2025, Vol. 41中国科学院微生物研究所、中国微生物学会主办
文章信息
- 吴佳, 王军
- WU Jia, WANG Jun
- 多重耐药鲍曼不动杆菌的噬菌体治疗
- Phage therapy for multidrug-resistant Acinetobacter baumannii
- 生物工程学报, 2025, 41(6): 2256-2274
- Chinese Journal of Biotechnology, 2025, 41(6): 2256-2274
- CSTR: 32114.14.j.cjb.250114
- DOI: 10.13345/j.cjb.250114
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文章历史
- Received: February 14, 2025
- Accepted: April 15, 2025
- Published: April 16, 2025
引用本文
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2. 中国科学院微生物研究所, 北京 100101
2. Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
鲍曼不动杆菌广泛存在于自然界和医疗环境中，它不仅对碳青霉烯类、氨基糖苷类、四环素类和多黏菌素等多种抗生素表现出高度耐药性，还能在医院环境中形成生物膜，保护细菌免受抗生素的攻击，甚至促进耐药基因水平转移，成为医院感染的重要病原体[1-4]。它可引起多种类型的感染，如呼吸机相关性肺炎、血流感染、尿路感染、脑膜炎和伤口感染等[5-6]。这些感染与高病死率和病残率相关，并导致患者住院时间延长和医疗费用增加[7-10]。研究发现，多重耐药鲍曼不动杆菌感染导致的死亡率可达30%–50%[11-12]，由耐碳青霉烯类鲍曼不动杆菌感染引起的死亡率可高达40%–70%[13]。2019年新型冠状病毒大流行期间，鲍曼不动杆菌特别是耐碳青霉烯类菌株引发了严重的医疗危机[14-15]。
目前，世界卫生组织(World Health Organization, WHO)已将鲍曼不动杆菌列为最危险的ESKAPE [指屎肠球菌(Enterococcus faecium)、金黄色葡萄球菌(Staphylococcus aureus)、肺炎克雷伯菌(Klebsiella pneumoniae)、鲍曼不动杆菌(Acinetobacter baumannii)、铜绿假单胞菌(Pseudomonas aeruginosa)、肠杆菌属(Enterobacter spp.)]之一[16]。在WHO抗生素耐药菌有效药物研发优先列表中，耐碳青霉烯类鲍曼不动杆菌被列为优先级1 (“关键”)的病原体[17]。本文结合我国2014–2023年鲍曼不动杆菌流行病学和耐药机制，综合分析了噬菌体治疗多重耐药鲍曼不动杆菌的现状，以期为噬菌体疗法的发展提供新思路。
1 鲍曼不动杆菌的流行病学及现状分析鲍曼不动杆菌能在医疗环境中传播和流行主要是由于其具有极强的黏附力，可附着在生物或非生物表面，对消毒剂和抗生素具有抵抗力，并能在饥饿条件下长期保持致病性[18-20]。其引起的感染呈全球性分布，且具有显著的地域差异：在中国、越南、伊朗等亚洲国家报告的高耐药菌株比例较高，尤其是重症监护病房(intensive care unit, ICU)[21-22]；法国、意大利、德国等地也报告了多重耐药克隆株(如国际克隆Ⅱ型)的持续传播，OXA-23是最常见的碳青霉烯酶基因[23-25]；美国耐碳青霉烯类鲍曼不动杆菌(carbapenem-resistant A. baumannii, CRAB)检出率逐年升高，部分地区超过70%[26]；尼日利亚西南部地区，携带NDM-1基因的鲍曼不动杆菌比例较高[27]。另外，鲍曼不动杆菌也呈现跨区域乃至国际传播。美国军方医疗体系中出现的多重耐药鲍曼不动杆菌-醋酸钙复合体感染与在伊拉克执行的军事行动有关[28]。意大利医疗环境中发现了与欧洲克隆Ⅰ型和Ⅱ型相关的多重耐药鲍曼不动杆菌流行株[29]。这些传播可能与患者和医护人员在不同医疗环境间的流动促进了耐药基因的广泛传播密切相关。
