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The Solution to MDR Infections: Bacteriophage Therapy, Where Are We Now?

Writer: Anthony Kharrat ‘26

Editor: David Han ‘24


Source: Berkley Lab New Center


In the last decade, the World Health Organization (WHO) released a list of multi-drug resistant (MDR) bacterial species considered global priority pathogens based on their high resistance levels and limited available treatments. As the current rate of antibiotic resistance development far surpasses the rate of antibiotic discovery, these bacteria pose a serious global public health challenge, especially in the near future. Estimates suggest that by 2050, more than 10 million people could die per year globally due to MDR infections which drastically exceeds the current 1.25 million deaths annually. [2] These projections emphasize the urgent need for an alternative to traditional antibiotic treatments: Bacteriophage Therapy.  


Bacteriophage Therapy, often referred to as BT, has regained traction in the scientific community as a promising alternative to antibiotics and a game-changer in the fight against MDR infections. But what exactly is BT? Analogous to how viruses infect, replicate, and kill human cells, bacteriophages are viruses targeted specifically to bacterial cells. The practice of BT harnesses these virulent properties of phages to combat bacterial infections. [1] The key advantages of BT such as its incredible specificity, adaptability to evolving bacteria, and ability to leave human cells unharmed make it an attractive option for treating MDR infections. [2] 


Although phages have been used therapeutically for decades in some parts of the world, particularly in Eastern Europe, they have yet to gain widespread acceptance in Western medicine primarily due to a lack of substantial clinical evidence and investment from large pharmaceutical companies. However, with growing concerns over antimicrobial resistance, the Western world is beginning to turn its head and increasingly show interest in BT. [1]


 In light of this, where do we stand in terms of clinical data? Currently, several BT clinical trials are underway in Western countries to assess its safety and efficacy, thereby bolstering clinical evidence. Over the past decade, a number of case studies and clinical trials have showcased BT’s effectiveness in treating diverse MDR infections, from lung infections in cystic fibrosis patients to urinary tract infections (UTIs). Prior to these human studies, numerous animal trials, primarily in mice and pigs, were conducted to initially validate BT’s efficacy and safety [3].


The first BT clinical trial was conducted in London in 2009, demonstrating both efficacy and safety in treating chronic otitis, a type of ear infection, caused by the MDR bacteria Pseudomonas aeruginosa. The trial consisted of 24 patients with chronic otitis who were randomly treated with either a single dose of Biophage-PA or a placebo. Symptoms were assessed weekly for 6 weeks and revealed significant improvements in patient clinical indicators and reductions in bacterial levels in the phage-treated group compared to the placebo group. [5] Currently, a clinical trial of BT in Cystic fibrosis subjects also colonized with MDR P. aeruginosa is ongoing with roughly 70 participants and employing a 4-phage cocktail. [6]


In 2020, the first clinical trial of BT was conducted for treating UTIs colonized with MDR E. coli, involving 97 patients. Participants were randomized into three groups: a Pyo bacteriophage solution, a placebo solution, or antibiotic treatment. Urine cultures were taken at the end of treatment and microbially tested. While success rates did not significantly differ between the groups, the Pyophage group experienced the fewest adverse effects. [7] Furthermore, there is currently another BT clinical trial for the treatment of UTIs colonized with E. coli underway that has recently begun recruiting participants and plans to administer a 3-phage cocktail. [8] 


In the realm of case studies, a 2017 success story involved the use of a personalized 9-phage cocktail to treat a 68-year-old diabetic patient with necrotizing pancreatitis complicated by an MDR A. baumannii infection. The administration of the phage cocktail led to a remarkable reversal of the patient's clinical deterioration and clearance of the infection. [9] In 2019, another successful case study highlighted the combination of BT with antibiotics in a 26-year-old cystic fibrosis (CF) patient, effectively treating MDR P. aeruginosa while awaiting a lung transplant. The treatment resulted in no adverse events, led to the resolution of the infection, and paved the way for a successful bilateral lung transplantation without pneumonia recurrence or CF exacerbation within 100 days. [10] 


Despite the promise of BT in combating MDR infections, certain limitations should be considered. While current published preclinical and clinical studies offer positive indicators, additional clinical trials are still needed to establish the safest and most effective BT dosages conclusively. Unlike antibiotics where concentrations of the drug decrease within the body over time, bacteriophages multiply. How this self-replicating feature of BT influences treatment efficacy and the potential for adverse effects is still not fully understood. [1] Another concern of BT is the potential development of bacteriophage resistance. Similar to bacteria developing resistance to antibiotics, they can also evolve to develop resistance to bacteriophages. To mitigate the risks of these bacteriophage-insensitive mutants (BIMs), phage cocktails are often used, sometimes in conjunction with antibiotics. 


