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Article(id=1248601467389632642, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1248601466106172220, articleNumber=1001-2494(2024)06-0549-06, orderNo=null, doi=null, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1659283200000, receivedDateStr=2022-08-01, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1775619387719, onlineDateStr=2026-04-08, pubDate=1711036800000, pubDateStr=2024-03-22, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1775619387719, onlineIssueDateStr=2026-04-08, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1775619387719, creator=13701087609, updateTime=1775619387719, updator=13701087609, issue=Issue{id=1248601466106172220, tenantId=1146029695717560320, journalId=1190317699101192196, year='2024', volume='59', issue='6', pageStart='469', pageEnd='558', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1775619387412, creator=13701087609, updateTime=1775619937245, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1248603772348420655, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1248601466106172220, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1248603772348420656, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1248601466106172220, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=549, endPage=554, ext={EN=ArticleExt(id=1248601467674845316, articleId=1248601467389632642, tenantId=1146029695717560320, journalId=1190317699101192196, language=EN, title=Application Progress of Bacteriophage in the Treatment of Multidrug-Resistant Bacterial Pneumonia, columnId=1248601467007947584, journalTitle=Chinese Pharmaceutical Journal, columnName=Original article, runingTitle=null, highlight=null, articleAbstract=

OBJECTIVE To review the latest progress of phage therapy in clinical application of multiple multidrug-resistant bacterial pneumonia, in order to provide documentary evidence for the application of phage in pulmonary infection. METHODS The keywords “phage” or “phage therapy” or “phage endolysin” or “engineered phage” and “pneumonia” were used in literature search on CNKI and pubmed, and the retrieved case reports were reviewed according to pathogen classification. RESULTS Clinical studies on randomized controlled trial(RCT) of phage therapy for the treatment of pneumonia had not been publicly reported, but phage had achieved good efficacy in the treatment of pneumonia infected by Pseudomonas aeruginosa, Staphylococcus aureus, Klebsiella pneumoniae and Acinetobacter baumannii, and only one adverse reaction had been reported. At the same time, this paper discussed the current difficulties of bacteriophage therapy, such as bacterial resistance, its own safety or the influence of immune system on its efficacy, and the latest development direction of phage endolysin and engineered phage therapy. CONCLUSION Bacteriophages have a promising future in the treatment of respiratory infections, especially those caused by multidrug-resistant bacteria. In the future, more in vivo studies may be needed to answer questions about the efficacy and safety of phage derivatives or engineered phage therapy.

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目的 由于多重耐药细菌的不断出现,噬菌体疗法再次出现在公众的视野里,笔者着重介绍噬菌体疗法在临床上用于多种多重耐药细菌性肺炎的现状,以期为噬菌体应用于肺部感染提供文献证据。方法 采用关键词“噬菌体”或“噬菌体疗法”或“噬菌体裂解酶”或“工程噬菌体”和“肺炎”在知网和pubmed网站进行文献检索,并将检索到的病例报告按照病原分类进行介绍。结果 用于治疗肺炎的噬菌体疗法随机对照试验(randomized controlled trial,RCT)临床研究尚无公开报道,但噬菌体在铜绿假单胞菌、金黄色葡萄球菌、肺炎克雷伯菌和鲍曼不动杆菌感染性肺炎的治疗中取得了较好的疗效,且仅有一例不良反应报告。同时,笔者探讨了噬菌体疗法目前面临的细菌耐药、自身的安全性或免疫系统对其疗效的影响等困难及噬菌体裂解酶和工程噬菌体两种噬菌体疗法的最新发展方向。结论 噬菌体在治疗呼吸道感染,特别是那些由多重耐药细菌引起的感染方面还是具有应用前景。未来会有更多的体内研究来回答噬菌体衍生物或是工程噬菌体治疗的有效性和安全性。

, correspAuthors=曹玲, authorNote=null, correspAuthorsNote=
*曹玲,女,教授,硕士生导师 研究方向:儿科呼吸系统疾病 Tel:(010)85695629
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付涵宇,女,硕士研究生 研究方向:多重耐药细菌肺部感染的噬菌体疗法

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付涵宇,女,硕士研究生 研究方向:多重耐药细菌肺部感染的噬菌体疗法

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付涵宇,女,硕士研究生 研究方向:多重耐药细菌肺部感染的噬菌体疗法

