In this article, we address the potential use of bacteriophages as a therapeutic alternative to conventional antibiotic treatments. We will start by showing why exploring new antimicrobial therapeutic options is imperative. Next, we will delve into the history of phage therapy and where we are today. We will then present a detailed view on the advantages and challenges of phage therapy.
Why the need for new treatments?
Antibiotic resistance has emerged as a significant worldwide healthcare problem. The CDC estimates that infections with antibiotic resistant bacteria lead to over two million illnesses and 23,000 deaths annually in the United States alone, resulting in an estimated $20 billion in excess direct medical costs. Resistance to carbapenems, antibiotics that are considered the “last line of defense”, is on the rise, leading to few therapeutic options in the case of infection with one of these resistant bacteria.
New antibiotics are needed to control these infections, but the development of new antibiotics has lagged due to economic and regulatory disincentives. Additionally, when new antibiotics are finally brought to the market, resistance is quickly developed, impairing their efficacy. In the face of these challenges, scientists are revisiting phage therapy as a potential treatment for antibiotic resistance.
A look at the history of phage therapy:
Phage therapy was first introduced by the French-Canadian scientist Felix d’Herelle, who co-discovered bacteriophages around 1910. Bacteriophages are a class of viruses that specifically target and kill bacteria. The bacteriophage first binds to specific surface receptors on the host bacteria before injecting its genetic material and hijacking the bacterial cell machinery. This process ultimately causes the bacteria to burst, killing the bacteria and releasing a multitude of newly formed phages to target and kill additional bacteria. d’Herelle later used these phages to successfully treat dysentery in a number of patients, providing proof of principle that bacteriophages could therapeutically treat bacterial infections.
Despite the promise of phage therapy, the development and wide availability of antibiotics in the early 1900s led to its limited usage in the Western world. Because phage therapy has been more prevalent in Eastern Europe, there are a number of reports on the efficacy of phage therapy in humans. Recently, an experimental phage cocktail was used to treat a multidrug resistant bacterial infection in the United States. While there are multiple reports of small-scale usage of phage therapy, there is little data among the Western world as far as phage therapy meeting clinical standards and no results from large-scale human phage therapy trials have been reported yet.
Numerous government agencies have expressed interest in greater clinical advancement for phage therapy. The European Union has contributed €3.8 million (US $5.8 million) to the PhagoBurn study, a major clinical trial aiming to investigate the efficacy of phage therapy for treating infections in burn victims. In the United States, the National Institutes of Health has recently awarded $5 million in funding to research projects investigating alternative therapeutic approaches to bacterial infections, including phage therapy. These efforts indicate that government agencies are placing a greater emphasis on phage therapy as a potential strategy for battling antibiotic-resistant infections.
The advantages of phage therapy over antibiotics:
Phage therapy provides a number of advantages compared to therapy with antibiotic compounds. These advantages are presented below.
Bacteriophages are easy to identify & isolate:
Bacteriophages are ubiquitous in nature, making them fairly simple to identify and isolate. While bacteria can mutate and adapt to resist antimicrobials such as antibiotic compounds, bacteriophages can also mutate and adapt to overcome these bacterial resistances. This means that additional bacteriophages can be screened and isolated to respond to resistant bacterial strains.
Bacteriophages are highly specific:
Another benefit of phage therapy is that bacteriophages are highly specific for their target bacteria. It has been more widely appreciated in recent years that usage of broad spectrum antibiotics can have off-target effects on patients, disrupting their healthy microbiota and exacerbating disease. The use of bacteriophages targeted towards a specific species of bacteria greatly minimizes the chance of off-target effects on the microbiome or on the human patient themselves, as bacteriophages do not directly affect human cells.
Bacteriophages can kill antibiotic-resistant bacteria:
Finally, bacteriophages may be effective in a variety of situations where antibiotics are generally ineffective, such as treating antibiotic-resistant bacteria or bacteria within a biofilm. The mechanism by which phages infect and kill bacteria is often completely different from the mechanism of antibiotic resistance, meaning antibiotic-resistant bacteria may still be sensitive to phages. Bacterial biofilms, which have emerged as a major public health problem, are generally resistant to antibiotics, which are unable to penetrate the matrix of the biofilm to kill bacteria. In contrast, bacteriophages may be more effective at killing bacterial biofilms than antibiotics, making them a viable alternative for this purpose. Bacteriophages may even be effective as additives to minimize food contamination and reduce the amount of antibiotics given to farm animals, one of the drivers of antibiotic resistance.
What are the challenges faced by phage therapy?
While the use of bacteriophages as a therapeutic for drug-resistant bacterial infections is promising, widespread use is still in early stages of development and faces some questions concerning indirect effects of the bacteriophage on human patients.
Release of byproducts:
As mentioned above, bacteriophages inject their genetic material into the bacteria and use it to make more copies of the phage, ultimately killing the bacteria. While bacteriophages do not directly affect human cells, there are concerns that byproducts of the infection process, such as bacterial toxins or either bacterial or viral products released when the bacteria burst, may affect human cells. Existing data suggests that treatment of bacteria with bacteriophages does not increase the release of bacterial products that elicit an immune response in humans, suggesting that phage therapy does not result in more harmful byproducts than treatment with antibiotics.
Transfer of resistant genes to naïve bacteria:
Another potential concern with phage therapy is that some bacteriophages are capable of integrating into the bacterial genome, potentially resulting in the incorporation of antibiotic resistance genes or other virulence factors into the viral genome and the transfer to naïve bacteria. Verification that bacteriophages used for phage therapy do not integrate into the bacterial genome is therefore an important regulatory check before they are incorporated into a bacteriophage cocktail.
Complying with regulatory standards:
The most pressing hurdle for phage therapy is passing clinical trials under modern regulatory standards. In order for therapeutics to be approved for use, their makeup and stability must be clearly defined. This process was initially designed for chemical compounds, and can be difficult with phages, especially because phage therapy often uses multiple phage isolates in a cocktail for a single treatment, all of which must be assessed. The PhagoBurn study has had numerous delays due to issues with documentation of modes of action and stability of phages. Resistance is usually minimized by changing the components of the cocktail over time, but adding new phages increases the regulatory burden. While the number of phages can be reduced to minimize the complexity of documentation, this eliminates one of the major benefits of phage therapy: the diversity of the cocktail minimizes the possibility of bacterial resistance.
Bacteriophage specificity:
The specificity of bacteriophages for their targets has also emerged as a potential complication. While the specificity of phages for their target minimizes the risk of off-target effects, it also means that more time is needed to know exactly what strain of bacteria an infected patient has, and whether a specific cocktail of phages will be effective. This may take time that is not available in a critical-care situation. Additionally, the PhagoBurn study found complications in enrolling participants into the trial, as patients were often infected with multiple bacterial species, while the study was trying to show validation of phages specifically targeted to one type of bacteria. This resulted in getting much fewer participants than required for approval, and ultimately led to one of the trials being canceled.
Conclusions:
The threat of multi-drug resistant bacteria has led numerous researchers and government agencies to explore new strategies for treating infections. While phage therapy deserves consideration as a serious alternative or complement to antibiotic therapy, more data is necessary from large-scale trials to proceed. To gain this data, solutions must be found for regulatory obstacles, such as those encountered by the PhagoBurn study. There has also been a push for an approval pathway more tailored to the specific needs of phage therapy, which may accelerate the process of phage clinical approval while still maintaining safety. By finding solutions to the remaining regulatory obstacles, phage therapy is poised to play a significant role in the fight against bacterial infections.
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