Phage therapy analysis of effectiveness in comorbid patients with wounds and surgical infections of various etiology based on the results of a comparative clinical study

Background. The continued importance of addressing the issue of treating purulent wounds and surgical infections of different origins and localization against the background of increased resistance of their main pathogens dictates the need to develop alternative protocols and search for new treatment strategies, the effectiveness of which is confirmed by objective diagnostic methods. Objective. The aim of the study was to analyze the effectiveness of phage therapy in comparison with traditional methods of local drug and systemic treatment in comorbid patients with surgical infection of various etiologies and localization by studying the microbiological spectrum, cytology of wound impressions and morphological, including electron microscopic examination of tissue biopsies. Material and methods. The results of the research are presented: a post-marketing, prospective, randomized, comparative clinical trial enrolling 70 adult patients with complicated skin, soft tissue, and bone infections of various etiologies and localizations, conducted at the Department of Wounds and Wound Infections, National Medical Research Center for Surgery named after A. Vishnevsky, Ministry of Health of the Russian Federation. During the study, clinical (edema, pain, the nature of wound discharge, the appearance of granulation tissue), laboratory (the presence and regression of signs of a systemic response to the presence of a surgical infection), microbiological (qualitative and quantitative), cytological and electron microscopic parameters were analyzed in all patients. Parametric data were evaluated based on the mean and standard deviation (SD) at 4 study points: point 1 (2±1 days), point 2 (4±1 days), point 3 (6±1 days) and point 4 (8±1 days). The key endpoint was the transition of the wound process into the regeneration phase. Results. According to the study protocol, all the patients included in the analysis had purulent-necrotic wounds of soft tissues and bones different etiology and localization, requiring surgical debridement. To randomize patients into groups, upon admission or intraoperatively, material was collected for qualitative and quantitative microbiological, cytological, morphological and electron microscopic studies. Randomization into groups of bacteriophages was possible in the presence of sensitivity of isolated cultures to the “Piobacteriophage complex” liquid (Piofag, JSC NPO Microgen, Russia). In the postoperative period, patients of group 1 (n=20) received systemic and local phage therapy (20 ml 3 times a day, according to the instructions), in group 2 (n=20) — systemic and local phage therapy, combined with local negative pressure (-120 mmHg, constant mode), delivery of bacteriophages to the surgical infection site was carried out using VitMobil instillation (VitMedical, Russia), systemic (levofloxacin 500 mg twice a day) and local (multicomponent polythylene glycol—based ointment with fluoroquinolones — Oflomelid, Russia) antibacterial therapy was performed in group 3 (n=30). An analysis of the treatment results indicates the high effectiveness of the proposed protocol in all study groups. In group 2 (local negative pressure with bacteriophage instillation in combination with systemic phage therapy) the best microbiological, cytological, histological and clinical efficacy was noted, indicating the potentiation of both methods of treating purulent wounds of various etiology and localization (the first signs of relief of the inflammatory phase were noted by 4±1 days after surgery). In general, key endpoints (the transition of the wound process to the regeneration phase) were achieved in all the studied groups with good tolerability of therapy and a high safety profile. No additional surgical interventions were required in any group, and no deaths were reported. No adverse events requiring discontinuation or change of treatment option have been reported. Based on the results obtained, the use of Pyobacteriophage complex liquid can be recommended for the complex treatment of purulent-necrotic wounds of various etiologies and localization in the presence of multiple antibiotic resistance, as well as in cases where systemic antibacterial therapy is contraindicated. The most effective is a combination of general and local phage therapy by various delivery routes (in particular, using vacuum devices with the possibility of instillation). Conclusion. The principles of treatment of soft tissues and bones severe surgical infection in comorbid patients in our country are still based on the method of active surgical treatment of wounds developed in the Department of Wounds and Wound Infections of the Vishnevsky Institute of Surgery (now, the Vishnevsky National Research Medical Center of Surgery of the Ministry of Health of the Russian Federation). In relation to the first phase of wound healing, the results of treatment will largely depend on the radicality and thoroughness of the primary surgical debridement of the purulent focus, general and local treatment in the perioperative period. The increasing problem of resistance, the formation of biofilm forms of pathogens in chronic wounds, and comorbidity, which limits us to using a number of reserve antibiotics due to their toxicity, determine the importance of finding alternative treatment protocols for such complex clinical situations. The results of the study are encouraging and demonstrate that practical healthcare should continue to pay attention to the study and use of bacteriophage drugs in the complex treatment of surgical infection. It is necessary to look for new ways to deliver these drugs directly to the infection site in order to maintain their optimal concentration and activity.