Phage Therapy: An Alternative Antimicrobial?

Phage therapy exploits a very simple truth: bacteriophages that target and destroy bacteria already exist. The purpose of phage therapy is to develop these viruses at a large – but controlled – scale. While the concept, and early technology, for the development of phage therapy has existed since the 1920s, the advent of antibiotics eclipsed this field and interest in it evaporated. However, antibiotic resistance has become an increasing threat – and large pharmaceutical companies are abandoning the no longer profitable field of antibiotic development. Resultantly, interest in phage therapy has been revived – although many challenges remain before its commercial viability becomes a reality. 

Bacteriophages and their Advantages

Phage is short for bacteriophage: a virus that infects bacteria. Bacteriophages are perhaps the most abundant biological entity on the planet. As viruses, phages are only capable of infecting hosts that express the appropriate receptors for their own binding proteins. Bacteria are also able to defend themselves to a limited extent – either through evolving different receptors, or through the use of the CRISPR/Cas system to eliminate phage genetic material from their genome. A genetic arms race can arise: the bacterium can evolve to be resistant to the phage; but the phage can also evolve to overcome this resistance. While this can be problematic, co-administration of multiple phages or phage-antibiotics cocktails can be a way around this.

Antibiotic treatment becomes challenging against bacteria with the capability to form biofilms. Even when the biofilm is made up of susceptible bacteria, permeating the structure can be a challenge for current therapeutic agents. The same is not true for bacteriophages engineered to degrade the biofilm. This can have wide potential applications in not only clinical settings, but also industrial environments – particularly food production and biotechnology. 

Bacteriophages are also naturally unimpeded by antibiotic resistance mechanisms. As the issue of multi-drug resistant strains grows, so does our need to find alternative solutions. Innovation in the field of antibiotics has languished – with the average antibiotic costing north of a billion to develop, while returning only a fraction of those costs in profits over its patented lifetime. Read more on the precarious future of antibiotics and the need for a re-imagination in their monetization and development funding in our article here. These concerns regarding the lessening impact of antibiotics have led to wider policy directives for the investigation of bacteriophage therapies – such as the PHAGOBURN project by the European Commission. The project aims to find effective phage solutions for treating drug-resistant E. coli and P. aeruginosa for burn wound infections.

The Two Sides of Specificity

The theoretical advantages bacteriophages could provide compared to antibiotics are significant. Their inherent specificity for destroying only the bacteria they can target can provide an antimicrobial solution that does not harm the entire microbiome of their recipient. This also leads to far improved safety profiles. Antibiotics can have common side effects relating to the digestive system, mostly due to their devastating effects on gut flora. But other classes of antibiotics can display rarer, yet even more debilitating, adverse events – for example, fluoroquinolones can cause tendonitis, permanent nerve damage or even heart problems. 

Naturally, this specificity can also translate to practical challenges. To preserve the advantage of their semi-targeted nature, the specific cause of any bacterial infection will need to be known before a phage can be administered. This can cause considerable delays compared to simply using a broad-spectrum antibiotic. The use of “cocktails” of multiple phages to provide a similar broad-spectrum antimicrobial effect is a plausible way around this limitation. 

Current Implementations

After the age of antibiotics arose in the middle of the 20th century, research on phage therapy came to a screeching halt in the Western world. This was not true in the Soviet sphere of influence however. Russia and much of Eastern Europe remained isolated from the Western scientific community, and the commercial pharmaceutical industry therein. They continued their work on phage therapies, which are even used in hospitals to this day in Russia, Poland and Georgia, and have provided meaningful insights for the advancement of the technology elsewhere.

This pre-existing research has informed recent European applications. A burn victim in Belgium was treated with a phage-antibiotic combination for pan-resistant Klebsiella pneumoniae infection, which proved highly effective. The phages were pre-adapted to pre-empt the possibility of the infection developing resistance to them. Pre-adaptation can significantly improve the continued efficacy of phage therapy, although it is a time-consuming process. In light of this, and other trials, Belgium began to implement a phage therapy framework to address legal and organizational inefficiencies. The framework is also centered on the compounding of multiple phages to formulate appropriate cocktails – particularly at the pharmacy level.

Future Outlooks

A key development that is needed for the facilitation of large-scale phage therapy is the development of local phage banks. These can act as libraries storing collections of phages to tackle common disease subsequent to susceptibility testing of the pathogens in question. The construction of such banks is no easy task – it requires gargantuan amounts of DNA sequencing work to ensure stored phages will not transfer antimicrobial resistance, virulence factor or toxin producing genes. Advancements in next-generation sequencing can make this a more cost-efficient affair than previously. 

Multiple banks already exist – for example, the Israeli Phage Bank, as well as commercial solutions such as the ones developed by Adaptive Phage Therapeutics (APT) which aims to provide phages that are ready to use. The regulatory landscape does limit the use of phage cocktails, which may be needed in multiple instances, as outlined above. While pre-made cocktails can gain approval on their own, the ad-hoc combination of phage therapies to provide tailor-made products for each scenario is not easily accommodated under current regulations. Interestingly, APT is also exploring the possibility of phage-based vaccines which display immunogenic antigens on phages that can target specific tissues. This shows the future potentials of capitalizing on our understanding and existing technologies for exploiting phages.

A key take-away is that multiple avenues of research need to be explored prior to the wider adoption of phage therapies. Phage therapy holds immense promise, but requires dedicated infrastructure and regulatory exploration. Further clinical studies are needed to clarify the efficacy of phage-antibiotic combinations, as well as phage cocktails. Closer collaboration between industry stakeholders and regulators will be critical in realizing the full potential of bacteriophages. Motivating the discovery of new antibiotics is a separate question that also needs to be addressed – but the last two decades and the emergence of antibiotic resistance have proven that we cannot rely on a singular treatment modality for bacterial disease.

Nick Zoukas, Former Editor, PharmaFEATURES