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Curr Opin Biotechnol, 2021, 68:15-22., articleTitle=Lysins breaking down the walls of Gram-negative bacteria, no longer a no-go, refAbstract=null), Reference(id=1248653099921986394, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1248601467389632642, doi=null, pmid=null, pmcid=null, year=2021, volume=68, issue=null, pageStart=151, pageEnd=159, url=null, language=null, rfNumber=[42], rfOrder=41, authorNames=LENNEMAN B R, FERNBACH J, LOESSNER M J, journalName=Curr Opin Biotechnol, refType=null, unstructuredReference=LENNEMAN B R, FERNBACH J, LOESSNER M J, et al. Enhancing phage therapy through synthetic biology and genome engineering[J]. Curr Opin Biotechnol, 2021, 68:151-159., articleTitle=Enhancing phage therapy through synthetic biology and genome engineering, refAbstract=null), Reference(id=1248653100018455389, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1248601467389632642, doi=null, pmid=null, pmcid=null, year=2019, volume=179, issue=2, pageStart=459, pageEnd=469, url=null, language=null, rfNumber=[43], rfOrder=42, authorNames=YEHL K, LEMIRE S, YANG A C, journalName=Cell, refType=null, unstructuredReference=YEHL K, LEMIRE S, YANG A C, et al. Engineering phage host-range and suppressing bacterial resistance through phage tail fiber mutagenesis[J]. 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J Integra Technol, 2021, 10(4):17-32., articleTitle=Strategies for the application of engineered phages in solving bacterial tolerance problems, refAbstract=null), Reference(id=1248653100257530722, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1248601467389632642, doi=null, pmid=null, pmcid=null, year=2020, volume=11, issue=2, pageStart=e00019, pageEnd=20, url=null, language=null, rfNumber=[45], rfOrder=44, authorNames=SELLE K, FLETCHER J R, TUSON H, journalName=mBio, refType=null, unstructuredReference=SELLE K, FLETCHER J R, TUSON H, et al. In vivo targeting of clostridioides difficile using phage-delivered CRISPR-Cas3 antimicrobials[J]. mBio, 2020, 11(2):e00019-20., articleTitle=et al. 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参考文献 病原 诊断 给药方式 剂量和疗程 结局 不良反应
[21] 铜绿假单胞菌 囊性纤维化 静脉注射 4×109 PFU·mL-1,每6 h 1次,8周 好转出院 无
[22] 铜绿假单胞菌 呼吸机相关性肺炎 静脉注射及
雾化吸入		 1×107 PFU·mL-1,100 mL,静脉注射;1×109
PFU·mL-1,4 mL,雾化吸入,1日2次,7 d		 好转出院 无
[23] 铜绿假单胞菌 难治性肺炎 静脉注射及
雾化吸入		 4×109 PFU·mL-1,静脉注射,每6 h 1次;雾
化吸入,每12 h 1次,2周		 好转出院 无
[23] 铜绿假单胞菌 难治性肺炎 静脉注射 4×109 PFU·mL-1,每12 h 1次,4周 好转出院 无
[24] 金黄色葡萄球菌 囊性纤维化 雾化吸入 2 mL,1日3次,6 d 好转出院 无
[25] 金黄色葡萄球菌 囊性纤维化 雾化吸入 剂量不明,4~6周1疗程,9个疗程 痰培养阴性 无
[26] 肺炎克雷伯菌 难治性肺炎 雾化吸入 1×109 PFU·mL-1,每4 h 1次,4次 炎症反应减少,产生抗
性突变体		 无
[27] 鲍曼不动杆菌 新冠病毒感染继发
肺部感染		 雾化吸入 1×108 PFU·mL-1,10 mL,每隔1 h给药2次 好转出院,产生抗性突
变体		 发热,IL-6,IL-8
细胞因子风暴
[27] 鲍曼不动杆菌 新冠病毒感染继发
肺部感染		 雾化吸入 1×108 PFU·mL-1,10 mL,每隔1 h给药2次 好转出院,产生抗性突
变体		 无
[27] 鲍曼不动杆菌 新冠病毒感染继发
肺部感染		 雾化吸入 1×108 PFU·mL-1,10 mL,每隔1 h给药2次 死于继发性肺炎克雷伯
菌感染		 无
[27] 鲍曼不动杆菌 新冠病毒感染继发
肺部感染		 雾化吸入 1×108 PFU·mL-1,10 mL,每隔1 h给药2次 感染清除,产生抗性突
变体,死于呼吸衰竭		 无
[28] 鲍曼不动杆菌 慢性阻塞性肺病继
发肺部感染		 雾化吸入 5 mL,从5×106 PFU·mL-1逐步增加到5×1010
PFU·mL-1,前两剂每日1次,其余每12 h
1次,共16 d		 感染清除 无
), ArticleFig(id=1248653096130335392, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1248601467389632642, language=CN, label=表1, caption=

