The educational content in this post, elaborated in collaboration with Lesaffre, was independently developed and approved by the GMFH publishing team and editorial board.

 

Phages therapy renaissance to treat bacterial infections

While microbiome research has focused mainly on bacteria, viruses that specifically target bacteria (bacteriophages or phages) exceed the number of bacteria (ie, 10-fold more phages than bacteria) and are new actors playing essential roles in host-microorganism interactions. It has been more than 100 years since phages were discovered1. However, phage therapy was widely abandoned since the discovery and use of antibiotics in the mid-1950s, only remaining in Eastern Europe. Additionally, it is only recently that reproducible protocols for metagenomic analysis of human fecal phageomes have become available2.

Nearly eight million people are expected to die every year from antibiotic-resistant bacteria by 2050. The crisis of antimicrobial resistance today brought on by the drying up of the antibiotic discovery pipeline and the resulting growth of pathogens resistant to many antibiotics has re-attracted researchers’ interest in phages3.

 

Bacteriophage therapy for difficult-to-treat infections: from bench to the clinic

Studies using gut models that mimic the gastrointestinal tract and infected mice with human pathogens showed specific phage cocktails are as effective as broad-spectrum antibiotics in inhibiting Escherichia coli and Salmonella growth, with high specificity and without disturbing the gut microbiome4-7.

Human data showed phage therapy could target hospital-acquired pathogens with high levels of antibiotic resistance, including Escherichia coli, Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa8. Phage therapy has shown promising results for treating gastrointestinal infections, pulmonary infections, urinary tract infections, endocarditis, and prostatitis in individual cases when administered as personalized phage preparations9,10.

In the personalized or precision phage therapy approach, phages are selected from a pre-existing library or directly from the environment and produced for an individual patient. Interestingly, personalized phage therapy in combination with antibiotics has shown efficacy in eradicating targeted bacteria in 61.3% of cases in 100 patients from 12 countries. It is worth highlighting that eradication was 70% less probable when no concomitant antibiotics were administered11. On the other hand, the approach of administering predefined bacteriophage cocktails has shown to be ineffective against some of the bacterial strains involved in infections, suggesting that customized phage therapy is the way forward12. While some non-serious adverse events are associated with phage therapy, they are limited to immune activation due to the administration route, bacterial residues in phage preparations, and possible chemical components in the purification process, and serious events are extremely rare13.

Despite growing phage therapy research, there are no approved phage medicines. There are currently limited centers around the world working on the application of phages in human health and phages used in patients are shared across clinical and academic centers. One exception is the Eliava Phage Therapy Center in Georgia, where phage therapy has been performed since 1919 and continues today. Nowadays, phages are used for compassionate use as a last-line treatment. In Europe, since 2011, phage therapy has been considered a medicinal product by the European Medicines Agency, with Belgium featuring the most innovative regulation that enables phage cocktails to be formulated by a hospital pharmacist and provided on prescription, thus allowing broad access to phages. In the United States, the FDA has not approved any phage therapy yet, but it is the country with the most phage-related industry-sponsored trials14,15.

 

Challenges of phage therapy and promising avenues for future research

Several hurdles exist in phage therapies. Although personalized phage therapy is less likely to induce bacterial phage resistance than non-personalized phage therapy, challenges mainly concern its development and market access, which are not straightforward in the current medicine models designed for static medicines. In addition, patients need to move to specialized centers for treatment. It has, therefore, been proposed that in the future, genetically engineered phages could help generate phages with more predictable and extended host ranges for different clinical indications12.

Additional challenges are related to the fact that phage samples are difficult to handle, and storage, freezing, or even exposure to light might hinder the isolation of therapeutic phages. No standards are available allowing the development of phage cocktails, which makes it difficult to compare outcomes of phage therapy between different studies. Phage cocktails also show host range specificity, in contrast to the broader spectrum activity of antibiotics, and mostly newly identified sequences do not have known counterparts in viral databases. Finally, as acknowledged before, phages lack regulatory and legal frameworks across countries, which hinders their generalized use in the clinic16,17.

Future avenues for phage therapy include its applications for conditions beyond the gut (eg, skin, urinary, and vaginal applications) and also beyond human use (eg, use in feedstock). In that regard, the international registry ‘Phagistry’ record the cases of patients treated with phages to better monitor efficacy and safety while designing future clinical trials in various clinical setting beyond the gut including wound infections, urinary tract infections, and respiratory infections18,19. Finally, integrating genomic surveillance into phage therapies may help identify patients that would benefit most from treatment, thus providing a scalable framework for precision phage therapy20.

