動與生物體致病的能力密切相關(guān)，例如鞭毛對于銅綠假單胞菌來說猶如細(xì)菌“馬達(dá)”，是決定毒力的關(guān)鍵。對鮑曼不動桿菌臨床分離株的流行病學(xué)研究發(fā)現(xiàn)，血液分離株比痰分離株更具運(yùn)動性[12]，這表明鮑曼不動桿菌可能也存在一種“馬達(dá)”影響其運(yùn)動能力，從而決定其毒力大小。 常見的細(xì)菌糖綴合物包括莢膜多糖、糖基化蛋白、脂多糖和聚糖。因?yàn)槿狈ηv膜的菌株很容易被補(bǔ)體殺死，所以鮑曼不動桿菌的莢膜多糖可以被認(rèn)為是其主要的毒力因子[13]。缺乏糖基化系統(tǒng)的細(xì)胞在生物膜形成方面存在缺陷[14]。鮑曼不動桿菌通過改變脂多糖的脂質(zhì)A，阻止抗生素黏菌素的結(jié)合，從而產(chǎn)生耐藥性[15, 16]。而菌毛聚糖可能已經(jīng)進(jìn)化為保護(hù)蛋白質(zhì)成分免受抗原識別，而且與亞抑制濃度的抗生素接觸后，聚糖結(jié)構(gòu)改變，會進(jìn)一步增強(qiáng)鮑曼不動桿菌的毒力[17, 18]。所以，糖綴合物在鮑曼不動桿菌中具有關(guān)鍵的結(jié)構(gòu)作用，是介導(dǎo)抵御各種不利生存環(huán)境、免疫逃避和調(diào)節(jié)以及毒力的第一道防線。 鐵、錳和鋅等微量金屬元素對生命的所有領(lǐng)域都是必不可少的，也是鮑曼不動桿菌生存所必需的[19-21]。 與其他革蘭氏陰性病原體類似，鮑曼不動桿菌使用分泌蛋白來促進(jìn)環(huán)境和宿主適應(yīng)。鮑曼不動桿菌中的蛋白質(zhì)分泌系統(tǒng)對于黏附宿主細(xì)胞、介導(dǎo)肺定植和傳播到其他器官、進(jìn)行細(xì)菌競爭等都有重要作用[22-26]。 總體來說，鮑曼不動桿菌能夠在對許多細(xì)菌病原體不利的環(huán)境中持續(xù)存在的特征，為其在人體定植和隨后的感染奠定了基礎(chǔ)。 二、傳播途徑 鮑曼不動桿菌有多種傳播途徑，包括空氣、水和表面接觸。鮑曼不動桿菌是一種院內(nèi)感染常見病原體，其環(huán)境污染與干燥或潮濕地區(qū)有關(guān)[27]。另外，其存活時間也與特定菌株相關(guān)，一些菌株的存活時間為4個月[28]，受污染的表面和醫(yī)療設(shè)備和/或患者和醫(yī)務(wù)人員的手衛(wèi)生可能會成為常見定植部位和有效的傳播方式，其中醫(yī)務(wù)人員可充當(dāng)載體，將細(xì)菌從受污染的表面帶到患者或患者之間[29, 30]。 三、臨床表現(xiàn) 鮑曼不動桿菌感染主要表現(xiàn)為醫(yī)院獲得性肺炎，特別是在氣管插管的患者中更易發(fā)生，不動桿菌可以在導(dǎo)管上形成生物膜，直接進(jìn)入肺泡，在組織中建立感染[31, 32]。其次是血流感染。血流感染通常發(fā)生在存在中心靜脈導(dǎo)管的情況下，或者繼發(fā)于廣泛的肺炎。另外，鮑曼不動桿菌也會引起皮膚和軟組織以及手術(shù)部位的感染（如骨髓炎、心內(nèi)膜炎、腦膜炎等），以及與導(dǎo)管相關(guān)的尿路感染[33-37]。這些情況的共同點(diǎn)是解剖屏障的破壞使鮑曼不動桿菌能夠直接進(jìn)入感染部位。由鮑曼不動桿菌引起的社區(qū)獲得性感染近年也越來越多。社區(qū)獲得性感染主要發(fā)生在溫暖、潮濕的熱帶環(huán)境中，特別是在澳大利亞、大洋洲和亞洲的部分地區(qū)，包括中國、泰國[38, 39]。但通常出現(xiàn)在有合并癥的患者中，包括大量吸煙、過度飲酒、糖尿病、癌癥和慢性阻塞性肺疾病患者[33, 38]。社區(qū)獲得性感染通常表現(xiàn)為急性肺炎，在極少數(shù)情況下會出現(xiàn)腦膜炎、蜂窩組織炎或原發(fā)性菌血癥[33]。在戰(zhàn)爭或自然災(zāi)害中，鮑曼不動桿菌也經(jīng)傷口、軟組織，侵入血液和骨骼造成感染[40, 41]。另外，還有鮑曼不動桿菌引起壞死性筋膜炎的報道，這些病例主要是HIV、肝硬化、實(shí)體器官移植或糖尿病等免疫功能低下的患者[42-47]。 四、診斷和治療 對于鮑曼不動桿菌感染的診斷，臨床上常采用細(xì)菌培養(yǎng)和宏基因組二代測序（mNGS）的檢測方法。痰液、肺泡灌洗液、血液、腦脊液、尿液、糞便、咽拭子、肛拭子、引流液、創(chuàng)面分泌物等多種生物標(biāo)本中均可檢出鮑曼不動桿菌。 