噬菌体在临床肺炎治疗中的应用情况

, figureFileSmall=null, figureFileBig=null, tableContent=
参考文献 病原 诊断 给药方式 剂量和疗程 结局 不良反应
[21] 铜绿假单胞菌 囊性纤维化 静脉注射 4×109 PFU·mL-1,每6 h 1次,8周 好转出院 无
[22] 铜绿假单胞菌 呼吸机相关性肺炎 静脉注射及
雾化吸入		 1×107 PFU·mL-1,100 mL,静脉注射;1×109
PFU·mL-1,4 mL,雾化吸入,1日2次,7 d		 好转出院 无
[23] 铜绿假单胞菌 难治性肺炎 静脉注射及
雾化吸入		 4×109 PFU·mL-1,静脉注射,每6 h 1次;雾
化吸入,每12 h 1次,2周		 好转出院 无
[23] 铜绿假单胞菌 难治性肺炎 静脉注射 4×109 PFU·mL-1,每12 h 1次,4周 好转出院 无
[24] 金黄色葡萄球菌 囊性纤维化 雾化吸入 2 mL,1日3次,6 d 好转出院 无
[25] 金黄色葡萄球菌 囊性纤维化 雾化吸入 剂量不明,4~6周1疗程,9个疗程 痰培养阴性 无
[26] 肺炎克雷伯菌 难治性肺炎 雾化吸入 1×109 PFU·mL-1,每4 h 1次,4次 炎症反应减少,产生抗
性突变体		 无
[27] 鲍曼不动杆菌 新冠病毒感染继发
肺部感染		 雾化吸入 1×108 PFU·mL-1,10 mL,每隔1 h给药2次 好转出院,产生抗性突
变体		 发热,IL-6,IL-8
细胞因子风暴
[27] 鲍曼不动杆菌 新冠病毒感染继发
肺部感染		 雾化吸入 1×108 PFU·mL-1,10 mL,每隔1 h给药2次 好转出院,产生抗性突
变体		 无
[27] 鲍曼不动杆菌 新冠病毒感染继发
肺部感染		 雾化吸入 1×108 PFU·mL-1,10 mL,每隔1 h给药2次 死于继发性肺炎克雷伯
菌感染		 无
[27] 鲍曼不动杆菌 新冠病毒感染继发
肺部感染		 雾化吸入 1×108 PFU·mL-1,10 mL,每隔1 h给药2次 感染清除,产生抗性突
变体,死于呼吸衰竭		 无
[28] 鲍曼不动杆菌 慢性阻塞性肺病继
发肺部感染		 雾化吸入 5 mL,从5×106 PFU·mL-1逐步增加到5×1010
PFU·mL-1,前两剂每日1次,其余每12 h
1次,共16 d		 感染清除 无
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噬菌体治疗多重耐药细菌感染性肺炎的应用现状
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付涵宇 1 , 曹玲 1, * , 甘霖 2 , 袁静 2
中国药学杂志 | 研究论文 2024,59(6): 549-554
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中国药学杂志 | 研究论文 2024, 59(6): 549-554
噬菌体治疗多重耐药细菌感染性肺炎的应用现状
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付涵宇1, 曹玲1, *, 甘霖2, 袁静2
作者信息
  • 1 首都儿科研究所附属儿童医院呼吸内科, 北京 100020
  • 2 首都儿科研究所细菌研究室, 北京 100020

    • 付涵宇,女,硕士研究生 研究方向:多重耐药细菌肺部感染的噬菌体疗法

通讯作者:

*曹玲,女,教授,硕士生导师 研究方向:儿科呼吸系统疾病 Tel:(010)85695629
Application Progress of Bacteriophage in the Treatment of Multidrug-Resistant Bacterial Pneumonia
Hanyu FU1, Ling CAO1, *, Lin GAN2, Jing YUAN2
Affiliations
  • 1 Department of Pulmonology, The Affiliated Children's Hospital, Capital Institute of Pediatrics, Beijing 100020, China
  • 2 Department of Bacteriology, Capital Institute of Pediatrics, Beijing 100020, China
出版时间: 2024-03-22
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摘要
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目的 由于多重耐药细菌的不断出现,噬菌体疗法再次出现在公众的视野里,笔者着重介绍噬菌体疗法在临床上用于多种多重耐药细菌性肺炎的现状,以期为噬菌体应用于肺部感染提供文献证据。方法 采用关键词“噬菌体”或“噬菌体疗法”或“噬菌体裂解酶”或“工程噬菌体”和“肺炎”在知网和pubmed网站进行文献检索,并将检索到的病例报告按照病原分类进行介绍。结果 用于治疗肺炎的噬菌体疗法随机对照试验(randomized controlled trial,RCT)临床研究尚无公开报道,但噬菌体在铜绿假单胞菌、金黄色葡萄球菌、肺炎克雷伯菌和鲍曼不动杆菌感染性肺炎的治疗中取得了较好的疗效,且仅有一例不良反应报告。同时,笔者探讨了噬菌体疗法目前面临的细菌耐药、自身的安全性或免疫系统对其疗效的影响等困难及噬菌体裂解酶和工程噬菌体两种噬菌体疗法的最新发展方向。结论 噬菌体在治疗呼吸道感染,特别是那些由多重耐药细菌引起的感染方面还是具有应用前景。未来会有更多的体内研究来回答噬菌体衍生物或是工程噬菌体治疗的有效性和安全性。

噬菌体  /  多重耐药菌  /  噬菌体裂解酶  /  工程噬菌体  /  肺炎

OBJECTIVE To review the latest progress of phage therapy in clinical application of multiple multidrug-resistant bacterial pneumonia, in order to provide documentary evidence for the application of phage in pulmonary infection. METHODS The keywords “phage” or “phage therapy” or “phage endolysin” or “engineered phage” and “pneumonia” were used in literature search on CNKI and pubmed, and the retrieved case reports were reviewed according to pathogen classification. RESULTS Clinical studies on randomized controlled trial(RCT) of phage therapy for the treatment of pneumonia had not been publicly reported, but phage had achieved good efficacy in the treatment of pneumonia infected by Pseudomonas aeruginosa, Staphylococcus aureus, Klebsiella pneumoniae and Acinetobacter baumannii, and only one adverse reaction had been reported. At the same time, this paper discussed the current difficulties of bacteriophage therapy, such as bacterial resistance, its own safety or the influence of immune system on its efficacy, and the latest development direction of phage endolysin and engineered phage therapy. CONCLUSION Bacteriophages have a promising future in the treatment of respiratory infections, especially those caused by multidrug-resistant bacteria. In the future, more in vivo studies may be needed to answer questions about the efficacy and safety of phage derivatives or engineered phage therapy.

