Phage therapy as an alternative for multidrug-resistant Klebsiella pneumoniae infections: literature review
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Published:
May 30, 2025
Keywords:
Phage therapy, Klebsiella pneumoniae, Multidrug resistance, Biofilms, Bacteriophages.
Main Article Content
Abstract
Introduction. The phenomenon of globalization and the indiscriminate use of antibiotics have led to the emergence of multidrug-resistant bacterial strains, posing a significant challenge to modern medicine. Klebsiella pneumoniae, an opportunistic pathogen, stands out for its ability to acquire resistance, particularly to carbapenems, leaving limited treatment options. Phage therapy emerges as a promising alternative against multidrug-resistant infections, especially in resource-limited countries. Objective. Analyze phage therapy as a therapeutic alternative for multidrug-resistant Klebsiella pneumoniae infections through a review of recent literature. Methodology. A bibliographic review was conducted using DeCS/MeSH terms such as “Bacteriophages,” “Phage Therapy,” and “Klebsiella pneumoniae” applying filters for articles published between 2019 and 2024 in databases such as PubMed and Web of Science. Studies in humans, systematic reviews, and original research related to phage therapy were included. Results. Studies highlight the effectiveness of phages such as RAM-1 and PSKP16 in eliminating biofilms and lysing MDR Klebsiella pneumoniae strains. Combining phage therapy with antibiotics showed significant synergy, reducing bacterial loads and mortality rates in preclinical models. Conclusion. Phage therapy represents a viable and promising alternative to combat multidrug-resistant Klebsiella pneumoniae infections. Although progress is encouraging, further clinical research and standardized regulations are needed for its widespread implementation. General Area of Study: Medicine. Specific area of study: Microbiology. Type of study: Systematic bibliographic.
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How to Cite
Barragán Cusme, J. D., & Barba Guzmán, C. V. (2025). Phage therapy as an alternative for multidrug-resistant Klebsiella pneumoniae infections: literature review. Anatomía Digital, 8(2.1), 127-143. https://doi.org/10.33262/anatomiadigital.v8i2.1.3439
Section
Articulos de revisión bibliográfica
References
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9. Yang J, Long H, Hu Y, Feng Y, McNally A, Zong Z. Klebsiella oxytoca Complex: Update on Taxonomy, Antimicrobial Resistance, and Virulence. Clinical Microbiology Reviews [Internet]. 2022 [cited 2025 January 11]; 35(1): 1–39. Available from: https://doi.org/10.1128/CMR.00006-21
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11. Ballén V, Gabasa Y, Ratia C, Ortega R, Tejero M, Soto S. Antibiotic resistance and virulence profiles of klebsiella pneumoniae strains isolated from different clinical sources. Frontiers in Cellular and Infection Microbiology [Internet]. 2021[cited 2025 January 12]; 11: 738223. Available from: https://doi.org/10.3389/fcimb.2021.738223
12. Dong N, Yang X, Chan EWC, Zhang R, Chen S. Klebsiella species: Taxonomy, hypervirulence and multidrug resistance. eBioMedicine [Internet]. 2022 [cited 2025 January 11]; 79: 103998. Available from: https://doi.org/10.1016/j.ebiom.2022.103998
13. Shah MRA, Bukhari SMAUS, Redaina, Adnan M, Imran M, Jamal M. Isolation, and characterization of lytic bacteriophage from wastewater to control clinical multidrug resistant Klebsiella pneumoniae. Kuwait Journal of Science [Internet]. 2023 [cited 2025 January 9]; 50(4):681–689. Available from: https://doi.org/10.1016/j.kjs.2023.01.012
14. Sadeqi S, Michniewski S, Nikkhahi F, Jameson E, Amin Marashi SM. Isolation of new Klebsiella pneumoniae phage PSKP16. Iranian Journal of Microbiology [Internet]. 2023 [cited 2025 January 9]; 15(1): 62–68. Available from: https://pubmed.ncbi.nlm.nih.gov/37069906/