鲍曼不动杆菌的传播及其带来的健康威胁已引起全球广泛关注。我国2个具有代表性的细菌耐药性监测网络——中国细菌耐药监测网(China antimicrobial surveillance network, CHINET)和全国细菌耐药监测网(China antimicrobial resistance surveillance system, CARSS) [30]，为我国乃至全球的抗感染治疗和公共卫生安全提供了宝贵的数据支持。
本文结合CARSS上的数据，总结了全国鲍曼不动杆菌检出率和耐碳青霉烯类鲍曼不动杆菌检出率的流行情况。2014–2023年，我国国内医院鲍曼不动杆菌检出率约为6.1%–7.7% (表 1)。其中，2023年鲍曼不动杆菌分离量创新高，达366 748株。碳青霉烯类抗生素具有广谱抗菌活性，是治疗多重耐药菌感染的重要药物。结合CARSS报告，2014–2023年全国CRAB平均耐药率超过53% (图 1)，其中河南省检出率最高，可达82.1%[31]。一项关于我国各地医院重症监护病房中临床耐碳青霉烯类鲍曼不动杆菌的流行病学和遗传特征的统计指出，全国不同省份77个ICU病房中，CRAB检出率为71.4%[32]。结合CARSS报告，ICU耐药菌检
| Year | A. baumannii (strains) | Clinically isolated bacteria (strains) | Detection rate (%) |
| 2014 | 171 662 | 2 227 420 | 7.7 |
| 2015 | 183 178 | 2 400 786 | 7.6 |
| 2016 | 208 689 | 2 727 605 | 7.7 |
| 2017 | 207 046 | 2 894 517 | 7.2 |
| 2018 | 227 091 | 3 234 372 | 7.0 |
| 2019 | 239 890 | 3 528 471 | 6.8 |
| 2020 | 219 921 | 3 249 123 | 6.8 |
| 2021 | 241 383 | 3 743 027 | 6.4 |
| 2022 | 298 753 | 4 928 509 | 6.1 |
| 2023 | 366 748 | 5 508 438 | 6.7 |
| Total | 2 364 361 | 34 442 268 | 7.0 |
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| 图 1 2014–2023年CARSS监测全国鲍曼不动杆菌对碳青霉烯类药物的耐药率 Fig. 1 The resistance rate of Acinetobacter baumannii to carbapenems in China by CARSS from 2014–2023. |
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出率远高于其他病区，最高至81.9%，成为医院感染防控和治疗的难点；对不同来源标本的CRAB检出率进行分析发现肺泡灌洗液中CRAB的出现频率最高[31]。因此，为应对多重耐药鲍曼不动杆菌，医院须加强患者监测和筛查，及时发现并隔离感染者。同时，提高医护人员手卫生标准、加强环境清洁消毒和医疗设备管理。
2 鲍曼不动杆菌的耐药机制和抗生素治疗鲍曼不动杆菌具有强大的获得性耐药和克隆传播的能力，多重耐药、广泛耐药、全耐药鲍曼不动杆菌呈现世界性流行趋势[5]，也已成为我国院内感染重要的病原菌之一。多重耐药鲍曼不动杆菌(multidrug-resistant A. baumannii, MDRAB)是指对5类抗菌药物中至少3类耐药的菌株，包括：头孢菌素、碳青霉烯类、含有β-内酰胺酶抑制剂的复合制剂(包括哌拉西林/他唑巴坦、头孢哌酮/舒巴坦、氨苄西林/舒巴坦)、氟喹诺酮类、氨基糖苷类抗生素；广泛耐药鲍曼不动杆菌(extensively drug-resistant A. baumannii, XDRAB)是指仅对1–2种潜在药物(替加环素和/或多黏菌素)敏感的菌株；全耐药鲍曼不动杆菌(pan-drug resistant A. baumannii，PDRAB)则指目前对所有潜在抗菌药物(包括多黏菌素、替加环素)均耐药的菌株[33-35]。