bacteriophage  /  multidrug resistance bacteria  /  bacteriophage lysin  /  engineered phage  /  pneumonia
付涵宇, 曹玲, 甘霖, 袁静. 噬菌体治疗多重耐药细菌感染性肺炎的应用现状. 中国药学杂志, 2024 , 59 (6) : 549 -554 .
Hanyu FU, Ling CAO, Lin GAN, Jing YUAN. Application Progress of Bacteriophage in the Treatment of Multidrug-Resistant Bacterial Pneumonia[J]. Chinese Pharmaceutical Journal, 2024 , 59 (6) : 549 -554 .
正文
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噬菌体是一种可以寄生并杀死宿主细菌的病毒[1],只要有细菌宿主存在的地方就有噬菌体的存在。噬菌体广泛存在于包含人类的自然界中,是生物圈中最丰富的生物[2]。噬菌体主要由蛋白质和核酸组成[3],遗传物质绝大多数为双链DNA,还包括单链DNA、单链RNA和极罕见的双链RNA。96%的噬菌体为有尾噬菌体,又分为3科:肌尾噬菌体科、长尾噬菌体科和短尾噬菌体科,其他类型噬菌体包括立方形噬菌体、丝状噬菌体和多形性噬菌体[4-5]。
噬菌体有4种常见的生命周期:裂解周期、溶原化周期、拟溶原化周期和慢性感染,每一个噬菌体周期至少包括5个阶段:吸附、核酸注射、病毒粒子组装、病毒粒子释放和进一步传播[6]。噬菌体与细菌表面蛋白、脂多糖等受体特异性识别导致永久噬菌体黏附,并进一步穿透细菌细胞的包膜和注射病毒遗传物质[7]。根据噬菌体类型和细菌细胞的生理条件,噬菌体基因组作为质粒样形式(拟溶原性)存在于细菌胞质或被纳入宿主基因组(溶原性的原噬菌体),与宿主基因组一起复制。在应激条件下,溶原性噬菌体亦可进入裂解循环,与裂解性噬菌体一样,进行病毒基因组的快速复制、结构和功能噬菌体蛋白的表达。随后,噬菌体病毒蛋白组装,装载病毒核酸,在内溶素、穿孔素等的作用下裂解宿主细胞、释放子代到细胞外环境[8]。
1919年,在通过自我给药证明噬菌体的安全性后,d' Herelle首次在人类身上使用噬菌体疗法成功地治疗了患有严重痢疾的三名患儿[9]。1927年,在印度霍乱疫情爆发期间,临床试验表明用噬菌体治疗的组死亡率从对照组的62.8%下降到8.1%。此外,将抗霍乱噬菌体引入村庄的饮水中,防止了更多感染的发生[10]。然而,在20世纪30年代末,美国等一些西方国家对噬菌体治疗的有效性和安全性提出了质疑,加上抗生素的发现,导致了人们对噬菌体治疗的兴趣下降[11]。此后,噬菌体疗法仅在东欧一些国家如俄罗斯、波兰和格鲁吉亚不断得到应用和进一步发展。如PhagoBioDerm是一种2000年在格鲁吉亚上市的含有能裂解5种一般化脓性微生物(铜绿假单胞菌、大肠杆菌、葡萄球菌、链球菌、变形杆菌)的噬菌体鸡尾酒外用敷贴[12],大小为4×5 cm,敷贴上噬菌体的浓度为×106 PFU·cm-2。清创后将其覆盖于伤口表面,之后5 d每天检查伤口,5 d后每2~4 d检查一次。当PhagoBioDerm破碎或完全降解(通常3~7 d)时,将其替换为新膜[13]。其可以有效治疗各种感染的伤口和溃疡。第一次使用噬菌体的吸入疗法成功的报道出现在1960年左右,Delacoste使用噬菌体鸡尾酒喷雾剂成功地治疗了难治性咳嗽患者[14]。噬菌体吸入背后的原理与雾化抗生素的概念相似,这可能会达到较高的肺内浓度,并改善肺部感染的预后[15]。与抗生素治疗相比,噬菌体治疗的一些关键优势是:天然存在,低毒性;可进行自我复制;与细菌共进化;高特异性,避免非靶向细菌的干扰;可以穿透生物膜[16]。随着各种多重耐药超级细菌的出现,噬菌体雾化剂作为抗生素替代品治疗多重耐药细菌性肺炎的前景似乎很有希望。
1 噬菌体在临床肺炎治疗中的应用
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目前国内外的噬菌体疗法仅有小规模的临床试验,尚无较为完备的临床诊疗指南或共识。尽管噬菌体疗法已在治疗细菌性腹泻、皮肤伤口感染、尿路感染等疾病研究中开展了随机对照试验(randomized controlled trial,RCT)临床研究[17-19],但用于治疗肺炎的噬菌体疗法RCT临床研究尚无公开报道[20]。通过对国内外的部分病例报告进行综述(表1),旨在为噬菌体疗法的临床应用提供依据。