Additionally, while the specificity of bacteriophages is an advantage of BT, it can also be a limitation. Because each phage is specific to a particular bacterial strain, a different phage is needed for each bacterial infection. This identification process and development of the appropriate phage cocktails can be very time-consuming and costly, disincentivizing pharmaceutical companies. It can also be a challenge in treating infections where the bacterial strain is unknown. In contrast, antibiotics can be prescribed without identifying the bacterial strain(s). However, this has contributed to rampant overprescription of antibiotics which has become a growing global health concern. [4]


Despite these potential limitations, the future implications of BT are promising and continue to be an active area of research. Regulatory bodies such as the U.S. Food and Drug Administration (FDA) are currently “on board” with BT and have been very thoughtful and considerate in their approach to regulating phage therapeutics. The National Institute of Health (NIH) supports BT, recently awarding $2.5 million to 12 institutes globally for further study. As previously mentioned, several clinical trials such as the CF and UTI trials are also underway and continue to prove the safety and efficacy of BT for MDR infections. [1] Furthermore, several universities across the U.S. including Brown University have initiated Phage Hunting Programs that aim to identify and genetically characterize bacteriophages for potential future BT use. 


Regarding new biotechnologies, innovations in the CRISPR/Cas gene-editing systems have created novel opportunities for BT. For instance, bacteriophages can be bioengineered to deliver a CRISPR/Cas programmed to disrupt antibiotic resistance genes and destroy antibiotic resistance plasmids. Ultimately, the field of bioengineered phages is still in its infancy, but will undoubtedly grow as clinical trials expand and BT gradually becomes a more widespread and accepted treatment option for MDR infections. [3]






Works Cited


[1] Barron, Madeline. 2022. “Phage Therapy: Past, Present, and Future.” American Society for Microbiology (October): https://asm.org/Articles/2022/August/Phage-Therapy-Past,-Present-and-Future#


[2] Furfaro, Lucy L., Matthew S. Payne, and Barbara J. Chang. 2018. “Bacteriophage Therapy: Clinical Trials and Regulatory Hurdles.” Frontiers in Cellular and Infection Microbiology 8 (October): 376. https://doi.org/10.3389/fcimb.2018.00376.


[3] Lin, Derek M, Britt Koskella, and Henry C Lin. 2017. “Phage Therapy: An Alternative to Antibiotics in the Age of Multi-Drug Resistance.” World Journal of Gastrointestinal Pharmacology and Therapeutics 8 (3): 162. https://doi.org/10.4292/wjgpt.v8.i3.162.


[4] Pires, Diana P, Ana Rita Costa, Graça Pinto, Luciana Meneses, and Joana Azeredo. 2020. “Current Challenges and Future Opportunities of Phage Therapy.” FEMS Microbiology Reviews 44 (6): 684–700. https://doi.org/10.1093/femsre/fuaa017.


[5] Wright, A., C.H. Hawkins, E.E. Änggård, and D.R. Harper. 2009. “A Controlled Clinical Trial of a Therapeutic Bacteriophage Preparation in Chronic Otitis Due to Antibiotic‐resistant Pseudomonas Aeruginosa ; a Preliminary Report of Efficacy.” Clinical Otolaryngology 34 (4): 349–57. https://doi.org/10.1111/j.1749-4486.2009.01973.x.


[6] Schooley, Robert T., Pranita Tamma. 2023. “A Phase 1b/2 Trial of the Safety and Microbiological Activity of Bacteriophage Therapy in Cystic Fibrosis Subjects Colonized With Pseudomonas aeruginosa.” ClinicalTrials.gov (October): https://clinicaltrials.gov/ct2/show/NCT05453578 


[7] Leitner, Lorenz, Aleksandre Ujmajuridze, Nina Chanishvili, Marina Goderdzishvili, Irina Chkonia, Sophia Rigvava, Archil Chkhotua, et al. 2021. “Intravesical Bacteriophages for Treating Urinary Tract Infections in Patients Undergoing Transurethral Resection of the Prostate: A Randomised, Placebo-Controlled, Double-Blind Clinical Trial.” The Lancet Infectious Diseases 21 (3): 427–36. https://doi.org/10.1016/S1473-3099(20)30330-3.


[8] German, Gregory. 2022. “Phage Therapy for the Treatment of Urinary Tract Infection.” ClinicalTrials.gov (October): https://clinicaltrials.gov/ct2/show/NCT05537519 


[9] Schooley, Robert T., Biswajit Biswas, Jason J. Gill, Adriana Hernandez-Morales, Jacob Lancaster, Lauren Lessor, Jeremy J. Barr, et al. 2017. “Development and Use of Personalized Bacteriophage-Based Therapeutic Cocktails To Treat a Patient with a Disseminated Resistant Acinetobacter Baumannii Infection.” Antimicrobial Agents and Chemotherapy 61 (10): e00954-17. https://doi.org/10.1128/AAC.00954-17.


[10] Law, Nancy, Cathy Logan, Gordon Yung, Carrie-Lynn Langlais Furr, Susan M. Lehman, Sandra Morales, Francisco Rosas, et al. 2019. “Successful Adjunctive Use of Bacteriophage Therapy for Treatment of Multidrug-Resistant Pseudomonas Aeruginosa Infection in a Cystic Fibrosis Patient.” Infection 47 (4): 665–68. https://doi.org/10.1007/s15010-019-01319-0.


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[Image] bacteriofaag_coordinatiegroep_virus_valt_bacterie_aan.webp [Internet] (November). Available from: https://www.uzleuven.be/en/bacteriophage-therapy 






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