鲍曼不动杆菌可通过内源性和获得性机制对多种抗生素产生抗性。内源性机制包括外排泵系统过表达、细胞膜通透性改变(外膜孔蛋白缺失或突变)、药物靶位点修饰以及耐药酶的产生[36-39]；获得性耐药机制包括质粒介导的耐药基因转移[40]、整合子介导的基因捕获[41]以及生物膜通过物理屏障和微环境调控增强耐药性[42]。其中最关键的耐药性机制是产生β-内酰胺酶，特别是水解碳青霉烯类和青霉素类抗生素的酶[43-44]。碳青霉烯类药物是治疗多重耐药鲍曼不动杆菌感染的首选药物，其早期的广泛应用导致了近年来鲍曼不动杆菌对碳青霉烯类药物耐药性的增加[45]。目前发现的碳青霉烯酶主要包括亚胺培南酶(imipenemase, IMP)、首尔亚胺培南酶(Seoul imipenemase, SIM)、维罗纳整合素金属- β-内酰胺酶(Virona integrin encoded metallo-β- lactamase, VIM)等金属酶[46-48]，以及苯唑西林酶(oxacillinase, OXA)家族中的一系列酶(OXA-21、OXA-23、OXA-27、OXA-51、OXA-58等)。金属酶水解碳青霉烯类药物的β-内酰胺环，导致对碳青霉烯类抗生素耐药；而苯唑西林酶是鲍曼不动杆菌中最为常见的一种酶，能够水解苯唑西林，对几乎所有β-内酰胺类抗菌药物产生耐药[49]。此外，全球范围内报道的重要的可转移碳青霉烯酶还包括肺炎克雷伯菌碳青霉烯酶(K. pneumoniae carbapenemase, KPC)、新德里金属β-内酰胺酶(New Delhi metallo-β- lactamase, NDM)和圣保罗金属β-内酰胺酶(Sao Paulo metallo-β-lactamase, SPM)[50]，均可导致该菌对碳青霉烯类药物耐药。这些耐药机制的累积效应使得用于治疗鲍曼不动杆菌感染的抗生素类别逐渐减少。
根据我国鲍曼不动杆菌感染诊治与防控专家共识，临床上治疗鲍曼不动杆菌需综合考虑病原菌的敏感性、感染部位及严重程度、患者病理生理状况和抗菌药物的作用特点；MDRAB感染根据药敏结果选用头孢哌酮舒巴坦、氨苄西林舒巴坦或碳青霉烯类，可联合应用氨基糖苷类或氟喹诺酮类抗菌药物等；XDRAB感染常采用两药甚至三药联合方案[51]。两药联合用药方案有：(1) 以含舒巴坦的复合制剂(头孢哌酮舒巴坦)或舒巴坦为基础的联合，联合以下一种：氟喹诺酮类、氨基糖苷类、多黏菌素、米诺环素/多西环素等[52-54]；(2) 以替加环素为基础的联合，联合以下一种：含舒巴坦的复合制剂(或舒巴坦)、碳青霉烯类、多黏菌素、氟喹诺酮类、氨基糖苷类[55-56]；(3) 以多黏菌素为基础的联合，联合以下一种：含舒巴坦的复合制剂(或舒巴坦)、米诺环素/多西环素、替加环素、碳青霉烯类(碳青霉烯类与多黏菌素一般需要三药联合)[52, 57-59]。PDRAB常需通过联合药敏试验筛选最有效的抗菌药物组合治疗方案[51]。国外有研究发现，鲍曼不动杆菌对多黏菌素异质性耐药，但异质性耐药菌株可部分恢复对其他抗菌药物的敏感性[60]，因此可选择多黏菌素联合β-内酰胺类抗生素或替加环素进行治疗。
近年来，一些新型抗生素和治疗策略正在加速研究。由舒巴坦和度洛巴坦(一种新型广谱β-内酰胺酶抑制剂)组成的静脉输注药物在治疗鲍曼不动杆菌引起的严重感染中效果显著，度洛巴坦通过抑制包括OXA-23、OXA-24和OXA-58在内的多种D类β-内酰胺酶恢复舒巴坦对鲍曼不动杆菌的抗菌活性，相较于多黏菌素，显示出更好的安全性和更低的肾毒性[61]。这种双重β-内酰胺酶抑制剂的组合在临床上较为罕见。目前，舒巴坦/度洛巴坦已在美国和中国批准上市，用于治疗18岁及以上患者由鲍不动杆菌-醋酸钙复合体敏感菌株引起的医院获得性肺炎(hospital acquired pneumonia, HAP)和呼吸机相关性肺炎(ventilator associated pneumonia, VAP)[62]。此外，头孢地尔作为一种铁载体头孢菌素，在体内外对CRAB具有广泛的抗菌活性[63-65]。尽管其目前已获美国食品药品监督管理局批准用于治疗鲍曼不动杆菌感染，但其耐药性仍需进一步研究[66]。依拉环素是新发现的一类抗生素，2023年9月至2024年11月启动的“依拉环素临床应用综合评价项目”表明其作为一种氟环素类抗菌药物，对CRAB肺部感染患者具有良好的疗效和安全性[67]，为解决全球耐药性问题提供了新的希望。