1.1 铜绿假单胞菌
目前,噬菌体治疗被较多地应用于囊性纤维化(cystic fibrosis, CF)继发的肺炎,最常见的病原体就是铜绿假单胞菌。Law等[21]报道了在一名26岁的CF等待肺移植的患者中使用噬菌体治疗成功的案例,患者在等待肺移植的过程中出现多重耐药(multidrug resistance,MDR)铜绿假单胞菌肺炎、持续呼吸衰竭。使用AB-PA01(由美国AmpliPhi Biosciences公司生产的含4种裂解性噬菌体的鸡尾酒制剂)静脉注射(4×109 PFU·mL-1,5 mL)进行8周治疗后,辅助氧使用量和痰液量均减少,症状明显好转,治疗结束后100 d内未出现铜绿假单胞菌肺炎复发和CF加重;9个月后,患者成功接受双侧肺移植。
此外,噬菌体治疗也常常用于临床上病情复杂的难治性肺部感染,使病情出现转机。Maddocks等[22]介绍了1名右下叶肺腺癌切除并纵隔淋巴结取样术后并发呼吸机相关性肺炎脓胸的患者,术后第2天患者白细胞计数、C反应蛋白升高,出现严重胸膜炎性胸痛,痰培养显示对哌拉西林他唑巴坦、环丙沙星和美罗培南敏感的铜绿假单胞菌中度生长。然而,美罗培南治疗1周后,患者症状没有明显好转,胸部CT提示双肺斑片状实变、右胸壁广泛皮下气肿,脓性分泌物培养显示对美罗培南、亚胺培南和哌拉西林-他唑巴坦耐药的铜绿假单胞菌生长。由于病情的严重性,采用AB-PA01静脉注射(×107 PFU·mL-1,100 mL)和雾化吸入(×109 PFU·mL-1,4 mL)两种方式进行辅助治疗,治疗后第3天患者氧合改善,7 d后患者从重症监护病房(intensive care unit, ICU)转出,停止噬菌体治疗。值得注意的是,患者从噬菌体治疗后5 d至噬菌体治疗结束后6个月,痰培养中均未见铜绿假单胞菌的生长。Aslam等[23]使用噬菌体鸡尾酒疗法以静脉注射伴或不伴雾化吸入的方式成功治疗了两名有严重气道并发症和难治性耐药铜绿假单胞菌肺炎的肺移植受者,这2例患者对噬菌体治疗的耐受性良好,没有发现相关的不良事件。同时作者指出,噬菌体治疗可以避免抗生素毒性,甚至有可能避免微生物易感性模式的潜在变化,使机体对抗生素更敏感。
1.2 金黄色葡萄球菌
金黄色葡萄球菌也是CF继发肺部感染较常见的病原体。Kutateladze 等[24]通过噬菌体雾化吸入治疗包括儿童和成人在内的CF继发金黄色葡萄球菌感染的患者,认为噬菌体治疗可降低痰中细菌的密度,改善病人的健康状况。Kvachadze等[25]报道了一例儿童CF患者,该患者接受噬菌体雾化吸入治疗金黄色葡萄球菌,共9次,每4~6周1次。据报道,在9个月的治疗中,噬菌体疗法可导致细菌滴度下降及抗生素使用量减少50%。
1.3 肺炎克雷伯菌
Li等[26]通过噬菌体雾化吸入治疗一例特重型颅脑损伤并伴有泛耐药肺炎克雷伯菌肺部感染的患者。每次使用×109 PFU·mL-1的噬菌体液5 mL,每隔4 h治疗1次,共治疗4次,取每次治疗前后的痰液进行细菌培养及噬菌体滴度测定。结果发现,对于肺部雾化吸入噬菌体治疗,连续治疗2次即可以达到裂解靶向菌的效果。患者经噬菌体治疗后,咳嗽咳痰症状好转。肺部CT显示,治疗后两侧胸腔积液明显减少,炎症反应减轻。然而,在治疗第4、5小时未检出肺炎克雷伯菌后,第6小时及以后的痰液标本中均培养出与之前裂解谱不同的肺炎克雷伯菌,说明经过噬菌体治疗,菌株发生了变化,细菌快速产生了噬菌体耐受,猜测其可能是单一噬菌体疗法的弊端之一。
1.4 鲍曼不动杆菌
Wu等[27]首次将噬菌体用于治疗新型冠状病毒感染(COVID-19)患者继发性细菌感染。患者共4名,新冠肺炎继发鲍曼不动杆菌肺部感染,采用两种噬菌体雾化吸入的方式进行治疗。其中两名患者脱离体外膜肺氧合后出院;一名患者治疗后第7天转出ICU,但1个月后死于呼吸衰竭;一名患者的鲍曼不动杆菌感染被治愈,然而其后续死于继发的耐碳青霉烯类肺炎克雷伯菌感染。种种证据表明,与抗生素治疗相比,噬菌体快速裂解细菌可减少革兰氏阴性菌的内毒素释放,然而一名患者在吸入治疗4 h后经历了白细胞介素-6(IL-6)和白细胞介素-8(IL-8)的剧烈波动,提示了在抗感染过程中噬菌体和免疫系统的协同,噬菌体治疗亦有可能引起细胞因子风暴。Tan等[28]利用噬菌体制剂与替加环素、多黏菌素E联合连续雾化16 d成功治疗一例因耐碳青霉烯类鲍曼不动杆菌而发生医院获得性肺炎的病例。本研究通过采集支气管肺泡灌洗液(bronchoalveolar lavage fluid,BALF)标本监测肺内噬菌体和细菌滴度,通过采集血样监测炎症因子变化。结果表明治疗1 h后BALF中检测到噬菌体颗粒,滴度逐渐升高,15 d后达到较高水平。这一观察结果提示噬菌体在原位复制。在噬菌体治疗的第7天,BALF培养物转阴,胸片显示双侧实变逐渐消失,肺功能改善。此外,患者的炎症因子谱和临床体征均显示噬菌体治疗后无明显毒副作用。
