There is a notable lack of investment in clinical trials with phage therapy by pharmaceutical companies.[18] One reason for this is that pharmaceutical companies have chosen to invest more in improving current treatments instead of creating novel therapies. This allows them to continue innovating while also saving the costs of bringing a new treatment into the market.[18] Since there is no licensed phage product for human therapy in the Western market, its costs are unknown. Unfortunately, the journey to bring phage therapy into the public market will remain an uphill battle as phage products are not yet profitable enough in the context of human use. [19] That said, this hurdle is common to researchers developing new antibiotics. Even if the antibiotic were to be profitable, pharmaceutical companies would prefer to improve existing drugs to maximize profits. A second reason is that investors are aware that the antibiotic field is not profitable.[20] This was exemplified in the recent bankruptcy of companies such as Achaogen. Plazomicin, their leading FDA-approved antibiotic used to treat infections caused by multidrug-resistant E. coli, struggled tremendously once in the market, earning less than $1 million in sales.[21] The choice of profitability over innovation poses a significant ethical concern regarding what should be prioritized by pharmaceutical companies: money or research. The current trend of choosing money may benefit pharmaceutical companies in the short term. Still, with the rise of antibiotic-resistance, the costs of deprioritizing research will eventually overshadow pharmaceutical profits as 10 million lives will be lost annually due to infections induced by antibiotic-resistant bacteria by 2050, emphasizing the importance of pursuing phage research and alternative therapies.[13]
Conclusion
Phage therapy provides a unique and innovative treatment against bacterial infections in two ways. First, the host-specificity of the bacteriophages used in phage therapy allows for only infectious bacteria to be targeted and killed at a site of infection, allowing the normal state of the gut microbiome to be maintained as the pathogenic bacteria are removed. Secondly, phage therapy is a potential solution to antibiotic resistance itself. Antibiotic resistance is caused by the overuse and misuse of antibiotics. As bacteria evolve to acquire multidrug resistance, fewer viable treatments will become available. With phage therapy, bacteriophages that target multidrug-resistant bacteria will be able to target and kill them with a higher success rate compared to antibiotics alone. While a major hurdle for the field includes low confidence from the pharmaceutical industry driven by recent failures in new antibiotics and the push to improve existing drugs instead of finding new ones, the full potential of phage therapy may be a promising avenue once obstacles like funding and knowledge gaps are addressed.
Endnotes
[1] Brinkac, L., Voorhies, A., Gomez, A., Nelson, K. E. 2017. "The Threat of Antimicrobial Resistance on the Human Microbiome." Microbial ecology 74: 1001-1008.
[2] Aminov, Rustam I. 2010. "A Brief History of the Antibiotic Era: Lessons Learned and Challenges for the Future ."Frontiers in Microbiology 1: 134.
[3] Kortright, Kaitlyn E., Chan, Benjamin K., Koff, Jonathan L., Turner, Paul E. 2019. "Phage Therapy: A Renewed Approach to Combat Antibiotic-Resistant Bacteria." Cell Host and Microbe 25: 219-232.
[4] Group, WHO Scientific Working. 1983. "Antimicrobial resistance." Bulletin of the World Health Organization 61: 383-394.
[5] Lushniak, Boris D. 1974. "Surgeon General's Perspectives ." Public health reports 129: 314-316.
[6] Vishwanath, V. K. 2014. "Off-label abuse of antibiotics by bacteria ." Gut microbes 5: 3-4.
[7] Kasman LM, Porter LD. 2020. Bacteriophages. StatPearls Publishing.
[8] M, Sharma. 2013. "Lytic bacteriophages: Potential interventions against enteric bacterial pathogens on produce." Bacteriophage 3 (2).
[9] Clokie, M. R., Millard, A. D., Letarov, A. V., & Heaphy, S. 2011. "Phages in nature." Bacteriophage 1 (1): 31-45.
[10] Summers, William C. 2012. "The strange history of phage therapy." (Bacteriophage) 2 (2). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3442826/.
[11] Fruciano, D.E., & Bourne S. 2017. "Phage as an antimicrobial agent: d'Herelle's heretical theories and their role in the decline of phage prophylaxis in the West." The Canadian journal of infectious diseases & medical microbiology = Journal Canadien des maladies infectieuses et de la microbiologie medicale 18: 19-26. https://pubmed.ncbi.nlm.nih.gov/18923687/.
[12] LaFee, Scott and Buschman, Heather. 2019. With OK From FDA, UC San Diego Researchers Prepare to Launch Novel Phage Study. January 8. https://health.ucsd.edu/news/releases/Pages/2019-01-08-FDA-okays-uc-san-diego-to-launch-novel-phage-study.aspx.
[13] Lin, D. M. (2017). Phage therapy: An alternative to antibiotics in the age of multidrug resistance. World journal of gastrointestinal pharmacology and therapeutics, 8, 162–173.
[14] Common Jack, Morley Daniel, Westra Edze R. and van Houte Stineke. 2019. "CRISPR-Cas immunity leads to a coevolutionary arms race between Streptococcus thermophilus and lytic phage." The Royal Society.
[15] Doron S, Melamed S, Ofir G, Leavitt A, Lopatina A, Keren M, Amitai G, Sorek R. 2018. "Systematic discovery of antiphage defense systems in the microbial pangenome." Science. https://pubmed.ncbi.nlm.nih.gov/29371424/.
[16] Burmeister AR, Turner PE. 2020. "Trading-off and trading-up in the world of bacteria-phage evolution." Curr Biol 30 (19): R1120-R1124. https://pubmed.ncbi.nlm.nih.gov/33022253/.
[17] Burmeister AR, Fortier A, Roush C, Lessing AJ, Bender RG, Barahman R, Grant R, Chan BK, Turner PE. 2020. "Pleiotropy complicates a trade-off between phage resistance and antibiotic resistance." Proc Natl Acad Sci U S A 117 (21): 11207-11216. https://pubmed.ncbi.nlm.nih.gov/32424102/.
[18] Taylor PW, Stapleton PD, Paul Luzio J. 2002. "New ways to treat bacterial infections." Drug Discov Today 7 (21). https://pubmed.ncbi.nlm.nih.gov/12546840/.
[19] A, Henein. 2013. "What are the limitations on the wider therapeutic use of phage?" Bacteriophage. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3821673/.
[20] Plackett, Benjamin. 2020. “Why big pharma has abandoned antibiotics.” Nature. https://www.nature.com/articles/d41586-020-02884-3
[21] Mullard, Asher. 2019. "Achaogen bankruptcy highlights antibacterial development woes." Nature 18.
Additional Note
All figures made with BioRender.com