鲍曼不动杆菌在抗生素选择的压力下易发展成多重耐药、泛耐药和全耐药。除了传统的抗生素组合疗法外，新抗生素的发现和合成也存在着重大挑战。此外，抗生素通过化学作用无差别抑制细菌生长，其广谱杀菌特性易破坏人体正常菌群，噬菌体则通过特异性识别并精准裂解病原菌而不影响正常菌群，成为治疗多重耐药菌最有希望的替代疗法。
3 多重耐药鲍曼不动杆菌的噬菌体疗法噬菌体由英国细菌学家Frederick William Twort于1915年和加拿大微生物学家Félix d'Herelle于1917年分别独立发现，Félix d'Herelle首次尝试用噬菌体治疗细菌性痢疾[68]。早期的噬菌体治疗取得了令人印象深刻的结果。面对抗生素选择的有限性和噬菌体裂解细菌的特异性，研究人员开始重新关注噬菌体疗法。越来越多的报道显示，噬菌体作为一种天然抗菌剂，在治疗细菌感染尤其是多重耐药菌感染方面具有巨大的潜力。2016年的“Patterson案例”成为噬菌体治疗复苏的里程碑事件(详见表 2案例)[69]。目前，比利时、法国和葡萄牙等欧洲国家已批准噬菌体疗法用于抗感染治疗，但尚无标准化的噬菌体制剂获批上市，仍以个性化治疗为主。与此同时，我国在噬菌体治疗领域进展迅速，已开展多项临床研究，并取得显著成果。
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噬菌体包括裂解性噬菌体和溶源性噬菌体。裂解性噬菌体是将DNA注入宿主细菌，在细菌中完成复制和衣壳组装后直接裂解细菌并释放子代噬菌体；而溶原性噬菌体是将DNA整合到宿主基因组中并随宿主基因组一同复制，只在特定条件下(如环境应激时)进入溶解周期[76]。用于治疗的噬菌体应具备宿主范围广、潜伏期短、暴发量大以及裂解宿主细胞的能力[77]。为确保安全性，治疗性噬菌体应不含毒力基因和溶源性相关基因，并对体外细胞无毒性[78]，因而裂解性噬菌体更适用于噬菌体治疗。
噬菌体治疗时还需考虑噬菌体制剂的稳定性。Bagińska等[79]研究了12种鲍曼不动杆菌噬菌体在不同条件下的稳定性，发现噬菌体在酸性条件下容易失活，与乙醇类消毒剂作用30 s即可导致其滴度明显下降，最佳储存方式为–70 ℃、pH 7.0–9.0。研究还发现噬菌体对紫外线显著敏感。滴度为108 PFU/mL的噬菌体vABWU2101经紫外照射10 min后，活性显著下降约16倍；延长照射60 min，噬菌体的活性降至102 PFU/mL，存活率低于0.000 05%[80]。Xiao等[81]发现噬菌体VP3无论是在LB培养基还是SM缓冲液中，经20周冷冻，与4 ℃、–80 ℃和–196 ℃ (具有保护作用)相比，–20 ℃对其破坏性最强。添加冷冻保护剂(30%甘油或10% DMSO)显著提高了–20 ℃下噬菌体的存活率。Xu等[82]发现噬菌体储存于–20 ℃和–80 ℃时，10%的DMSO比30%的甘油保护效果更好。另一项研究发现将噬菌体ϕAB2储存在4 ℃、pH 7.0的2%氯仿溶液中330 d后，存活率仅下降5%[83]。噬菌体储存方式多种多样，但对每种噬菌体应单独优化储存条件，避免反复冻融影响噬菌体活性。
根据噬菌体的抗菌机制，噬菌体疗法分为单一疗法、噬菌体鸡尾酒疗法、噬菌体与抗生素联合疗法，以及噬菌体衍生酶(解聚酶、内溶素)等。
3.1 噬菌体单一疗法单一噬菌体通常只针对特定细菌种类或菌株，而不伤害正常菌群，具有高度的宿主特异性。鲍曼不动杆菌因其容易在宿主组织和医疗设备(如尿管)表面形成生物膜，加大了治疗难度[84-86]。目前，已有大量数据表明噬菌体不仅可以抑制生物膜的形成，还能有效去除已形成的生物膜，明显提高感染动物的生存率。研究发现噬菌体vB_AbaM-SHI可独立杀死鲍曼不动杆菌并抑制细菌生物膜的形成[87]。噬菌体vABWU2101、vB_abaM-iMe-aB2和vB_AbM_WUPSU对已形成的生物膜表现出良好的活性，并以剂量依赖的方式阻止生物膜形成[80, 88-89]。在菌血症和败血症模型实验中，噬菌体vB_AbaM_3054、vB_AbaM_3090、FG02、CO01和PD-6A3能显著降低动物体内的细菌载量，并提高存活率[90-92]。