VARANASI  : A team of scientists in Banaras Hindu University have conducted an important study that would greatly benefit those suffering from chronic wounds, particularly with diabetic foot ulcers. The team led by Prof. Gopal Nath of Department of Microbiology, Institute of Medical Sciences, BHU, in its study found out that wounds that took months to years to heal could be cured in a matter of days to months. The findings of study has been published in National Center for Biotechnology Information, National Institutes of Health, United States.

A wound is defined as a breach in the skin or other body tissues due to injury. An acute wound is defined as a recent break that is yet to progress through sequential stages of healing. Those wounds where the normal healing process is stalled either due to underlying pathology (vascular and diabetes etc.) or infection beyond 3 months is defined as a chronic wound. While chronic wounds always get infected, contaminated/ dirty wounds are reasonably susceptible to infection. Infection with antibiotic-resistant bacteria and biofilm formation are critical factors halting the standard healing progress.

These wounds cause significant psychological and physical morbidity, e.g., increased pain leading to loss of function and mobility; distress, anxiety, depression, social isolation; and amputation, even death. Chronic wounds are considered a global problem. The direct medical cost of skin infections only in the United States (US) is approximately 75 billion US dollars , whereas US$25 billion of this amount is used for chronic wound treatment.

Traditional chronic wound treatment strategies (e.g., compression, warming, vacuum-assisted closure device, irrigation) are often successful in healing wounds. Still, many wounds have been observed recalcitrant to these treatments, leading to persistence and recurrent infections. Both infections (caused by multidrug-resistant strains) and subsequent biofilm formation are the primary cause of the persistence of the wounds because conventional antibiotic therapy does not work. Search for alternatives to antibiotics has now become a compulsion. Fortunately, bacteriophage therapy is a reemerging solution to antibiotic-resistant bacteria. Bacteriophages exhibit numerous potential advantages as an alternative antimicrobial therapy for treating MDR bacterial infection. The advantages include clinical safety, bactericidal activity, increased concentration where needed, negligible disturbance to the microbiome, biofilm degrading activity, ease and rapidity in isolation and cost-effectiveness of pharmaceutical formulations. In addition, the phages are known to penetrate poorly vascularized tissues and have been seen to be poor in inducing immunological response. Most notably, “phages are the only medicine that multiplies”.

The scientists led by Prof. Gopal Nath carried out phage therapy of acute and chronic infected wounds in animals and clinical studies. It was shown efficacy against Pseudomonas aeruginosa in a mice wound model. Furthermore, they evaluated the efficacy of phage cocktails in animal models’ acute and chronic osteomyelitis caused by methicillin-resistant Staphylococcus aureus. Moreover, they also observed biofilm eradication from K wire in rabbits wound infection model.

Clinical trials are necessary to demonstrate the safety and efficacy of data generated in the preclinical experiments before getting translated reliably into clinical practice. Clinical trials of phage therapy initiated by the Banaras Hindu University have reported the efficacy of topical phage in healing chronic wounds in three prospective exploratory studies and no adverse events mimicking the results in vivo animal models.

A clinical study by Gupta et al. (2019) demonstrated the significant role of bacteriophage therapy in the chronic wounds associated with antibiotic-resistant bacteria. The study employed a total of twenty patients with chronic non-healing ulcers for more than six weeks duration. A significant improvement could be achieved in the form of complete wound epithelization within a few weeks.

Another study by Patel DR et al.(2020) employing forty-eight patients having a minimum of one eligible full-thickness wound that did not heal in 6 weeks with convention wound management showed the promising result, and significant improvement was observed in the wound healing in > 82% by the end of follow-up of three months. Furthermore, the study projected that specific phage therapy is equally effective regardless of the diabetic or non-diabetic status of the patient. However, the healing was relatively delayed in diabetic patients.

Both studies provide nearly unequivocally that topical phage therapy attributed to complete clinical wound healing in patients’ refractory to conventional therapy. Furthermore, the status of antibiotic resistance of the bacteria implicated in chronic would not influence the outcome of the therapy.

Another successful recently published non-randomized prospective, open blinded, the case-control study by Bhartiya et al.(2021) to see the effect of bacteriophages has shown encouraging results on the healing process of infected acute traumatic wounds. The average number of days required for complete granulation of wounds and attaining sterility and healing with primary intention was half compared to control, i.e., conventional therapy.

Due to phages high specificity for their bacterial host, phage cocktail formulations usually guarantee a broader spectrum of activity and decreases the likelihood of the emergence of phage-resistant bacterial mutants. Therefore, all of these studies employed a cocktail of bacteriophages for therapy.

Topical phage therapy represents a safe, promising, and potentially transformative treatment for recalcitrant infected cutaneous wounds and warrants concerted research in the light of the current embodiment of MDR and drying pipeline of effective antibiotics in our armamentarium. The history of bacteriophage therapy goes for ~100 years, with a good safety record. Even if this therapy is used for topical infections, the menace of AMR may come down to at least 30%.

The team involved in the clinical studies carried out at Institute of Medical Sciences Banaras Hindu comprised of : Prof Gopal Nath, Prof SK Bhartiya, Prof VK Shukla, Dr. Pooja Gupta, Dr. Harishankar Singh, Dr Dev Raj Patel, Mr. Rajesh Kumar, Dr. Rina Prasad, Mr. Subhas Lalkarn etc.

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