2 噬菌体疗法的应用条件与面临的挑战
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目前,国内外噬菌体治疗前均应先进行治疗的评估,噬菌体治疗需要满足以下条件:①患者临床依据,患者必须为细菌感染,药敏结果为多重耐药或是抗生素疗效欠佳;②噬菌体对靶细菌的体外疗效依据;③遗传学依据,噬菌体均已通过基因测序证明不含有已知的细菌耐药基因;④选用裂解性噬菌体,不含有溶原性基因以避免整合入细菌基因组;⑤产品保证无菌和低内毒素含量(≤5 EU·kg-1);⑥有实验性新药或伦理批件[29]。同时,噬菌体疗法也面临着一些挑战。
2.1 细菌耐药
与抗生素类似,细菌可以对特定的噬菌体产生耐药性,包括阻断噬菌体受体、生产竞争性抑制剂来阻断噬菌体的吸附,重复感染排斥系统和限制性修饰系统来阻止噬菌体DNA进入宿主细胞以及一种靶向外来核酸的细菌免疫系统——CRISPR-Cas系统来降解噬菌体核酸[30]。作为对细菌抗病毒机制的反应,噬菌体不断进化以保留抗细菌能力。目前,使用噬菌体鸡尾酒制剂已被推荐为降低细菌噬菌体耐药性发展风险的一种策略[31]。
2.2 毒性与溶原性
革兰氏阴性菌和革兰氏阳性菌产生的噬菌体裂解液通常含有内毒素,包括脂多糖和脂磷壁酸。噬菌体在裂解细菌后释放的内毒素可能会引发促炎反应,并最终导致全身器官衰竭,即Jarisch Herxheimer效应[32]。此外,溶原性噬菌体遗传物质与宿主结合,可以改变感染细菌的表型,这种转化可能诱发细菌的致病性。研究表明,防止这种溶原性转化可以通过过氧化氢促进活性氧、谷胱甘肽和转录抑制因子的过表达来实现[33]。
2.3 免疫系统的识别与拮抗
噬菌体作为一种外来的具有免疫原性的病毒,可以激活人体适应性免疫系统和先天免疫系统。Krut等[34]研究发现,噬菌体介导的先天免疫细胞的激活主要是基于模式识别受体(pattern recognition receptor, PRR)对噬菌体来源的DNA和RNA的识别。因此,根据噬菌体类型、剂量和核酸合成活性的不同,特异性PRR参与和免疫激活的程度也会有所不同。其次,噬菌体的免疫原性促进噬菌体中和抗体的形成,特异性的IgG或IgA可以限制噬菌体的增殖速率、阻碍治疗的成功并随着反复给药而增加。
2.4 制剂的制备
用于肺部感染的噬菌体制剂的制备包括生产、纯化和吸入配方。对于标准化的噬菌体鸡尾酒制剂来说,其中噬菌体的稳定性可能有所不同,这就需要针对每个噬菌体优化生产工艺以及进行一系列的稳定性评估。此外,目前临床上采用的噬菌体治疗多为个性化治疗,这种量身定制的治疗方式对患者来说不可避免地要花费时间和成本[16]。
3 两种噬菌体疗法的应用现状
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3.1 噬菌体裂解酶
噬菌体裂解酶通常是一类肽聚糖水解酶,在噬菌体复制周期结束时产生,并依赖宿主细菌进行合成。这些酶能快速裂解细菌细胞壁中的肽聚糖,导致肽聚糖降解、细胞质膜膨出和细胞裂解,并释放子代噬菌体[35]。由于肽聚糖是细菌细胞壁的主要和必要成分、是细菌存活的必要条件。因此宿主细菌对噬菌体裂解酶产生耐药性的可能性很低[36]。
噬菌体裂解酶有更广泛的裂解谱。Gong等[37]研究发现,噬菌体裂解酶LysEFm5比编码它的噬菌体具有更广的抗菌谱,能够裂解23株肠球菌中的19株,其中包括7株万古霉素耐药菌株。Kim等[38]使用纯化的LysSS测定其体外抗菌活性。结果发现,重组LysSS对MDR鲍曼不动杆菌、MDR大肠杆菌、MDR肺炎克雷伯菌、铜绿假单胞菌和沙门氏菌均有一定的抑制活性。此外,LysSS对16株MDR鲍曼不动杆菌的最低抑菌浓度(MIC)为0.063~0.25 mg·mL-1。在250 mg·mL-1以下,LysSS对A549人肺细胞无细胞毒性作用。
目前已经开展了一些一期临床试验来证实噬菌体裂解酶治疗的安全性。Jun等[39]进行了一项单中心、随机双盲、安慰剂对照、静脉注射裂解酶的一期临床研究。该研究评估了健康男性志愿者静脉滴注单次递增剂量SAL200(0.1、0.3、1、3和10 mg·kg-1)后的药动学、药效学和耐受性。结果表明,SAL200耐受性良好,在本临床研究中未观察到严重不良事件。志愿者血生化、血常规、凝血功能、尿常规、生命体征和体格检查结果均无临床意义。Lu等[40]通过体外观察和体内动物实验证明内溶酶LysP108显示出良好的抗菌潜力,可作为治疗耐甲氧西林金黄色葡萄球菌(methicillin-resistant staphylococcus aureus, MRSA)引起的感染的候选药物。通过扫描电镜观察发现,LysP108具有较强的杀菌能力,可从体外直接裂解金黄色葡萄球菌并抑制和破坏细菌生物膜。体内动物实验表明,与单药治疗相比,联合注射LysP108和万古霉素后感染MRSA小鼠皮下脓肿面积明显缩小,证实了LysP108与万古霉素的协同抗菌作用。