感染CRAB的动物模型经单一噬菌体治疗后，被感染组织器官(肺、肝和脾)的组织学损伤和细菌清除率得到显著改善，蜡螟在48 h内的生存率从0增加至70%，小鼠7 d内的生存率从0增加至60%[93]。目前已有报道介绍了单一噬菌体疗法在临床案例中的应用。一名颅骨切除术患者给予静脉注入107 PFU/mL噬菌体制剂，间隔2 h一次，连续治疗8 d，结果显示患者对首次治疗耐受良好，未表现出噬菌体相关的不良反应[74]。近期深圳市第三人民医院报道了一例XDRAB肺部感染患者接受噬菌体治疗的案例。该患者接受了2个阶段的噬菌体BA3吸入治疗，每个阶段为期10 d；结果显示，治疗后患者呼吸道中的细菌负荷显著降低，临床症状趋于稳定，治疗效果显著；然而，研究团队在第一阶段治疗后发现，噬菌体的丰度趋于稳定，病原体负荷持续较高；这一现象提示长期噬菌体治疗可能引发病原体对噬菌体的耐受性，从而降低治疗效果[94]。
3.2 噬菌体鸡尾酒疗法噬菌体鸡尾酒疗法是一种利用多种噬菌体共同作用于特定病原体，以达到更广泛的杀菌效果并减少耐药性的治疗方法。设计噬菌体鸡尾酒需要对目标病原体进行噬菌体筛选，使用特定的方法来获得高滴度和纯度的噬菌体，并将筛选出的噬菌体按照一定比例混合形成噬菌体鸡尾酒。
研究发现，与单一噬菌体相比，噬菌体鸡尾酒Ab105-2phiΔCI404ad和vB_AbaP_B3bbi表现出更强的抗生物膜活性[94]。在小鼠菌血症模型中发现噬菌体鸡尾酒(vB_AbaS_D0和vB_AbaP_D2)在体内外均表现出比单一噬菌体更好的疗效，且显著降低了细菌抗性的发生[95]。一项由耐多黏菌素鲍曼不动杆菌引起的败血症小鼠模型研究发现，即使在小鼠感染6、12、24 h后给予低剂量噬菌体鸡尾酒(ΦAb4、ΦAb7和ΦAb14)治疗，其死亡率仍可下降20%–60%，这表明即使治疗延迟，患者仍能从低剂量噬菌体鸡尾酒治疗中受益[96]。Ilomuanya等[97]将噬菌体鸡尾酒(ɸAB140和ɸAB150)包裹在壳聚糖微粒中用于治疗由鲍曼不动杆菌引起的糖尿病伤口感染的动物模型，不仅解决了伤口周围的免疫细胞导致的噬菌体滴度下降和噬菌体失活问题，还有效清除了伤口表面的细菌。
目前，已有多例噬菌体鸡尾酒疗法在临床案例中的报道。著名的“Patterson案例”就是使用多种噬菌体鸡尾酒来治疗伴有坏死性胰腺炎和多重耐药鲍曼不动杆菌感染的糖尿病患者。在缺乏有效抗生素的情况下，研究者通过精心筛选和混合9种不同噬菌体制剂，制备成3种噬菌体混合物ΦPC、ΦIV和ΦIVB，对患者进行了为期36周的腹腔灌注和静脉注入治疗，成功扭转了患者的临床恶化情况[69]。尽管在治疗过程中出现了噬菌体耐药性，但通过不断迭代优化噬菌体鸡尾酒配方，最终解决了患者的感染问题，具体方案见表 2案例1。Liu等[98]对“Patterson案例”中使用的9种噬菌体和3株鲍曼不动杆菌进行了全基因组测序和比较基因组学分析，发现鸡尾酒ΦPC中的C2P12、C2P21和C2P24基因序列相同，且前2种鸡尾酒ΦPC、ΦIV中的噬菌体均属于肌尾科噬菌体；体外斑点试验发现患者体内分离的鲍曼不动杆菌在噬菌体开始治疗后的2 d内，鸡尾酒ΦPC和ΦIV中所有噬菌体裂解效率开始降低；ΦIVB中的噬菌体AbTP3Φ1属于短尾科，在噬菌体治疗期间未发现噬菌体耐药菌。这表明尽管病原菌在噬菌体的选择压力下产生了抗性菌株，但在噬菌体治疗前对噬菌体进行完整的基因组分析，有助于研究人员更理性地设计噬菌体混合物，最大限度地提高治疗成功率。
除了为患者定制个性化噬菌体治疗方案外，还有一些研究关注噬菌体在医疗环境中的应用。在一项为期3年的前瞻性研究中，Chen等[99]使用雾化噬菌体鸡尾酒对医院重症监护室中感染CRAB患者周围环境进行消毒，消毒期间重症监护室中CRAB的比例从65.3%显著下降至55.0%；CRAB感染的新发病例率为每1 000名患者日数4.4例，显著低于从未进行噬菌体消毒的对照病房(每1 000名患者日数8.9例)。Zurabov团队[100]通过评估ICU潜在病原菌，在ICU开展了一项为期28 d的噬菌体鸡尾酒雾化消杀以预防医院获得性肺炎的发生；雾化期间患者未出现任何不良反应，并且所有患者的支气管肺泡灌洗液中的多重耐药菌均得以清除，炎症标志物(包括C-反应蛋白和前降钙素)也得到显著下降，为噬菌体的广泛应用提供了宝贵的经验和数据支持。
