Prophylactic phage administration provides a time window for delayed treatment of vancomycin-resistant Enterococcus faecalis in a murine bacteremia model
IntroductionVancomycin-resistant Enterococcus faecalis (VRE) poses a significant challenge in clinical settings due to its resistance to multiple antibiotics. Phage therapy offers a promising alternative to address this resistance crisis. However, critical gaps remain regarding optimal dosing, thera...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmicb.2024.1504696/full |
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| author | Wei-Xiao Wang Jiao-Yang Yu Xiu-Zhen Chen Xiu-Zhen Chen Shi-Yong Fu Hui Li Peng-Cheng Yi Yun-Yao Ren Shuang-Lin Gu Jing-Han Gao Jing Fan Yan-Mei Sun Jie Feng Shi-Wei Wang Wei Chen Wei Chen |
| author_facet | Wei-Xiao Wang Jiao-Yang Yu Xiu-Zhen Chen Xiu-Zhen Chen Shi-Yong Fu Hui Li Peng-Cheng Yi Yun-Yao Ren Shuang-Lin Gu Jing-Han Gao Jing Fan Yan-Mei Sun Jie Feng Shi-Wei Wang Wei Chen Wei Chen |
| author_sort | Wei-Xiao Wang |
| collection | DOAJ |
| description | IntroductionVancomycin-resistant Enterococcus faecalis (VRE) poses a significant challenge in clinical settings due to its resistance to multiple antibiotics. Phage therapy offers a promising alternative to address this resistance crisis. However, critical gaps remain regarding optimal dosing, therapeutic design, and treatment timing for phage therapy targeting VRE-induced bacteremia.MethodsThe biological and genomic characteristics of a novel lytic phage specific to VRE were investigated. Its in vitro bactericidal and antibiofilm activities were evaluated, along with its synergy with antimicrobial agents. In vitro safety and protective efficacy were assessed using a mouse bacteremia model. The impact of phage therapy on gut microbiota was examined through 16S rDNA gene sequencing.ResultsWe isolated and characterized a novel lytic phage, vB_EfaS-1017, specific to vancomycin-resistant E. faecalis. This phage features a circular, double-stranded DNA genome (40,766 bp), sharing 91.19% identity and 79% coverage with Enterococcus phage vB_EfaS_SRH2. vB_EfaS-1017 exhibited robust bactericidal and antibiofilm activity in vitro and demonstrated synergy with levofloxacin. Safety assessments confirmed its non-toxicity to mammalian cells and lack of hemolytic activity. In a mouse bacteremia model, phage treatment alone rescued 60% of infected mice, while combining phage with levofloxacin increased survival to 80%. Prophylactic administration of phage 24 hours prior to infection failed to prevent mortality. However, a combination of prophylactic phage administration and delayed treatment rescued 60% of mice, compared to 100% mortality in the delayed treatment alone group. Additionally, phage therapy helped maintain or restore gut microbiota balance.DiscussionThese findings underscore the potential of phage-antibiotic combinations as a superior therapeutic strategy against VRE infections. The observed synergy between phages and antibiotics highlights a promising approach to overcoming bacterial resistance and improving clinical outcomes. Furthermore, prophylactic phage administration may provide a critical time window for effective delayed treatment. Further preclinical research is essential to refine phage therapy protocols for clinical application. |
| format | Article |
| id | doaj-art-9fc29216f6c94ff3aa88ae58cf94f0ff |
| institution | Kabale University |
| issn | 1664-302X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Microbiology |
| spelling | doaj-art-9fc29216f6c94ff3aa88ae58cf94f0ff2025-01-24T07:13:52ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2025-01-011510.3389/fmicb.2024.15046961504696Prophylactic phage administration provides a time window for delayed treatment of vancomycin-resistant Enterococcus faecalis in a murine bacteremia modelWei-Xiao Wang0Jiao-Yang Yu1Xiu-Zhen Chen2Xiu-Zhen Chen3Shi-Yong Fu4Hui Li5Peng-Cheng Yi6Yun-Yao Ren7Shuang-Lin Gu8Jing-Han Gao9Jing Fan10Yan-Mei Sun11Jie Feng12Shi-Wei Wang13Wei Chen14Wei Chen15Department of Tuberculosis, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, ChinaKey Laboratory of Resources Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi’an, ChinaClinical Research Center, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, ChinaDepartment of Infectious Diseases, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, ChinaClinical Research Center, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, ChinaDepartment of Blood Transfusion, The Second Affiliated Hospital of Nanchang University, Nanchang, ChinaDepartment of Tuberculosis, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, ChinaDepartment of Tuberculosis, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, ChinaClinical Research Center, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, ChinaClinical