然而,由于革兰阴性菌具有一层不渗透外膜,这种细胞壁与革兰阳性菌相比的差异使得前一种菌株对外源添加的裂解酶不甚敏感[36],这成为裂解酶治疗的1个有待攻克的问题。最近已经探索并推进了3种不同程度的研究路线,包括使用具有内在活性的裂解酶,因为带正电荷的C端会破坏外膜的稳定性,利用物理或化学手段破坏外膜的完整性,用蛋白质工程为裂解酶装备必要的工具来克服革兰氏阴性菌的外膜[41]。
3.2 工程噬菌体
对于溶原性噬菌体来说,它们的基因组可以与宿主染色体稳定整合,从而产生了1个固定的原噬菌体,所以通常可以通过与细菌基因组相同的方法对溶原性噬菌体进行操作。相比之下,裂解性噬菌体需要专门的基因工程方法,这些方法可以分为两大类:同源重组和基因组重启,即外源组装的合成噬菌体DNA的激活[42]。
噬菌体受体结合蛋白及其相关结构域可以被设计来重定向噬菌体特异性和避免细菌对其的耐药性。Dunne等[5]将受体结合蛋白和溶原工程结合,改造了李斯特菌噬菌体PSA受体结合蛋白,将温和的、宿主谱窄的噬菌体重新编程为裂解性噬菌体,扩大了宿主范围。Yehl等[43]通过研究噬菌体的自然进化和结构建模,在T3噬菌体尾部纤维蛋白中确定了宿主范围决定区域(host-range-determining regions, HRDRs),并通过定点突变对这些区域进行基因工程改造。结果发现,突变的HRDRs导致了宿主范围改变的噬菌体的产生,通过防止耐药性的出现,选择的噬菌体能够在体外长期抑制细菌的生长。
CRISPR-Cas系统是由负责识别靶序列的 CRISPR 元件和切割靶序列的 Cas蛋白组成[44]。通过CRISPR-Cas 系统,噬菌体可以被重新编程以优化其治疗潜力。Selle等[45]基于存在于大多数艰难梭菌基因组中的保守型I-B CRISPR-Cas系统,对噬菌体CD24-2的基因组进行修饰,编码了一个细菌基因组靶向CRISPR序列。这个序列在感染过程中被转导到细菌细胞中,并与噬菌体的宿主裂解基因同时表达。由CRISPR RNA指导的天然表达的I-B型Cas效应蛋白造成的不可修复的基因组损伤与噬菌体本身的细菌裂解过程协同,提高了噬菌体在体外和艰难梭菌小鼠感染模型中的杀伤能力。
4 展望
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综上,对于病情复杂或是多重耐药细菌导致的肺炎来说,噬菌体疗法作为抗生素治疗的替代或补充治疗选择在临床上均已经有了许多个例的研究。尽管噬菌体疗法还是面临着细菌耐药、自身的安全性或者免疫系统对其疗效的影响等重重困难,然而随着噬菌体衍生物治疗以及工程噬菌体技术的发展,这些困难也在逐渐被我们克服。在未来,可能还需要更多的体内研究来回答噬菌体衍生物或是工程噬菌体治疗的有效性和安全性。尽管有这些挑战,噬菌体在治疗呼吸道感染,特别是那些由多重耐药细菌引起的感染方面还是具有相当光明的前景。
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  • 接收时间：2022-08-01
  • 首发时间：2026-04-08
  • 出版时间：2024-03-22
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  • 收稿日期：2022-08-01
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    1 首都儿科研究所附属儿童医院呼吸内科, 北京 100020
    2 首都儿科研究所细菌研究室, 北京 100020

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*曹玲,女,教授,硕士生导师 研究方向:儿科呼吸系统疾病 Tel:(010)85695629
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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