3.3 噬菌体联合抗生素疗法尽管噬菌体疗法对耐药鲍曼不动杆菌具有良好活性，但它面临着与抗生素类似的困境，即细菌对噬菌体产生抗性。然而，噬菌体和抗生素抗菌机制的差异使两者联合对抗耐药性成为可能。噬菌体与抗生素联合治疗的优势包括增强对细菌的抑制作用、有效穿透生物膜以及减少细菌对噬菌体或抗生素耐药性的出现[101]。
研究发现，噬菌体与抗生素联合使用，不仅降低了抗生素使用浓度，而且相较于单一疗法表现出显著的协同作用。噬菌体vABWU2101与替加环素(1/32–1/4 MIC)联合处理下，显著降低了多重耐药性鲍曼不动杆菌的细胞活性；与1/2 MIC联合处理，未观察到存活细菌[80]。Luo等[102]的研究发现，噬菌体YC#06与抗生素联合使用具有剂量依赖性，低剂量(感染复数，multiplicity of infection，MOI=0.01)和中等剂量(MOI=1)的噬菌体YC#06与抗生素联合使用能够获得最佳的协同抗菌效果，而高剂量(MOI= 100)噬菌体虽然在短期内有效，但长期效果不佳。因此在治疗时需要选择适度的噬菌体剂量以达到最大的协同效果。此外，这种协同作用还表现在对抗生物膜上，噬菌体vABWU2101和替加环素的联合治疗能去除60.55%–85.68%的生物膜[80]。噬菌体pB23、噬菌体YC#06分别与抗生素联用不仅能有效去除成熟的生物膜，还能有效预防生物膜的形成[102-103]。
噬菌体与抗生素的协同作用已在多种动物模型中得以证实。噬菌体AGC01和美罗培南联合治疗能将蜡螟幼虫的生存率从35%提升至77%[104]。与单独使用噬菌体pB23 (83.33%)或单独使用美罗培南(50.0%)相比，联合治疗使斑马鱼感染生存率达到了100%[103]。在鲍曼不动杆菌AB900引发的严重菌血症小鼠模型中，噬菌体øFG02与头孢他啶的联合治疗，能够持续刺激鲍曼不动杆菌发生突变，丧失荚膜，从而对噬菌体产生抗性，对头孢他啶敏感，这一发现凸显了噬菌体与抗生素联合在恢复抗菌活性和减少抗生素用量方面的临床潜力[105]。为进一步减少噬菌体抗性，Grygorcewicz等[106]采用噬菌体鸡尾酒Aba-1、Aba-2、Aba-3、Aba-4和Aba-6与抗生素联合治疗。
本文搜集了近年来国内外报道的噬菌体治疗鲍曼不动杆菌感染的临床案例(表 2)。结合该表分析发现：71.4% (5/7)的重症患者病情得以改善或治愈[69-72, 75]，28.6%患者因放弃治疗无法评估疗效[73-74]，但在所有案例中均未发现噬菌体治疗相关的不良反应，一定程度上说明了噬菌体治疗的安全性。针对不同的感染部位，需要选择不同的治疗方式，现有的方式多为静脉注射、雾化吸入、局部灌注或两者相结合。噬菌体与传统抗生素之间的增效或协同作用已在体外和动物模型系统中得到证明。但是也有研究报道发现噬菌体与抗生素联合发生拮抗反应：噬菌体与多黏菌素B/多黏菌素E联用时效果反而不如单独使用多黏菌素B/E[107]。结合现有的临床案例中，不论是单一噬菌体治疗(案例7)还是联合治疗(案例1和3)均有噬菌体耐药菌的出现，因此在治疗前需正确选择噬菌体和抗生素类型，谨慎考虑两者的使用顺序，并在治疗过程中不断加强监测，优化治疗方案，以达到最佳治疗效果。
3.4 噬菌体衍生酶治疗单一噬菌体或鸡尾酒疗法因宿主范围窄、噬菌体耐药性以及临床制剂等方面的限制，短时间内无法用于临床治疗[108-109]。因此，研究者们开始关注噬菌体衍生酶，如解聚酶和内溶素。
噬菌体解聚酶相比于噬菌体颗粒不能直接诱导细菌死亡，而是通过降解细菌表面多糖物质，增强了细菌对宿主免疫反应和抗菌治疗的敏感性[110]。已发现的大多数解聚酶如Dp49[111]、DpoMK34[112]、K2[113]和Dpo48[114]能特异性降解鲍曼不动杆菌表面的荚膜多糖。解聚酶K2和Dpo48比DpoMK34具有更高的热稳定性，70 ℃仍能保持活性[112-114]。Dp49能有效降解多种多位点序列分型(multilocus sequence typing, MLST)的鲍曼不动杆菌荚膜，比其亲本噬菌体IME285具有更高的细菌敏感性[111]。使用DpoMK34处理细菌，导致噬菌体吸附率从95%显著下降到9%[112]。此外，研究还发现使用解聚酶K2预处理细菌或在细菌攻击后注射解聚酶K2，均能有效保护幼虫抵御细菌[113]。
