Antibiotic resistance develops when bacteria become less sensitive to antibiotics, rendering them less effective or ineffective at killing bacteria and treating infections. We urgently need new therapeutic strategies to combat bacterial infections and curb the antimicrobial resistance crisis as quickly as possible. A potential solution is combining antibiotics with bacteriophages, ubiquitous viruses that infect and kill bacteria. When combined with antibiotics, phages could enhance bacterial killing, overcome resistance mechanisms, and provide a more effective treatment for bacterial infections. In this article, we will discuss the science behind combined antibiotic and bacteriophage therapy and delve into the benefits, challenges, and future implications of this potential solution to the antibiotic resistance crisis.
Understanding Bacteriophages and Antibiotics
Bacteriophages, commonly known as phages, are found ubiquitously in the environment, anywhere there are bacteria, including soil, seawater, and the human gut. To infect bacteria, bacteriophages first attach to bacteria in a specific manner. The bacteriophage then injects its genetic material, harnessing the host’s cellular machinery to produce more bacteriophages. Eventually, the newly formed phages burst out of the bacterial cell, killing it and allowing the phages to infect other bacteria.
Antibiotics, on the other hand, are substances that inhibit or kill microorganisms, particularly bacteria. Since their discovery, antibiotics have been used extensively in human medicine to treat bacterial infections, saving countless lives. They typically function by disrupting essential processes in bacterial cells, such as protein synthesis, cell wall synthesis, or DNA replication. However, the overuse and misuse of antibiotics have led to the emergence of antibiotic-resistant bacteria, a significant global health concern. Bacteria can develop antibiotic resistance through various mechanisms, including mutation or acquiring resistance genes from other bacteria. These resistant bacteria can survive and multiply in the presence of antibiotics, rendering the drugs ineffective. Therefore, developing strategies to combat antibiotic resistance has become an urgent task for scientists worldwide.
The Concept of Combination Therapy: Synergistic Effects and Mechanisms
A potential strategy to combat antibiotic resistance is a combination therapy that utilises bacteriophages alongside antibiotics. Studies have shown that phages are more effective at eradicating bacterial infections when combined with sub-lethal doses of antibiotics, in a phenomenon known as phage-antibiotic synergy (PAS). Several possible mechanisms may describe the synergistic effects of combining phages with antibiotics. A study delved into the mechanism of PAS, demonstrating that the addition of antibiotics to phage-infected bacteria led to excessive swelling or filamentation of bacteria, and delayed lysis resulted in an increase in phage production and a resulting increase in the size of phage plaques, which more effectively killed bacteria.
There are several advantages to combining bacteriophages with antibiotics for bacterial clearance. Firstly, combination therapy enhances the efficiency and effectiveness of bacterial infection treatment. One proposed mechanism is the sequential targeting approach, where phages first target the bacteria, causing stress and making them more susceptible to the subsequent application of antibiotics. The replication of phages within bacteria generates bacterial debris or lysates, which may interfere with the protective mechanisms bacteria use to resist antibiotics. Furthermore, phages can help maintain a low bacterial density, thereby reducing the occurrence of mutations and the likelihood of bacteria developing resistance. Importantly, combined treatment improves the effectiveness of antibiotics for treating bacterial biofilms, which are inherently hard to eradicate. Research indicates that some phages produce enzymes that degrade the biofilm matrix, facilitating the penetration of antibiotics.
Recent Studies and Success Stories
Several recent studies and success stories have demonstrated the effectiveness of combining bacteriophages and antibiotics. A preclinical study showed that a phage-antibiotic combination eradicated an Acinetobacter baumannii infection more effectively than a phage-only treatment. A recent study published in Nature Communications reported the successful clearance of an extensively drug-resistant Pseudomonas aeruginosa blood infection after liver transplantation using combined phage-antibiotic therapy. This case study highlighted the safety of combination therapy in immunocompromised patients and children. A high-profile case from 2018 sparked interest in phage therapy when a multidrug-resistant Mycobacterium abscessus infection in a cystic fibrosis patient was successfully treated with a custom cocktail of bacteriophages alongside antibiotics. These cases highlight the potential of bacteriophage and antibiotic combination therapy in a clinical setting, inspiring hope for new strategies against antibiotic-resistant bacteria.
Challenges and Considerations
Despite its potential, combining bacteriophages and antibiotics is not without its challenges. Determining the optimal phage dosage and the appropriate timing for administration can be complex. Each bacteriophage is specific to a particular type of bacteria, and thus, it can be difficult to identify the correct phage-antibiotic combination for a given infection. Additionally, phages are sensitive to temperature, pH, and storage conditions, rendering their formulation, storage, and delivery challenging. Overcoming these hurdles requires significant research and technical advancement.
Safety concerns also exist when it comes to bacteriophage-antibiotic combination therapy. While bacteriophages have generally shown a good safety profile in preliminary studies, potential side effects or unforeseen immunological reactions cannot be ruled out entirely, and there is a lack of validated, appropriately controlled clinical trial data supporting their use. Hence, extensive preclinical and clinical research is required to ascertain the safety, efficacy, and potential adverse effects of combination therapy to treat bacterial infections.
Future Directions and Clinical Implementation
Ongoing research and future directions in the field of combination therapy include the development of more robust, broad-range bacteriophages and the design of targeted antibiotic molecules that work synergistically with phages. Investigation into personalised phage-antibiotic therapy represents a cutting-edge approach in this field. The use of bioinformatics and metagenomics to identify and design effective phage-antibiotic combinations is another exciting direction.
Clinical implementation of bacteriophage-antibiotic combination therapy requires careful consideration of regulatory aspects. The traditional drug approval pathways may not apply to bacteriophages due to their unique biological properties. Regulations need to be adapted to accommodate the dynamic nature of phages and the fact that they can evolve. Moreover, establishing standardised protocols for phage identification, isolation, purification, and scalable production will be critical for their clinical application.
The combination of bacteriophages and antibiotics has emerged as a potentially powerful strategy against bacterial infections, particularly those resistant to conventional treatments. However, the path to broad clinical application of this approach remains riddled with challenges. Nonetheless, recent success stories provide evidence that combined therapy could indeed be a feasible solution to antibiotic resistance. Future efforts must focus on overcoming technical challenges and refining therapeutic strategies. Ultimately, the synergistic relationship between bacteriophages and antibiotics could prove to be a game-changer, redefining our capabilities in the fight against microbial infections.