15. Saqr E, Sadik MW, El-Didamony G, Askora A. Analysis of a new phage, KZag1, infecting biofilm of Klebsiella pneumoniae: genome sequence and characterization. BMC Microbiology [Internet]. 2024 [cited 2025 January 9]; 24(211): 1–18. Available from: https://doi.org/10.1186/s12866-024-03355-9
16. Oh HK, Cha K, Hwang YJ, Cho J, Jo Y, Myung H. Complete genome sequence of a novel bacteriophage, PBKP05, infecting Klebsiella pneumoniae. Archives of Virology [Internet]. 2019 [cited 2025 January 9]; 164:885–888. Available from: https://doi.org/10.1007/s00705-018-04121-9
17. Saha S, Malaker R, Islam Sajib MS, Hasanuzzaman MD, Rahman H, Ahmed ZB, et al. Complete Genome Sequence of a Novel Coronavirus (SARS-CoV-2) Isolate from Bangladesh. Microbiology Resource Announcements [Internet]. 2020 [cited 2025 January 9]; 9(24): 19–21. Available from: https://doi.org/10.1128/mra.00568-20
18. Domingo-Calap P, Beamud B, Vienne J, González-Candelas F, Sanjuán R. Isolation of four lytic phages infecting Klebsiella pneumoniae K22 clinical isolates from Spain. International Journal of Molecular Sciences [Internet]. 2020 [cited 2025 January 27]; 21(2): 425. Available from: https://doi.org/10.3390/ijms21020425
19. Hesse S, Rajaure M, Wall E, Johnson J, Bliskovsky V, Gottesman S, et al. Phage resistance in multidrug-resistant klebsiella pneumoniae st258 evolves via diverse mutations that culminate in impaired adsorption. MBio [Internet]. 2020 [cited 2024 December 27]; 11(1): 1–14. Available from: https://doi.org/10.1128/mbio.02530-19
20. Gholizadeh O, Ghaleh HEG, Tat M, Ranjbar R, Dorostkar R. The potential use of bacteriophages as antibacterial agents against Klebsiella pneumoniae. Virology Journal [Internet]. 2024 [cited 2025 January 27]; 21(191). Available from: https://doi.org/10.1186/s12985-024-02450-7
21. Liang Z, Shi YL, Peng Y, Xu C, Zhang C, Chen Y, et al. BL02, a phage against carbapenem- and polymyxin-B resistant Klebsiella pneumoniae, isolated from sewage: A preclinical study. Virus Research [Internet]. 2023 [cited 2025 January 27]; 331:199126. Available from: https://doi.org/10.1016/j.virusres.2023.199126
22. Bao J, Wu N, Zeng Y, Chen L, Li L, Yang L, et al. Non-active antibiotic and bacteriophage synergism to successfully treat recurrent urinary tract infection caused by extensively drug-resistant Klebsiella pneumoniae. Emerging Microbes & Infections [Internet]. 2020 [cited 2025 January 27]; 9(1):771–774. Available from: https://doi.org/10.1080/22221751.2020.1747950
23. Zhao M, Li H, Gan D, Wang M, Deng H, Yang QE. Antibacterial effect of phage cocktails and phage-antibiotic synergy against pathogenic Klebsiella pneumoniae. ASM Journals mSystems [Internet]. 2024 [cited 2025 January 27]; 9(9):1–14. Available from: https://doi.org/10.1128/msystems.00607-24
24. Ponsecchi G, Olimpieri T, Poerio N, Antonelli A, Coppi M, Di Lallo G, et al. Characterization of four novel bacteriophages targeting multi-drug resistant Klebsiella pneumoniae strains of sequence type 147 and 307. Frontiers in Cellular and Infection Microbiology [Internet]. 2024 [cited 2025 January 16]; 14: 1473668. Available from: https://doi.org/10.3389/fcimb.2024.1473668
25. Bai R, Guo J. Interactions, and Implications of Klebsiella pneumoniae with Human Immune responses and metabolic pathways: A comprehensive review. Infection and Drug Resistance [Internet]. 2024 [cited 2025 January 16]; 17: 449–462. Available from: https://doi.org/10.2147/IDR.S451013
26. Weber-Dąbrowska B, Żaczek M, Łobocka M, Łusiak-Szelachowska M, Owczarek B, Orwat F, et al. Characteristics of Environmental Klebsiella pneumoniae and Klebsiella oxytoca Bacteriophages and Their Therapeutic Applications. Pharmaceutics [Internet]. 2023 [cited 2025 January 16]; 15(2):434. Available from: https://doi.org/10.3390/pharmaceutics15020434