解聚酶在增强人和小鼠免疫系统中发挥着重要作用。DpoMK34以剂量依赖的方式增强血清杀伤鲍曼不动杆菌MK34的能力，在50%血清浓度下可完全消除病原菌[112]。小鼠脓毒症模型中，单次腹腔注射50 μg的K2解聚酶便能将小鼠的生存率提高至60%，有效降低促炎细胞因子水平[113]。此外，解聚酶Dpo1通过降解胞外聚合物(extracellular polymeric substances, EPS)成分可以去除20%生物膜，减弱菌株毒力[114]。而噬菌体φAB6尾刺蛋白(tail spike protein, TSP)可以抑制生物膜形成并分解已形成的生物膜，可防止鲍曼不动杆菌黏附到医疗器械表面[116]。
尽管单个噬菌体分解酶可以对抗细菌生物膜，但完全消除细菌生物膜可能需要多噬菌体解聚酶混合物或将其与抗生素联合使用。Chen等[117]发现解聚酶Dpo71与多黏菌素组合在体外表现出协同效果，能将感染鲍曼不动杆菌蜡螟幼虫的生存率从40% (单独使用Dpo71)提升至80%。但并非所有解聚酶与多黏菌素结合都产生协同效应。如经解聚酶DpoMK34处理的鲍曼不动杆菌MK34对抗生素的敏感性未发生改变[112]。细菌EPS被解聚酶TF破坏后，对黏菌素的耐药性暂时增加[118]。因此，在选择治疗方案时需谨慎合理选择以达到最佳治疗效果。
内溶素是噬菌体在生命周期最后一步产生的消化细菌细胞壁肽聚糖的酶[119-120]。由于肽聚糖的高度保守性，内溶素具有比噬菌体更广泛的宿主范围和更低的抗性风险[121]。近年来越来越多的动物实验证明内溶素对抗细菌感染的有效性[122-124]。而革兰氏阴性菌因外膜的存在阻碍了内溶素与肽聚糖的接触[91, 125]。因此，许多研究借助外膜通透剂增强内溶素对病原菌的抗菌效果[126-127]。如内溶素ABgp46在柠檬酸和苹果酸的作用下可将多重耐药鲍曼不动杆菌的数量降至检测限以下[127]。多黏菌素作为一种阳离子抗生素，通过与革兰氏阴性菌外膜的脂质A相互作用而破坏外膜[128]。因其具有肾毒性，容易被其他耐受性较好的抗生素所取代[129-130]。将内溶素与黏菌素联合使用不仅可以减少黏菌素用量，降低毒性，还具有显著的抗菌效果[120, 124, 126, 131-132]。如内溶素ElyA1和黏菌素联合使用可将黏菌素对多重耐药鲍曼不动杆菌的MIC降低75%。用该剂量治疗感染的大蜡螟发现其存活率比单独使用黏菌素更高[121]。LysABP-01和黏菌素组合对MDRAB和XDRAB感染均表现出协同效果，甚至将LysABP-01的MIC减少为原来的1/32，黏菌素的MIC值减少为原来的1/8[132]。但有研究报道显示内溶素和黏菌素的联合使用对黏菌素抗性菌株无效[121]。
最新研究还发现将外膜破坏肽或多阳离子肽与内溶素融合可绕过外膜屏障。将内溶素LysKP213N与外膜破坏肽CecA融合发现CecA-LysKP213在体内外均对革兰阴性菌的抗菌活性增强[126]。在内溶素PA90的N端引入外膜破坏肽thanatin，发现Tha-PA90使全身感染鲍曼不动杆菌小鼠的促炎细胞因子表达下降为原来的1/45，各类器官中的细菌负荷降低，生存率提高[133]。lysAB-vT2-fusion是一种融合了疏水氨基酸的内溶素，将其与多黏菌素联合使用不仅能抑制多重耐药鲍曼不动杆菌，还能抑制噬菌体耐药菌[134]。内溶素LysECD7与脂多糖结合肽融合形成2种融合蛋白Lys-MSI和Lys-Li5-MSI，体外实验表明两者对鲍曼不动杆菌展现出显著的抗菌活性，但Lys-Li5-MSI在体内并没有展现出预期的治疗效果，无法减少感染小鼠组织中的细菌负荷[135]。
