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The promise of phages in the fight against antibiotic resistance
For nearly a century, antibiotics have been essential for treating bacterial infections, transforming medicine, and significantly increasing life expectancy. However, their overuse has led to the rise of antibiotic-resistant bacteria, one of the most serious challenges we face today. In 2021 alone, bacterial antimicrobial resistance was responsible for an estimated 1.14 million deaths worldwide, and projections suggest that over 39 million people could die from antibiotic-resistant bacteria by 2050.
To address this urgent challenge, a promising alternative is bacteriophage (phage) therapy, which uses viruses that infect and destroy bacteria without harming human cells. Although phage therapy is gaining attention in combating antibiotic resistance, it is not a new concept. In fact, it was used in the early 20th century to treat bacterial infections before antibiotics became widely available. Today, phage therapy is still used in some Eastern European countries, particularly in Georgia, offering valuable insights into its therapeutic potential.
This study highlights the 14-year experience (2008–2022) of a Belgian consortium with phage therapy, documenting the outcomes of 100 cases, including both successes and challenges. A wide variety of infections were treated, such as respiratory tract, bone, and bloodstream infections, with Staphylococcus aureus and Pseudomonas aeruginosa being the most frequently targeted bacteria. This comprehensive study provides valuable insights into the potential of phage therapy.
Phage therapy as personalized medicine
Phages are highly specific viruses, usually targeting a limited number of strains within the same species, unlike antibiotics, which work against a range of different species. For example, a phage that effectively kills a S. aureus strain that causes an infection in one patient might be completely ineffective against a different S. aureus strain infecting another patient.
The Belgian consortium used phages as personalized medicines, tailoring treatments to each individual. For every patient, the killing ability of individual phages or cocktails (combinations of multiple phages) is tested against the bacterial strain causing the infection. This ensures that the most effective phages are selected to combat the harmful bacteria.
In some cases, researchers even “pre-adapt” the phages to make them more efficient in killing the patient’s strain. By co-culturing phages with the patient’s strain in the lab, they can select phages that acquire beneficial modifications in key proteins, such as those involved in bacterial recognition, allowing them to eliminate the bacteria more efficiently.
What about bacteria developing resistance to phages?
Just as bacteria can develop resistance to antibiotics, they can also become resistant to phages, decreasing long-term effectiveness. For 16 patients in the study, bacteria were isolated before and after treatment to examine resistance. In 7 cases (43.8%), bacteria became less sensitive to the therapeutic phages.
To understand this reduced sensitivity, the bacterial genomes were sequenced to identify genetic changes. The analysis revealed alterations in bacterial surface structures such as pili and lipopolysaccharides (LPS), which serve as receptors for the phages used in treatments. Modifications in these structures prevent phages from attaching to bacteria, making them unable to kill their target.
Interestingly, pili help bacteria stick to human tissues, while LPS act as toxins that trigger inflammation. When these structures change to resist phages, bacteria often lose some of their ability to cause disease (virulence). The study evaluated this decrease in virulence by infecting Galleria mellonella larvae with either phage-resistant or phage-susceptible bacteria and monitored their survival rates. In two out of three cases, phage-resistant strains were less virulent, resulting in higher larval survival.
One particularly noteworthy case involved Patient 91. Here, the phage-resistant bacteria exhibited mutations not only in pili and LPS but also in an efflux pump, which is also used by phages as receptors in addition to being a key protein used to expel antibiotics. These mutations compromised the pump’s function, re-sensitizing the bacteria to antibiotics. As a result, the phage-resistant bacteria were not only less virulent but also more vulnerable to antibiotic treatment, ultimately aiding in clearing the infection.
So, is phage therapy efficient for curing difficult to treat infections?
Among the hundred phage therapy cases studied, 77.2% showed improvement of at least one symptom associated with the infection, and eradication of the targeted bacteria was achieved in 61.3% of the cases. Adverse effects were rare, with only 15 reported across all cases, seven of which were non-serious. Importantly, all adverse effects were resolved.
In 69% of the cases, phage therapy was combined with antibiotic treatment, which was associated with a higher likelihood of complete bacterial eradication. Laboratory evaluations of phage-antibiotic combinations for 10 patients revealed phage-antibiotic synergy in 9 cases. This synergy means that when phages and antibiotics are used together, they kill bacteria more effectively than either one could on its own.
These findings underscore the effectiveness of phage therapy, particularly when used in combination with antibiotics, and support its role as a promising strategy for combating antibiotic-resistant infections.
Link to the original post: Pirnay, JP., Djebara, S., Steurs, G. et al. Personalized bacteriophage therapy outcomes for 100 consecutive cases: a multicentre, multinational, retrospective observational study. Nat Microbiol 9, 1434–1453 (2024). https://doi.org/10.1038/s41564-024-01705-x
Featured image: NIH Bioart (https://bioart.niaid.nih.gov/) modified with inkscape.
Additional: Naghavi, M., Vollset, S. E., Ikuta, K. S., Swetschinski, L. R., Gray, A. P., Wool, E. E., … & Dekker, D. M. (2024). Global burden of bacterial antimicrobial resistance 1990–2021: a systematic analysis with forecasts to 2050. The Lancet, 404(10459), 1199-1226.
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