A safe bioadhesive system for topical delivery of combined antimicrobials in treatment of skin infections in veterinary medicine

Bacterial and fungal skin infections are common both in humans and animals, especially in companion animals such as cats and dogs. Use of systemic antimicrobial drugs for the treatment of skin infections has resulted in increased antimicrobial resistance (AMR) in both animals and humans. Under “One Health” approach, one of the strategies to overcome AMR is topical delivery of combined antimicrobials, which allows enhanced efficacy at lower amounts of antimicrobials. Staphylococcus aureus (S. aureus), Staphylococcus pseudintermedius (S. pseudintermedius), Malassezia pachydermatis (M. pachydermatis) and Microsporum canis (M. canis) related skin infections are very common in cats and dogs, and this also poses a risk for humans who come into contact with the infected animals. Chlorhexidine digluconate (CHX) and miconazole nitrate (MN) are amongst the commonly used antimicrobials used for topical treatment of such dermal infections. In this study, we aimed to develop a safe bioadhesive system for delivery of combination of CHX and MN for topical treatment of skin infections providing higher antimicrobial efficacy than that of the currently available formulations. For this purpose, gel formulations were prepared using a bioadhesive biopolymer, chitosan which itself exerts antimicrobial activity as well as anti-inflammatory and penetration enhancing properties. Tris-EDTA was also incorporated into the formulations to increase the antimicrobial activity. Furthermore, CHX loaded chitosan nanoparticles were also prepared and incorporated into the gels in combination with MN. The formulations were investigated in regard to their applicability, spreadability and safety properties as well as their drug release profiles, and he antimicrobial activity of the formulations was shown against S. aureus ATCC 29213, S. pseudintermedius, M. pachydermatis and M. canis. Gels with a suitable viscosity, adhesion and spreadability properties for topical application on the skin, which would provide frequency of application was obtained without showing any cytotoxicity. Different release profiles were obtained for CHX and MN. Due to its low solubility, MN release was found to be low, whilst with CHX, release was found to be higher and rapid when incorporated as a solution, but sustained release was obtained when incorporated into chitosan nanoparticles. It was found that both MN and CHX accumulated on the surface of the membrane. By this means, a prolonged release on the site of appli