2. Martinez Loaiza W, Rivera Ruiz AK, Opsina Patiño CC, Chavez Vivas M. Bacterial resistance in hospital-acquired infections acquired in the intensive care unit: a systematic review. Acta Medica Hradec Kralove Czech Republic [Internet]. 2023 [cited 2025 January 4]; 66(1): 1–10. Available from: https://dx.doi.org/10.14712/18059694.2023.8
3. Wagenlehner FME, Dittmar F . Re: Global Burden of Bacterial Antimicrobial Resistance in 2019: A Systematic Analysis. European Urology [Internet]. 2022 [cited 2025 January 4]; 82(6): 658. Available from: https://doi.org/10.1016/j.eururo.2022.08.023
4. Castanheira M, Deshpande LM, Mendes RE, Canton R, Sader HS, Jones RN. Variations in the occurrence of resistance phenotypes and carbapenemase genes among enterobacteriaceae isolates in 20 years of the SENTRY antimicrobial surveillance program. Open Forum Infectious Diseases [Internet]. 2019 [cited 2025 January 4]; 6(supp 1):23–33. Available from: https://doi.org/10.1093/ofid/ofy347
5. Hitchcock NM, Gomes Nunes DD, Shiach J, Saraiva Hodel KV, Viana Barbosa JD, Pereira Rodriguez LA, et al. Current clinical landscape, and global potential of Bacteriophage therapy. Viruses [Internet]. 2023 [cited 2025 January 4]; 15(4): 1020. Available from: https://doi.org/10.3390/v15041020
6. Di Pilato V, Pollini S, Miriagou V, Rossolini GM, D’Andrea MM. Carbapenem-resistant Klebsiella pneumoniae: the role of plasmids in emergence, dissemination, and evolution of a major clinical challenge. Expert Review of Anti-infective Therapy [Internet]. 2024 [cited 2025 January 11]; 22(1–3): 25–43. Available from: https://doi.org/10.1080/14787210.2024.2305854
7. Li Y, Kumar S, Zhang L, Wu H. Klebsiella pneumonia and Its Antibiotic Resistance: A Bibliometric Analysis. BioMed Research International [Internet]. 2022 [cited 2025 January 11]. Available from: https://doi.org/10.1155/2022/1668789
8. Wang M, Earley M, Chen L, Hanson BM, Yu Y, Liu Z, et al. Clinical outcomes, and bacterial characteristics of carbapenem-resistant Klebsiella pneumoniae complex among patients from different global regions (CRACKLE-2): a prospective, multicentre, cohort study. Lancet Infectious Diseases [Internet]. 2022 [cited 2025 January 12]; 22(3): 401–412. Available from: https://pubmed.ncbi.nlm.nih.gov/34767753/
9. Yang J, Long H, Hu Y, Feng Y, McNally A, Zong Z. Klebsiella oxytoca Complex: Update on Taxonomy, Antimicrobial Resistance, and Virulence. Clinical Microbiology Reviews [Internet]. 2022 [cited 2025 January 11]; 35(1): 1–39. Available from: https://doi.org/10.1128/CMR.00006-21
10. Wang G, Zhao G, Chao X, Xie L, Wang H. The characteristics of virulence, biofilm, and antibiotic resistance of klebsiella pneumoniae. International Journal of Environmental Research and Public Health [Internet]. 2020 [cited 2025 January 12]; 17(17):6278. Available from: https://doi.org/10.3390/ijerph17176278
11. Ballén V, Gabasa Y, Ratia C, Ortega R, Tejero M, Soto S. Antibiotic resistance and virulence profiles of klebsiella pneumoniae strains isolated from different clinical sources. Frontiers in Cellular and Infection Microbiology [Internet]. 2021[cited 2025 January 12]; 11: 738223. Available from: https://doi.org/10.3389/fcimb.2021.738223
12. Dong N, Yang X, Chan EWC, Zhang R, Chen S. Klebsiella species: Taxonomy, hypervirulence and multidrug resistance. eBioMedicine [Internet]. 2022 [cited 2025 January 11]; 79: 103998. Available from: https://doi.org/10.1016/j.ebiom.2022.103998
13. Shah MRA, Bukhari SMAUS, Redaina, Adnan M, Imran M, Jamal M. Isolation, and characterization of lytic bacteriophage from wastewater to control clinical multidrug resistant Klebsiella pneumoniae. Kuwait Journal of Science [Internet]. 2023 [cited 2025 January 9]; 50(4):681–689. Available from: https://doi.org/10.1016/j.kjs.2023.01.012
14. Sadeqi S, Michniewski S, Nikkhahi F, Jameson E, Amin Marashi SM. Isolation of new Klebsiella pneumoniae phage PSKP16. Iranian Journal of Microbiology [Internet]. 2023 [cited 2025 January 9]; 15(1): 62–68. Available from: https://pubmed.ncbi.nlm.nih.gov/37069906/
