Advocating for phage therapy

As antibiotic-resistant infections continue to rise globally, the development and application of phage therapy represents not only a promising but also a mandatory alternative approach to tackle this major public-health threat.

Bacteriophages (phages) are the most abundant organisms in the biosphere and are viruses that specifically target bacteria. Following the discovery of phages in 1915, researchers and clinicians quickly realized the potential to co-opt their biology and use them as therapeutic agents to treat bacterial infections. However, the discovery and subsequent use of antibiotics between the 1930s and 1960s meant that phage therapy was largely abandoned by most countries as antibiotics were more convenient and had broader spectrum activity¹. An exception were countries in the former USSR, including Georgia, where phage therapy was and is still performed today. Indeed, the Eliava Institute in Tbilisi, Georgia, provided phage therapy to soldiers and civilians suffering from bacterial infections during the Second World War² and the Eliava Phage Therapy Center continues to develop and apply phage therapy to patients.

The emergence of antimicrobial resistance is one of the biggest global public-health threats and is predicted to cause the death of 10 million people annually by the year 2050 (ref. ³). While there are growing efforts to discover and develop new antibiotics, this has not always been a priority. Following the emergence of resistant bacterial pathogens towards many of the main antibiotics used in the clinic, and the antibiotic-discovery pipeline having dried out, phage therapy must be reconsidered as an alternative to fight difficult-to-treat infections. However, there are currently no approved phage medicines available and many phages used in treatments are shared across clinical and academic networks.

Infections treated with phage therapy range from pulmonary infections, urinary tract infections, endocarditis to prostatitis, among other indications⁴. The most common bacterial pathogens that are targeted by phage therapy include Escherichia coli, Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae and Pseudomonas aeruginosa. Most of these bacteria belong to the ESKAPE (Enterococcus faecium, S. aureus, K. pneumoniae, Acinetobacter baumannii, P. aeruginosa and Enterobacter sp.) group of hospital-acquired pathogens that are showing high levels of antibiotic resistance, many of which are listed in the recently published 2024 WHO Bacterial Priority Pathogens List⁵.

In general, there are two approaches for phage therapy⁶. In the first approach, a phage therapy is a pre-defined, finished product consisting of one or more bacteriophage strains (non-personalized phage therapy). In the second approach, the active phages are selected from a pre-existing phage library and specifically produced for an individual patient (personalized phage therapy). Unfortunately, recent randomized controlled trials using non-personalized phages have failed to demonstrate efficacy⁷. However, personalized phage preparations have shown some promising results in individual cases⁸. What was unknown until recently was whether personalized phage therapy, specifically in combination with antibiotics, also shows efficacy in larger patient cohorts.

Promising results are now reported in this issue of Nature Microbiology. Pirnay and colleagues present the results from a retrospective, observational analysis of the first 100 consecutive, personalized phage therapy cases of bacterial infections in patients from 35 hospitals and 12 countries. The authors used 43 batches of phages, often in combination with antibiotics, and showed clinical improvement in 77.2% of cases, and eradication of the targeted bacteria in 61.3% of cases, with 7 cases of non-serious suspected adverse drug reactions. Importantly, the authors also show that eradication was 70% less probable when no concomitant antibiotic treatment was applied. A limitation of the study is that the clinical outcomes were determined by clinicians caring for the patients and not by pre-specified criteria. However, these findings indicate that personalized phage therapy can be effective in combination with antibiotics, and may pave the way for the design of future randomized controlled clinical trials. The findings are also discussed in an accompanying News & Views article by Jonathan Iredell, Holly Sinclair and Ameneh Khatami.

Although personalized phage therapy is less likely to induce bacterial phage resistance compared with pre-defined phage cocktails (as it does not carry a surplus of ineffective phages, which puts less selection pressure towards bacterial phage resistance), it is very challenging to organize from a logistical point of view. Specific phages or bacteria need to be sent from, or sent to, phage therapy centres. Additionally, some patients need to be transferred to specific centres for treatment. It has, therefore, been proposed that the future of modern phage therapy may involve cell-free and on-site synthetic phage production^4,9.

Several other hurdles exist for the field. Standards for the development of phage cocktails are lacking, making it difficult to compare different treatments and their outcomes across studies. Many reports are also based on single case studies and are typically for compassionate use as a last-line treatment. This contrasts with the evaluation of other antimicrobial treatments, which are not used for difficult-to-treat infections during trials, perhaps giving phage therapy an unreasonably high bar to reach. Regulatory and legal frameworks are also lacking and inconsistent across countries, although some headway has been made. Belgium, the location of the consortium behind the study by Pirnay and colleagues, has implemented a magistral phage therapy framework where phage preparations can be formulated by a hospital pharmacist and provided on prescription, thus avoiding certain regulatory requirements while ensuring patient safety¹⁰.

What is clear is that the development of therapeutic phages will require a coordinated effort of multiple stakeholders not limited to researchers, clinicians, funders, regulatory bodies and governments⁴. Important recent initiatives to help drive phage therapy development include the creation of ‘Phagistry’ — an international registry for patients receiving phage therapy with the aim to systematically collect metadata related to diagnosis, phages, treatment and outcomes. Furthermore, INCATE provides financial support for start-ups and innovators trying to tackle drug-resistant bacterial infections. This includes phage therapy ventures.

The recent results using personalized phage therapy are promising. It will be important to perform carefully designed, randomized controlled clinical trials to further assess the benefit-to-risk for a specific indication. More support is also needed both financially and logistically for researchers and clinicians developing these therapies. We must all advocate for phage therapy in order for it to become a viable treatment option to help overcome the antimicrobial resistance crisis.