 

 

References:

  1. Barr JJ. A bacteriophages journey through the human body. Immunol Rev. 2017; 279(1):106-122. doi: 10.1111/imr.12565.
  2. Shkoporov AN, Ryan FJ, Draper LA, et al. Reproducible protocols for metagenomic analysis of human faecal phageomes. Microbiome. 2018; 6(1):68. doi: 10.1186/s40168-018-0446-z.
  3. Naghavi M, Vollset SE, Ikuta KS and the rest of Global Burden Disease 2021 Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance 1990-2021: a systematic analysis with forecasts to 2050. Lancet. 2024; 404(10459):1199-1226. doi: 10.1016/S0140-6736(24)01867-1.
  4. Cieplak T, Soffer N, Sulakvelidze A, et al. A bacteriophage cocktail targeting Escherichia coli reduces coli in simulated gut conditions, while preserving a non-targeted representative commensal normal microbiota. Gut Microbes. 2018; 9(5):391-399. doi: 10.1080/19490976.2018.1447291.
  5. Hu YOO, Hugerth LW, Bengtsson C, et al. Bacteriophages synergize with the gut microbial community to combat Salmonella. mSystems. 2018; 3(5):e00119-18. doi: 10.1128/mSystems.00119-18.
  6. Moye ZD, Woolston J, den Abbeele PV, et al. A bacteriophage cocktail eliminates Salmonella typhimurium from the human colonic microbiome while preserving cytokine signaling and preventing attachment to and invasion of human cells by Salmonella in vitro. J Food Prot. 2019; 82(8):1336-1349. doi: 10.4315/0362-028X.JFP-18-587.
  7. Dissanayake U, Ukhanova M, Moye ZD, et al. Bacteriophages reduce pathogenic Escherichia coli counts in mice without distorting gut microbiota. Front Microbiol. 2019; 10:1984. doi: 10.3389/fmicb.2019.01984.
  8. WHO bacterial priority pathogens list, 2024: Bacterial pathogens of public health importance to guide research, development and strategies to prevent and control antimicrobial resistance (WHO, 2024). Available: https://www.who.int/publications/i/item/9789240093461
  9. Strathdee SA, Hatfull GF, Mutalik VK, et al. Phage therapy: from biological mechanisms to future directions. Cell. 2023; 186(1):17-31. doi: 10.1016/j.cell.2022.11.017.
  10. Uyttebroek S, Chen B, Onsea J, et al. Safety and efficacy of phage therapy in difficult-to-treat infections: a systematic review. Lancet Infect Dis. 2022; 22(8):e208-e220. doi: 10.1016/S1473-3099(21)00612-5.
  11. Pirnay JP, Djebara S, Steurs G, et al. Personalized bacteriophage therapy outcomes for 100 consecutive cases: a multicentre, multinational, retrospective observational study. Nat Microbiol. 2024; 9(6):1434-1453. doi: 10.1038/s41564-024-01705-x.
  12. Pirnay JP, Kutter E. Bacteriophages: it’s a medicine, Jim, but not as we know it. Lancet Infect Dis. 2021; 21(3):309-311. doi: 10.1016/S1473-3099(20)30464-3.
  13. Liu D, Van Belleghem JD, de Vries CR, et al. The safety and toxicity of phage therapy: a review of animal and clinical studies. Viruses. 2021; 13(7):1268. doi: 10.3390/v13071268.
  14. Yang Q, Le S, Zhu T, et al. Regulations of phage therapy across the world. Front Microbiol. 2023; 14:1250848. doi: 10.3389/fmicb.2023.1250848.
  15. Pirnay JP, Verbeken G, Ceyssens PJ, et al. The magistral phage. Viruses. 2018; 10(2):64. doi: 10.3390/v10020064.
  16. Shkoporov AN, Hill C. Bacteriophages of the human gut: the “known unknown” of the microbiome. Cell Host Microbe. 2019; 25(2):195-209. doi: 10.1016/j.chom.2019.01.017.
  17. Sutton TDS, Hill C. Gut bacteriophage: current understanding and challenges. Front Endocrinol. 2019; 10:784. doi: 10.3389/fendo.2019.00784.
  18. Jassim SAA, Limoges RG. Natural solutions to antibiotic resistance: bacteriophages ‘The Living Drugs’. World J Microbiol Biotechnol. 2024; 30(8):2153-2170. doi: 10.1007/s11274-014-1655-7.
  19. Kim P, Sanchez AM, Penke TJR, et al. Safety, pharmacokinetics, and pharmacodynamics of LBP-EC01, a CRISPR-Cas3-enhanced bacteriophage cocktail, in uncomplicated urinary tract infections due to Escherichia coli (ELIMINATE): the randomised, open-label, first part of a two-part phase 2 trial. Lancet Infect Dis. 2024. doi: 10.1016/S1473-3099(24)00424-9.
  20. Koncz M, Stirling T, Mehdi HH, et al. Genomic surveillance as a scalable framework for precision phage therapy against antibiotic-resistant pathogens. Cell. 2024; 187(21):5901-5918.e28. doi: 10.1016/j.cell.2024.09.009.