Phages versus Antibiotics To Treat Infected Diabetic Wounds in a Mouse Model: a Microbiological and Microbiotic Evaluation

Abstract

Diabetes is marked by a range of complications, including chronic infections that can lead to limb amputation. The treatment of infected wounds is disrupted by arteriopathies that reduce tissue perfusion as well as by the critical development of bacterial resistance. We evaluated the impact of a local application of bacteriophages compared to that of a per os administration of amoxicillin-clavulanic acid in a mouse model of Staphylococcus aureus wound infection. We found that phage treatment resulted in improved clinical healing and a reduction in local bacterial load at 7 and 14 days postinfection. Unlike antibiotics, phage therapy did not deplete the intestinal microbiota of treated animals. Amoxicillin resulted in a reduction of alpha and beta diversities of the murine microbiota and disturbed architecture even 7 days after the end of treatment, whereas phage treatment did not impinge on the microbiota. IMPORTANCE The management of diabetic foot infections is frequently a dead end for surgeons and infectious disease specialists. When the pathogen to be treated is not resistant to conventional antibiotics, the latter tend to unbalance the intestinal microbiota, which is linked to multiple pathologies. A local treatment with bacteriophages, in addition to being as much or even more effective than antibiotics from a clinical and microbiological point of view, makes it possible to respect the patient’s microbiota. These results suggest that the use of this therapeutic alternative is a major avenue and that the introduction of recommendations for their use is now necessary.

Phage therapy of wound-associated infections

“…It is also suggested that bacteria can only resist the combination treatment by becoming avirulent, which would enable the infection to be cleared by the host's immune system and thus still achieve the desired outcome of curing the patient. Phageantibiotic synergy is thought to be caused by a mechanism whereby bacteria elongate at a cellular level due to the action of the antibiotics, promoting the replication of phages and possibly external attachment to the bacteria as it exhibits a larger surface area (Huon et al 2020). Furthermore, phageantibiotic synergy seems to work better when phages are administered before antibiotics (Pirnay et al 2021).…”

Preclinical data and safety assessment of phage therapy in humans

“…Having established the basic infection parameters and the lysis and stability profiles of potential new phage products in vitro , it is essential to determine their effectiveness in the context of the infection in question in vitro in order to ascertain if the anticipated efficacy can be obtained. This can be achieved through phage efficacy testing in defined polymicrobial or complex bacterial communities such as biofilms, appropriate cell lines or simulated ex vivo infection model [ 44 , 45 , 46 , 47 , 48 ]. The most informative and useful models are discussed below with an emphasis on their merits and limitations.…”

“…Phages encoding enzymes (such as depolymerase) which can chemically degrade the extracellular polymeric substances found in biofilms have been shown to be particularly useful for these purposes [ 45 ]. Importantly, phages are highly effective in pre-treatment studies at preventing biofilm formation of pathogenic bacteria associated with nosocomial, oral, urinary tract and wound infections [ 44 , 45 , 46 , 47 , 48 ]. Interestingly, phages have also been shown to be an excellent adjunct to antibiotics to clear Staphylococcus aureus in biofilm, further supporting combined phage/antibiotic therapy [ 51 ].…”

Characterization and Sequencing of a Novel Phage Abp95 Against Multi-genotypes of Carbapenem-resistant Acinetobacter Baumannii

“…Although the primary host AB 2013−95 is an antibiotic-sensitive strain (Table 1), 55 of the 58 isolates are carbapenemresistant A. baumannii strains. About 6.3% of people with diabetes develop diabetic foot worldwidr, and at the infected diabetic foot ulcers, Staphylococcus aureus accounted for 42% [41], but A. baumannii is becoming one of the main bacteria in diabetic foot ulcers infections [42]. Diabetic patients suffer from shortage of tissue perfusion and limb necrosis due to microvascular disease, which obstructs the effect of active antibiotics against bacteria from chronic wound infection [41].…”

“…About 6.3% of people with diabetes develop diabetic foot worldwidr, and at the infected diabetic foot ulcers, Staphylococcus aureus accounted for 42% [41], but A. baumannii is becoming one of the main bacteria in diabetic foot ulcers infections [42]. Diabetic patients suffer from shortage of tissue perfusion and limb necrosis due to microvascular disease, which obstructs the effect of active antibiotics against bacteria from chronic wound infection [41]. At the same time, due to the massive use of antibiotics, drugresistant bacteria develop on such wounds.…”