β-內(nèi)酰胺類抗生素是鮑曼不動桿菌感染的首選抗菌藥物。舒巴坦用于抑制大多數(shù)病原體的β-內(nèi)酰胺酶，對不動桿菌具有直接的抗菌活性。隨著舒巴坦耐藥率的不斷增加，碳青霉烯類藥物成為重要的治療選擇。β-內(nèi)酰胺類抗生素療效的最佳預(yù)測指標(biāo)是血清藥物濃度保持在最低抑制濃度（MIC）以上的時間。所以，對于耐藥病原體，延長碳青霉烯類藥物的輸注可以最大限度地延長高于MIC的時間，從而達(dá)到最優(yōu)化的治療效果[48-50]。蒙特卡羅模擬對不動桿菌屬的風(fēng)險分析顯示，每8小時給予1 g美羅培南（維持3 h輸注）將獲得最佳的殺菌率。與快速輸注相比，延長碳青霉烯輸注時間可降低死亡率，且沒有任何證據(jù)表明耐藥性出現(xiàn)率增加。然而，延長輸注時間，藥物藥代動力學(xué)顯示藥物峰值水平下降[49, 51]。因此，對于MIC為4～16 g/ml的分離株，應(yīng)延長輸注時間，但對于MIC較高的分離株（≥16 g/ml），建議間歇給藥，以達(dá)到高于MIC的峰值水平。 氟喹諾酮類藥物和氨基糖苷類藥物不作為經(jīng)驗(yàn)性治療的首選，因?yàn)轷U曼不動桿菌對這兩種藥物的耐藥率都很高[52, 53]。在敏感性允許的情況下，氨基糖苷類藥物可能是一種潛在的治療選擇[54]。 治療耐藥鮑曼不動桿菌的一種選擇藥物是替加環(huán)素。雖然替加環(huán)素對鮑曼不動桿菌菌株的MIC（2 g/ml）通常較低，但該藥物的血清濃度也較低，即使MIC為2 g/ml，在使用替加環(huán)素治療時結(jié)果可能較差，如增加死亡率，無法清除菌血癥和發(fā)生突破性菌血癥[55]。一項(xiàng)系統(tǒng)評價和薈萃分析（非特定于不動桿菌感染）也發(fā)現(xiàn)，替加環(huán)素治療會導(dǎo)致較高的住院死亡率、較低的微生物根除率和住院時間延長的趨勢[56]。 目前，多黏菌素通常是耐藥鮑曼不動桿菌的最后治療選擇。研究發(fā)現(xiàn)，多黏菌素在肺泡內(nèi)的藥物濃度相對較差，靜脈輸注2小時后采集的支氣管肺泡灌洗標(biāo)本中，尚未檢測到多黏菌素[57]。且多黏菌素具有較明顯的腎毒性和神經(jīng)毒性，所以霧化多黏菌素被用于臨床治療中。相較于靜脈用藥，霧化多黏菌素可能會在肺部達(dá)到非常高的濃度，最大限度地減少全身暴露和毒性，同時，鮑曼不動桿菌肺炎患者得到了良好的治療效果[58, 59]。但需要注意，多黏菌素可能對肺組織有毒并誘導(dǎo)支氣管痙攣，并且累積劑量依然有發(fā)生腎毒性的可能[60, 61]。 事實(shí)上，鮑曼不動桿菌對替加環(huán)素和多黏菌素的耐藥率也逐年上升，聯(lián)合治療成為改善治療結(jié)果的選擇。2012年《中國鮑曼不動桿菌感染診治與防控專家共識》指出，對于MDR，可選用舒巴坦或碳青霉烯類藥物聯(lián)合氟喹諾酮類或氨基糖苷類藥物。對于廣泛耐藥（XDR），可選擇舒巴坦聯(lián)合下述任何一種：米諾環(huán)素（或多西環(huán)素），多黏菌素，氨基糖苷類，碳青霉烯類抗生素；或多黏菌素聯(lián)合下述任何一種：舒巴坦，碳青霉烯類抗生素；抑或替加環(huán)素聯(lián)合下述任何一種：舒巴坦，碳青霉烯類，多黏菌素，喹諾酮類，氨基糖苷類抗生素；甚至三藥聯(lián)合：舒巴坦+多西環(huán)素+碳青霉烯類抗生素，或者亞胺培南+利福平+多黏菌素或妥布霉素[67]。在所有聯(lián)合方案中，最合理的一種可能是多黏菌素聯(lián)合碳青霉烯類，在多項(xiàng)體外研究中均發(fā)現(xiàn)其具有協(xié)同作用[62-66]，這種協(xié)同作用尤其適用于對碳青霉烯類具有中等耐藥性的分離株（例如碳青霉烯類MIC為4～16 g/ml）[63]。在非菌血癥XDR不動桿菌肺炎病例中，作為碳青霉烯類或其他藥物全身治療的輔助手段，可以考慮添加吸入性多黏菌素。 最后，目前迫切需要對聯(lián)合治療進(jìn)行前瞻性隨機(jī)研究，進(jìn)一步確定聯(lián)合方案是否有用，聯(lián)合治療方案是否優(yōu)于單一治療，以便指導(dǎo)今后如何選擇藥物治療。
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