Research Center, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, ChinaClinical Research Center, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, ChinaKey Laboratory of Resources Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi’an, ChinaState Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing, ChinaKey Laboratory of Resources Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi’an, ChinaDepartment of Tuberculosis, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, ChinaClinical Research Center, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, ChinaIntroductionVancomycin-resistant Enterococcus faecalis (VRE) poses a significant challenge in clinical settings due to its resistance to multiple antibiotics. Phage therapy offers a promising alternative to address this resistance crisis. However, critical gaps remain regarding optimal dosing, therapeutic design, and treatment timing for phage therapy targeting VRE-induced bacteremia.MethodsThe biological and genomic characteristics of a novel lytic phage specific to VRE were investigated. Its in vitro bactericidal and antibiofilm activities were evaluated, along with its synergy with antimicrobial agents. In vitro safety and protective efficacy were assessed using a mouse bacteremia model. The impact of phage therapy on gut microbiota was examined through 16S rDNA gene sequencing.ResultsWe isolated and characterized a novel lytic phage, vB_EfaS-1017, specific to vancomycin-resistant E. faecalis. This phage features a circular, double-stranded DNA genome (40,766 bp), sharing 91.19% identity and 79% coverage with Enterococcus phage vB_EfaS_SRH2. vB_EfaS-1017 exhibited robust bactericidal and antibiofilm activity in vitro and demonstrated synergy with levofloxacin. Safety assessments confirmed its non-toxicity to mammalian cells and lack of hemolytic activity. In a mouse bacteremia model, phage treatment alone rescued 60% of infected mice, while combining phage with levofloxacin increased survival to 80%. Prophylactic administration of phage 24 hours prior to infection failed to prevent mortality. However, a combination of prophylactic phage administration and delayed treatment rescued 60% of mice, compared to 100% mortality in the delayed treatment alone group. Additionally, phage therapy helped maintain or restore gut microbiota balance.DiscussionThese findings underscore the potential of phage-antibiotic combinations as a superior therapeutic strategy against VRE infections. The observed synergy between phages and antibiotics highlights a promising approach to overcoming bacterial resistance and improving clinical outcomes. Furthermore, prophylactic phage administration may provide a critical time window for effective delayed treatment. Further preclinical research is essential to refine phage therapy protocols for clinical application.https://www.frontiersin.org/articles/10.3389/fmicb.2024.1504696/fullvancomycin-resistant Enterococcus faecalisphage therapysynergyprophylactic administrationbacteremiamouse |
| spellingShingle | Wei-Xiao Wang Jiao-Yang Yu Xiu-Zhen Chen Xiu-Zhen Chen Shi-Yong Fu Hui Li Peng-Cheng Yi Yun-Yao Ren Shuang-Lin Gu Jing-Han Gao Jing Fan Yan-Mei Sun Jie Feng Shi-Wei Wang Wei Chen Wei Chen Prophylactic phage administration provides a time window for delayed treatment of vancomycin-resistant Enterococcus faecalis in a murine bacteremia model Frontiers in Microbiology vancomycin-resistant Enterococcus faecalis phage therapy synergy prophylactic administration bacteremia mouse |
| title | Prophylactic phage administration provides a time window for delayed treatment of vancomycin-resistant Enterococcus faecalis in a murine bacteremia model |
| title_full | Prophylactic phage administration provides a time window for delayed treatment of vancomycin-resistant Enterococcus faecalis in a murine bacteremia model |
| title_fullStr | Prophylactic phage administration provides a time window for delayed treatment of vancomycin-resistant Enterococcus faecalis in a murine bacteremia model |
| title_full_unstemmed | Prophylactic phage administration provides a time window for delayed treatment of vancomycin-resistant Enterococcus faecalis in a murine bacteremia model |
| title_short | Prophylactic phage administration provides a time window for delayed treatment of vancomycin-resistant Enterococcus faecalis in a murine bacteremia model |
| title_sort | prophylactic phage administration provides a time window for delayed treatment of vancomycin resistant enterococcus faecalis in a murine bacteremia model |
| topic | vancomycin-resistant Enterococcus faecalis phage therapy synergy prophylactic administration bacteremia mouse |
| url | https://www.frontiersin.org/articles/10.3389/fmicb.2024.1504696/full |
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