此外已有研究发现一些独立于外膜通透剂的内溶素可对革兰氏阴性菌发挥抗菌活性，如内溶素LysSS[125]、LysSAP26[136]、Ply6A3[91]、LysP53[132]和Abtn-4[137]。内溶素LysSAP26能在体外抑制ESKAPE病原菌的生长，对CRAB的最小抑制浓度和最小杀菌浓度相同，并以剂量依赖性保护全身性鲍曼不动杆菌感染的小鼠[136]。在小鼠模型中，适当剂量的LYsSS (125 mg)能显著提高感染鲍曼不动杆菌小鼠的存活率，但高剂量(500 mg)可能引起毒性反应，降低存活率[125]。Lendel等[138]发现内溶素LysAm24、LysAp22、LysECD7和LysSi3可通过不同机制对抗生物膜。LysAp22通过降解酸性胞外多糖来破坏生物膜结构，LysAm24则通过与胞外DNA (extracellular DNA, eDNA)的强静电相互作用发挥其抗生物膜功能，而LysECD7能同时与eDNA及胞外多糖发生作用。它们均能显著抑制鲍曼不动杆菌和肺炎克雷伯菌的单种生物膜及混合生物膜的形成。内溶素Abtn-4不仅可以有效减少生物膜的形成，还能抑制噬菌体耐药突变株的生长[137]。
大多数噬菌体内溶素在4–40 ℃范围内保持活性[139]，部分内溶素如LysKP213[126]和PHAb10[140]在较高温度时表现出显著的热稳定性。LysKP213在95 ℃孵育20 h仍保留44.4%的裂解活性，121 ℃灭菌30 min后保留57.5%的活性[126]。PHAb10在100 ℃处理1 h后仍保留几乎100%的杀菌活性[140]。基于内溶素的广谱抗菌活性以及独特的热稳定性特征不仅能够有效满足急性患者的需求，还极大地拓展了其在疫苗设计、食品加工、生物技术生产和医疗等领域的潜在应用。表 3结合不同噬菌体疗法的机制和特点，系统性地总结了其优缺点和可能存在的问题。
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尽管目前尚缺乏噬菌体酶治疗鲍曼不动杆菌感染的临床报道，但已有研究为其临床应用奠定了基础。例如，Jun等[141]公布了针对耐药金黄色葡萄球菌的内溶素SAL200的I期临床试验结果，研究发现，健康男性在静脉输注SAL200后未出现严重不良事件，表明该疗法具有良好的安全性，为噬菌体酶在更多临床场景中的应用提供了有力支持。
鉴于现行的生物安全标准和法规，噬菌体衍生酶相较于完整的噬菌体，其临床应用更具可行性和可操作性。未来的研究方向应包括：加大噬菌体衍生酶与抗菌肽、纳米粒子以及银、铜、锌等金属元素的联合应用研究，同时开发高效的递送系统，以确保制剂在储存和运输过程中的稳定性，并能够安全且精准地到达作用部位。这些策略将成为应对多重耐药菌感染、提升临床疗效的关键所在。
4 结论与展望噬菌体疗法作为对抗耐药菌的替代疗法显示出巨大的潜力，但在国内外缺乏统一的临床管理规范，在实际应用中面临着诸多挑战。首先，分离特定噬菌体的过程耗时较长；其次，选择合适的噬菌体和确定最佳剂量对于噬菌体疗法的有效性和安全性至关重要。尽管噬菌体在体外测试中未显示出对人类细胞系的毒性[142-143]，但最近的研究表明，噬菌体在治疗期间可以进入人体血液并在肠道中积累[75]，噬菌体也可能被真核细胞识别，引发特定的细胞反应[144]，其在体内高剂量应用的有效性和安全性仍需进一步验证。当前研究已揭示了多种细菌对抗噬菌体的防御机制，包括噬菌体结合受体的改变[145]、流产感染系统、成簇规律间隔的短回文重复序列/ CRISPR关联蛋白(clustered regularly interspaced short palindromic repeats/CRISPR-associated proteins, CRISPR-Cas)系统和限制性修饰系统[146]等。尽管这些机制与抗生素抗性有所不同，但可能导致相同的后果——治疗失败。噬菌体抗性的扩散对噬菌体疗法的效能构成了严峻考验。
尽管面临重重挑战，但是许多国家都有噬菌体治疗相关的临床应用报道，临床治疗有效率超过70%[147]。近日，由我国复旦大学附属中山医院胡必杰教授主导，联合中国噬菌体研究联盟等多方机构共同撰写的《噬菌体治疗临床应用管理专家共识(2024版)》[148]正式发布。这份专家共识为我国噬菌体治疗的临床应用提供了规范化指导，明确了噬菌体治疗的适应症、治疗流程、安全性评估及风险管理等关键环节。其发布不仅为我国积极应对细菌耐药危机提供了新的策略，也为噬菌体疗法的良性健康发展奠定了坚实的基础。
作者贡献声明
吴佳：方案设计、初稿写作；王军：监督指导、经费支持、稿件润色修改。
作者利益冲突公开声明
作者声明没有任何可能会影响本文所报告工作的已知经济利益或个人关系。
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