Phage Therapy: An Innovative Alternative for the Treatment of Diabetic Foot Infections

The management of DFIs is becoming increasingly complex due to biofilm formation and the emergence of antibiotic-resistant bacterial strains.

Phage therapy, which uses viruses capable of eliminating bacteria, has shown promising potential in the treatment of DFIs, particularly those caused by Staphylococcus aureus (identified in nearly 50% of DFI cases).

Preclinical studies have demonstrated that phage therapy reduces bacterial load and promotes healing of infected Diabetic Foot Ulcers (DFUs) while preserving the integrity of the gut microbiota. This contrasts with antibiotics, which can disrupt microbiota balance and contribute to the emergence of resistant strains. Preclinical findings suggest that phages offer therapeutic benefits beyond infection control: they also help limit host side effects by preserving microbiota balance and reducing inflammation.

However, existing animal models are primarily based on the induction of type 1 diabetes. This approach does not accurately reflect the pathophysiology of type 2 diabetes, which is the most prevalent form among patients with DFIs. In addition, most wounds studied are acute, whereas chronic wounds more closely reflect real-life clinical conditions. These limitations highlight the need for more standardized and clinically relevant models to fully exploit the potential of phage therapy. Despite these limitations, these results have enabled the evaluation of phage therapy in clinical settings.

Clinical case reports have already demonstrated the effectiveness of phage therapy, particularly in complex and chronic infections. However, these case studies present limitations, including small sample sizes and the absence of control groups.

To confirm the efficacy and safety of phage therapy, several randomized, controlled, double-blind clinical trials are currently underway, including REVERSE2, DANCE, and PhagoPied (see table below).

*(Study published on 09/05/2025)

** Standard treatment includes: antibiotic therapy adapted to bacteriological sampling, glycemic control, local wound care, and offloading.

Preliminary results are encouraging. In the pilot REVERSE study, TP-102 treatment was well tolerated and led to greater bacterial reduction and improved DFU healing compared to placebo. However, the small sample size (13 patients in the TP-102 group) does not allow definitive conclusions regarding superiority. The REVERSE2 study, conducted in a larger patient population, is expected to provide more robust evidence.

These findings highlight the growing therapeutic potential of phage therapy in complex infections. Indeed, phage therapy is increasingly being explored for other indications, including respiratory, urinary, bone, and joint infections. Nevertheless, challenges remain, particularly regarding production costs and complexity, management of bacterial resistance, and regulatory harmonization.

Concrete efforts are underway to address these challenges. Regulatory discussions are progressing at the European level to support personalized phage therapies. In parallel, initiatives such as dynamic phage banks and combined phage-antibiotic strategies are being developed. These approaches aim to improve outcomes, limit resistance, and ultimately facilitate the integration of phage therapy into clinical practice, especially for patients who do not respond adequately to conventional antibiotic treatments.