Phage Therapy: Fight Against Antimicrobial Resistance

Antimicrobial resistance: a growing global health concern

Antimicrobial resistance (AMR) in bacteria (antibiotic resistance) refers to bacterial strains that have obtained resistance, through various mechanisms such as mutations, to drugs designed against them¹. While it is difficult to assess the true extent of the burden caused by AMR, it is estimated a total of 4.95 million global mortalities in 2019 can be linked to AMR, with AMR being directly responsible for at least 1.27 million deaths¹. Excessive and often unnecessary use of antibiotics in both humans and livestock is greatly exacerbating AMR^2,3. Moreover, many bacterial pathogens have developed Multidrug Resistance (MDR), making them an even greater concern. AMR not only presents a risk of high disease burden and mortality but is also projected to cause devastating economic losses4. In developing nations like Pakistan, addressing AMR is of the utmost importance.

Phage therapy: a potential solution

One aspect of combating AMR is to establish other methods of therapy for bacterial infections. Amongst these, phage therapy is a strong candidate to be established as a standard form of treatment in both clinical and veterinary settings. Phage therapy involves the use of bacteriophages (viruses with only bacteria as their natural hosts for infection and replication) to develop therapies against bacterial infections⁵.

The process of phage therapy can broadly be categorized into the following: (i) phage isolation; (ii) phage screening and host range determination; (iii) phage characterization; (iv) phage therapy administration and monitoring^5,6. Phages are generally isolated from environmental sources such as sewage systems or hospitals, expected to be rich in phage diversity⁶. The phages thus isolated are then screened against a preferably large sample of (pathogenic) bacteria to determine their host range⁶. Some vital phage characteristics to be determined include burst size, molecular characterization and immune system interaction(s)⁶. Before phage therapy can be standardized, it must first be tested and monitored in appropriate model organisms⁶.

Advantages of Phage Therapy

1. As phages replicate and multiply within the bacteria, relatively lower dosage would be required, potentially even just a single dose⁷.
2. Phage-induced bactericidal mechanisms differ from antibiotic bactericidal mechanisms. Thus, phage therapy is a viable option for use against AMR and MDR bacterial pathogens^7,8.
3. Phages possess bacterial host specificity and, therefore, offer less of a threat to the natural human microbial flora^7,8.
4. Phages can be grouped and used in tandem as “phage cocktails” to expand their host range.
5. The discovery and development of phage therapies is comparatively more rapid, owing to their natural abundance and low cytotoxicity⁸.
6. Phages are naturally occurring, and therefore present a more environmentally friendly approach⁷.

Limitations of Phage Therapy

1. Pharmacologically, some phages are not ideal therapeutic agents with poor absorption capacity and survival⁷.
2. Phage therapies or cocktails would have to be extensively purified and examined to ensure they do not trigger any immune response. Although, this is not unique to phages and occurs in many other pharmaceutical products, such as protein-based ones, being developed^7,8.
3. Phages have narrow bacterial host ranges. However, this limitation can easily be overcome by combining different phages (phage cocktails) or even combining them with other antimicrobial products^7,8.

Conclusion and future perspective

The growing concern of AMR in pathogenic bacteria has become a health crisis worldwide that requires immediate attention to avoid catastrophic consequences. Phage therapy has shown great potential as an alternative treatment for bacterial pathogens, particularly those resistant to traditional treatments (i.e. antibiotics). However, there are certain aspects of phage therapy that require further clarity and development before they can be standardized in clinical and farm settings. Considering AMR has greatly been exacerbated by excessive antibiotic use, better policies and regulations need to be kept in place to avoid a similar course with phage therapy. Nevertheless, phages have already been successfully implemented as therapies against bacterial pathogens in some countries (Russia, Georgia and Poland) for decades^5,6,8. Proper development and management of phage therapies present great potential to combat AMR and MDR.

Written by: Aqsa Ahsan Research Associate PhageoteX

References

→ Murray, C. J. et al. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet 399, 629–655 (2022).
→ Martin, M. J., Thottathil, S. E. & Newman, T. B. Antibiotics overuse in animal agriculture: A call to action for health care providers. Am. J. Public Health 105, 2409–2410 (2015).
→ Tarrant, C. & Krockow, E. M. Antibiotic overuse: managing uncertainty and mitigating against overtreatment. BMJ Qual. Saf. 31, 163–167 (2021).
→ Jonas, O. B., Irwin, A., Berthe, F. C. J., Le Gall, F. G. & Marquez, P. V. Drug-Resistant Infections. Drug-Resistant Infect. 2, (2017).
Abedon, S. T., García, P., Mullany, P. & Aminov, R. Phage Therapy: Past, Present and Future. 8, 1–7 (2017).
→ Jo, E. & Zaczek, M. Bacteriophage Procurement for Therapeutic Purposes. 7, 1–14 (2016).
→ Loc-carrillo, C. & Abedon, S. T. Pros and cons of phage therapy. Bacteriophage 1, 111–114 (2011).
→ Chan, B. K., Abedon, S. T. & Loc-carrillo, C. Phage Cocktails and the Future of Phage Therapy. Future Microbiol. 8, 769–783 (2013)