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噬菌体鸡尾酒联合阿米卡星治疗产碳青霉烯酶多黏菌素耐药肺炎克雷伯菌菌血症的研究

Phage cocktail amikacin combination as a potential therapy for bacteremia associated with carbapenemase producing colistin resistant Klebsiella pneumoniae.

机构信息

Department of Microbiology, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.

Center of Excellence in Antimicrobial Resistance and Stewardship Research, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

出版信息

Sci Rep. 2024 Nov 22;14(1):28992. doi: 10.1038/s41598-024-79924-9.

DOI:10.1038/s41598-024-79924-9
PMID:39578508
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11584731/
Abstract

The increasing occurrence of hospital-associated infections, particularly bacteremia, caused by extensively drug-resistant (XDR) carbapenemase-producing colistin-resistant Klebsiella pneumoniae highlights a critical requirement to discover new therapeutic alternatives. Bacteriophages having host-specific bacteriolytic effects are promising alternatives for combating these pathogens. Among 12 phages isolated from public wastewater in Thailand, two phages-vB_kpnM_05 (myovirus) and vB_kpnP_08 (podovirus) showed broad-host range, producing bacteriolytic activities against 81.3% (n = 26) and 78.1% (n = 25) of 32 XDR carbapenemase-producing colistin-resistant K. pneumoniae, with capsular types-K15, K17, K50, K51, K52/wzi-50 and K2/wzi-2. Both phages showed short replication times, large burst sizes with rapid adsorptions. They exhibited significant stability under various environmental conditions. Genomic analysis revealed that both phages are genetically distinct phages from Myoviridae and Podoviridae family, with the lack of toxin, virulence, lysogeny and antibiotic resistance genes. These characteristics highlighted their promising potential for utilizing in phage therapy for combating XDR K. pneumoniae. Although phage cocktail combining vB_kpnM_05 and vB_kpnP_08 provided significant bacteriolysis for longer duration (8 h) than its monophage (6 h), bacterial regrowth was observed which suggested an evitable development of phage resistance under phages' selection pressures. Future study will be undertaken to elucidate the precise mechanisms by which these XDR K. pneumoniae developed phage resistance and their associated fitness cost. Remarkably, combining phage cocktail with amikacin at their sub-inhibitory concentrations produced potent synergy by completely suppressing bacterial regrowth in vitro. Our study demonstrated the significant therapeutic and prophylactic effectiveness of a phage cocktail-amikacin combination as a promising alternative strategy for overcoming bacteremia associated with XDR K. pneumoniae having carbapenemase and colistin resistance in vivo.

摘要

越来越多的医院相关感染，特别是由广泛耐药（XDR）碳青霉烯酶产生的多黏菌素耐药肺炎克雷伯菌引起的菌血症，凸显出迫切需要发现新的治疗替代品。具有宿主特异性溶菌作用的噬菌体是对抗这些病原体的有前途的替代品。在泰国公共废水中分离出的 12 种噬菌体中，两种噬菌体-vB_kpnM_05（肌病毒）和 vB_kpnP_08（痘病毒）表现出广泛的宿主范围，对 32 株 XDR 碳青霉烯酶产生的多黏菌素耐药肺炎克雷伯菌中的 81.3%（n=26）和 78.1%（n=25）产生溶菌活性，其荚膜类型为-K15、K17、K50、K51、K52/wzi-50 和 K2/wzi-2。两种噬菌体均具有较短的复制时间、较大的爆发量和快速的吸附作用。它们在各种环境条件下表现出显著的稳定性。基因组分析表明，两种噬菌体均为肌病毒科和痘病毒科的遗传上不同的噬菌体，缺乏毒素、毒力、溶原性和抗生素耐药基因。这些特性突出了它们在噬菌体治疗中对抗 XDR 肺炎克雷伯菌的潜在应用前景。尽管噬菌体鸡尾酒组合 vB_kpnM_05 和 vB_kpnP_08 比其单噬菌体（6 小时）提供了更长时间（8 小时）的显著杀菌作用，但观察到细菌再生，这表明在噬菌体的选择压力下不可避免地会发展出噬菌体耐药性。未来的研究将致力于阐明这些 XDR 肺炎克雷伯菌产生噬菌体耐药性的精确机制及其相关的适应成本。值得注意的是，将噬菌体鸡尾酒与阿米卡星在亚抑菌浓度下联合使用可在体外完全抑制细菌再生，产生强大的协同作用。我们的研究表明，噬菌体鸡尾酒-阿米卡星联合使用具有显著的治疗和预防效果，是一种有前途的替代策略，可以克服体内具有碳青霉烯酶和多黏菌素耐药性的 XDR 肺炎克雷伯菌菌血症。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21e/11584731/61a23d8f2f9a/41598_2024_79924_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21e/11584731/6abf5346bd07/41598_2024_79924_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21e/11584731/b9f4c7fd9cca/41598_2024_79924_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21e/11584731/3d35d6ed4e0c/41598_2024_79924_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21e/11584731/2a3d24b26b47/41598_2024_79924_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21e/11584731/806e45785629/41598_2024_79924_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21e/11584731/ce61defdba69/41598_2024_79924_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21e/11584731/4fd0133676bb/41598_2024_79924_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21e/11584731/61a23d8f2f9a/41598_2024_79924_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21e/11584731/6abf5346bd07/41598_2024_79924_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21e/11584731/b9f4c7fd9cca/41598_2024_79924_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21e/11584731/3d35d6ed4e0c/41598_2024_79924_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21e/11584731/2a3d24b26b47/41598_2024_79924_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21e/11584731/806e45785629/41598_2024_79924_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21e/11584731/ce61defdba69/41598_2024_79924_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21e/11584731/4fd0133676bb/41598_2024_79924_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21e/11584731/61a23d8f2f9a/41598_2024_79924_Fig8_HTML.jpg

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[1]
First detection of multidrug-resistant and toxigenic Pasteurella aerogenes in sow vaginal discharge: a novel threat to swine health in Thailand.

Sci Rep. 2024-10-26

[2]
Aging-induced dysbiosis worsens sepsis severity but is attenuated by probiotics in D-galactose-administered mice with cecal ligation and puncture model.

PLoS One. 2024

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Sci Rep. 2024-10-9

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Bacteriophages isolated from mouse feces attenuates pneumonia mice caused by Pseudomonas aeruginosa.

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