Phage Therapy for Diabetic Foot Infections

The number of adults living with diabetes worldwide is expected to reach approximately 783 million by 2045, which is a staggering healthcare burden. The condition occurs when the body cannot regulate blood glucose due to an inability to produce or use insulin. In the long-term, it can result in major health issues, including blindness, kidney failure, cardiovascular disease, lower limb amputation and even death.

One significant complication of diabetes is poor circulation and reduced immune responses in the periphery. Diabetic foot ulcers (DFUs) are wounds that form on the feet of people with diabetes. These can subsequently be infected by opportunistic bacteria called, diabetic foot infections (DFIs). These infected ulcers are a common and highly morbid consequence of longstanding and/or poorly managed diabetes.

Diabetes cases have surged dramatically since the 1980s, escalating from 108 million to 536.6 million in 2021. This alarming trajectory resulted in an estimated two million deaths in 2021 alone, with almost 50% of fatalities occurring in individuals under the age of seventy.

DFIs pose a significant global health challenge, with 19% to 34% of diabetic individuals predicted to develop a DFI in their lifetime. Furthermore, the condition has an extremely poor prognosis, with five and 10-year survival rates of approximately 50% and 25%, respectively.  Lower extremity amputations have a devastating effect on patient welfare and mortality rates are worse than some common cancers.

Antimicrobial Resistance

Additionally, treatment of DFIs imposes a significant strain on healthcare resources, costing the U.K.’s NHS up to £962 million each year. In the U.S., the cost of amputations alone is $1.38 billion annually.

The issues affecting patients with DFIs are further compounded by high and increasing rates of antimicrobial resistance (AMR), which occurs when bacteria and viruses become resistant to standard treatments and is a leading global health threat. It is projected to kill an estimated ten million people a year and cost around $1 trillion in healthcare costs by 2050, according to the World Health Organization and the World Bank, respectively. This threat is driven by the overuse and misuse of antibiotics in humans, animals, and the environment.

The global spread of pathogens resistant to many or all standard treatments raises the possibility that once routine but critical procedures, such as surgery and chemotherapy, could become increasingly prone to the risk of infection.

Antibiotics are traditionally used for treatment of DFIs but the chronic nature of the infection means the risk of developing an AMR infection is particularly high. Furthermore, many of the key pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), are already extremely resistant to common antibiotics. Now more than ever, new, and alternative treatments for DFIs are urgently needed.

Potential for phage therapy

One promising treatment to help address the growing threat of AMR is the use of bacteriophages (or phages). These biological organisms are predators of bacteria that infect, replicate in, and kill bacterial targets as part of their life cycle. This natural biocidal action has positioned phages as a potential alternative to antibiotics.

While there are not yet any phage products licensed as human medicines for phage therapy, they are already used as food treatment agents and in agriculture to treat plant diseases. In a few cases, phages have been used to treat infections in humans, but only when all other treatments have failed.

This “compassionate use” approach has been used to treat DFIs, and phages offer several advantages when compared to conventional treatments. Phages can kill antibiotic-resistant bacteria and if a bacterium does become resistant to a specific phage, countless others can be isolated from the environment.

Phages have evolved the ability to actively penetrate biofilms (communities of bacteria encased in a protective matrix that are often present in diabetic foot ulcers) and kill bacteria even in difficult-to-treat infections. Since phages consist only of protein and DNA, they are considered to be intrinsically safer than chemical antibiotics.

Phage therapy has been compassionately used in several countries to successfully treat DFIs, including Scotland. In a study of ten patients, performed in Glasgow and Edinburgh, amputation was prevented in six cases; clear clinical improvement was seen in two, and one patient withdrew for an unrelated medical reason. Only one of the patients who completed treatment failed to show a response. These successes are particularly impressive as they were in patients with severe infections where all other treatments had failed.

A healthcare economic analysis on the use of phages to treat DFIs, conducted by Healthcare Improvement Scotland, concluded “base case results indicate that bacteriophage therapy, plus standard of care, is less costly and more effective than standard of care only.”

Expanding the market

The benefits of phage therapy are proving to be a viable solution in tackling DFIs where antibiotics are failing. However, such treatments are currently restricted to compassionate use pathways, i.e., they can only be used as a last resort where all other treatments have failed. This severely limits the number of patients that can be treated and means that only very severe infections are suitable for phage therapy.

Our company, U.K.-based NexaBiome, is pioneering the use of phages to treat DFIs with its patented phage stabilization technology. Unlike the restricted, unlicensed, compassionate use of phages currently applied, the company is planning to take a product through the full clinical trials pathway, resulting in a licensed medicine that can be widely applied to all patients.

This technology will enable the development of phage-treated wound dressings that are room-temperature stable, meaning they can be widely deployed both in the hospital environment or by outpatients in the community.

The U.K. government has recently addressed the potential of phage therapy in the fight against AMR, as part of the new five-year national action plan to protect people and animals from the risks of drug-resistant infections.

In response to recommendations outlined in a report by the U.K. government’s Science and Technology Committee, there is now a heightened focus on the need for more investment in infrastructure, phage manufacturing, and support for clinical trials.

Such support would accelerate the commercial development of phage therapeutics in the U.K., providing a significant benefit to public health and positioning the U.K. at the forefront of developments in this exciting field.

Phages are a promising addition to our arsenal of antimicrobial therapies, with their effectiveness demonstrated in compassionate use applications and early-stage clinical trials. An increasing appreciation of the potential for these treatments underscores their promise to reshape the care of DFIs and address the complex challenges posed by diabetes and AMR on a global scale.

Through continued investment and collaboration, phage therapy could emerge as a cornerstone in the fight against DFIs and contribute significantly to improving patient outcomes and reducing healthcare burdens worldwide.

 Jason Clark, PhD, is CSO at NexaBiome.