Treating infections caused by antibiotic-resistant bacteria with bacteriophage therapy

Bacteriophages were first discovered by Felix d’Herelle when he first speculated that phages were responsible for recovery from diarrheal illnesses caused by bacterial infections.[10] To test his hypothesis, d’Herelle proposed a potential treatment against avian typhosis (Salmonella gallinarum) that utilized laboratory-produced phages as therapeutic agents and successfully administered the treatment in February 1919.[11] This treatment is the first field trial for phage therapy, where phage suspensions were administered orally, through injections, or directly on the surface of an infection.
Interest in phage therapy has recently increased due to the increased demand for alternative therapies to antibiotics. Additionally, unlike antibiotics, the host-specificity of phages ensures that the gut microbiome remains healthy as specific bacterial populations can be targeted and killed, leaving the endogenous community alone. A key player in this research field is UC San Diego's Center of Innovative Phage Applications and Therapeutics (IPATH). In 2019, the FDA approved IPATH's first clinical trial with phage therapy.  The trial involves using a bacteriophage cocktail to treat Staphylococcus aureus-infected ventricular assist devices in patients. With approximately 10 participants, this study is currently evaluating the efficacy and tolerability of phage therapy combined with antibiotic treatments.[12]

Challenges/Roadblocks of Phage Therapy

While phage therapy has the potential of saving tens of millions of lives as an alternative to antibiotics,[13] there are many obstacles that researchers must overcome in order to administer the treatment to the general public. These include preventing phage-resistance and finding adequate sources of funding to support new research.
Phage-resistance can arise in many ways, including the CRISPR-Cas system in bacteria. With CRISPR-Cas, phage-derived sequences are integrated into the bacterial genome as CRISPR loci that can be used by Cas proteins to recognize and cleave viral nucleic acid when present (Figure 4).[14] If a phage is repeatedly introduced to the bacterial colony, the chances of that phage's genome being derived into a CRISPR loci increases, leading to phage resistance in bacteria. Beyond CRISPR, researchers have discovered more than 45,000 bacterial genomes that contain phage-resistant characteristics and are yet to fully understand the mechanisms behind them.[15] Luckily, scientists have observed a ‘trade-off’ in bacteria between phage-resistance and antibiotic resistance. In essence, bacteria with high antibiotic resistance tend to have low phage resistance and vice versa.[16] However, certain studies have also observed cases of pleiotropy which allows for the co-expression of phage-resistance and antibiotic-resistance.[17]