15. Saqr E, Sadik MW, El-Didamony G, Askora A. Analysis of a new phage, KZag1, infecting biofilm of Klebsiella pneumoniae: genome sequence and characterization. BMC Microbiology [Internet]. 2024 [cited 2025 January 9]; 24(211): 1–18. Available from: https://doi.org/10.1186/s12866-024-03355-9
16. Oh HK, Cha K, Hwang YJ, Cho J, Jo Y, Myung H. Complete genome sequence of a novel bacteriophage, PBKP05, infecting Klebsiella pneumoniae. Archives of Virology [Internet]. 2019 [cited 2025 January 9]; 164:885–888. Available from: https://doi.org/10.1007/s00705-018-04121-9
17. Saha S, Malaker R, Islam Sajib MS, Hasanuzzaman MD, Rahman H, Ahmed ZB, et al. Complete Genome Sequence of a Novel Coronavirus (SARS-CoV-2) Isolate from Bangladesh. Microbiology Resource Announcements [Internet]. 2020 [cited 2025 January 9]; 9(24): 19–21. Available from: https://doi.org/10.1128/mra.00568-20
18. Domingo-Calap P, Beamud B, Vienne J, González-Candelas F, Sanjuán R. Isolation of four lytic phages infecting Klebsiella pneumoniae K22 clinical isolates from Spain. International Journal of Molecular Sciences [Internet]. 2020 [cited 2025 January 27]; 21(2): 425. Available from: https://doi.org/10.3390/ijms21020425
19. Hesse S, Rajaure M, Wall E, Johnson J, Bliskovsky V, Gottesman S, et al. Phage resistance in multidrug-resistant klebsiella pneumoniae st258 evolves via diverse mutations that culminate in impaired adsorption. MBio [Internet]. 2020 [cited 2024 December 27]; 11(1): 1–14. Available from: https://doi.org/10.1128/mbio.02530-19
20. Gholizadeh O, Ghaleh HEG, Tat M, Ranjbar R, Dorostkar R. The potential use of bacteriophages as antibacterial agents against Klebsiella pneumoniae. Virology Journal [Internet]. 2024 [cited 2025 January 27]; 21(191). Available from: https://doi.org/10.1186/s12985-024-02450-7
21. Liang Z, Shi YL, Peng Y, Xu C, Zhang C, Chen Y, et al. BL02, a phage against carbapenem- and polymyxin-B resistant Klebsiella pneumoniae, isolated from sewage: A preclinical study. Virus Research [Internet]. 2023 [cited 2025 January 27]; 331:199126. Available from: https://doi.org/10.1016/j.virusres.2023.199126
22. Bao J, Wu N, Zeng Y, Chen L, Li L, Yang L, et al. Non-active antibiotic and bacteriophage synergism to successfully treat recurrent urinary tract infection caused by extensively drug-resistant Klebsiella pneumoniae. Emerging Microbes & Infections [Internet]. 2020 [cited 2025 January 27]; 9(1):771–774. Available from: https://doi.org/10.1080/22221751.2020.1747950
23. Zhao M, Li H, Gan D, Wang M, Deng H, Yang QE. Antibacterial effect of phage cocktails and phage-antibiotic synergy against pathogenic Klebsiella pneumoniae. ASM Journals mSystems [Internet]. 2024 [cited 2025 January 27]; 9(9):1–14. Available from: https://doi.org/10.1128/msystems.00607-24
24. Ponsecchi G, Olimpieri T, Poerio N, Antonelli A, Coppi M, Di Lallo G, et al. Characterization of four novel bacteriophages targeting multi-drug resistant Klebsiella pneumoniae strains of sequence type 147 and 307. Frontiers in Cellular and Infection Microbiology [Internet]. 2024 [cited 2025 January 16]; 14: 1473668. Available from: https://doi.org/10.3389/fcimb.2024.1473668
25. Bai R, Guo J. Interactions, and Implications of Klebsiella pneumoniae with Human Immune responses and metabolic pathways: A comprehensive review. Infection and Drug Resistance [Internet]. 2024 [cited 2025 January 16]; 17: 449–462. Available from: https://doi.org/10.2147/IDR.S451013
26. Weber-Dąbrowska B, Żaczek M, Łobocka M, Łusiak-Szelachowska M, Owczarek B, Orwat F, et al. Characteristics of Environmental Klebsiella pneumoniae and Klebsiella oxytoca Bacteriophages and Their Therapeutic Applications. Pharmaceutics [Internet]. 2023 [cited 2025 January 16]; 15(2):434. Available from: https://doi.org/10.3390/pharmaceutics15020434