Co-delivery of azithromycin and nisin through liposomes for skin infection to reduce antimicrobial drug resistance

Antimicrobial therapeutics are commonly used to treat infections caused by microorganisms. The standalone use of antimicrobial drugs frequently results in resistance development and reduced efficacy over prolonged treatments. Owing to funding challenges for developing novel drugs, one of the main European Medicines Agency activities to combat AMR is focusing on alternative therapies. Combination strategies integrating antimicrobial peptides with conventional drugs have demonstrated lower risk of resistance emergence and enhanced clinical efficacy. Nisin is generally recognized as safe peptide and has potential for clinical use. The aim of this study is to develop azithromycin and nisin-loaded liposome formulations for the topical treatment of skin infections that are both locally effective and capable of minimizing AMR. Liposomes were prepared by thin film hydration method, and homogeneous, stable, biocompatible liposomes demonstrated high encapsulation efficiencies (85 %). The optimized formulations were evaluated via in vitro release and ex vivo permeation studies by the Franz cell system. Approximately 250 μg/cm² of AZM was released from combined formulations. The permeation through human cadaver skin and fluorescence imaging (Vertical Histological Cross-Section and Z-Stack) studies were performed to understand the performance and potential dermal applications of formulations. Labeled liposomes successfully localized within the skin layers by penetrating the stratum corneum. Antimicrobial activity and biofilm eradication against Staphylococcus aureus results showed that combined liposomal formulations were more effective than AZM-loaded formulations. In conclusion, this study presents co-delivery of AZM and nisin through liposome formulations as an effective treatment option for skin infection to reduce AMR.