Synergistic antimicrobial effect of daptomycin and ethyl lauroyl arginate containing self-emulsifying drug delivery system against bacterial infections

This study aimed to enhance the antimicrobial properties of daptomycin by ion-pairing with ethyl lauroyl arginate (ELA) and incorporation in a self-emulsifying drug delivery system (SEDDS). Daptomycin was ion-paired with the ELA and the hydrophobic ion pair (HIP) was loaded into SEDDS. SEDDS 1 consisted of 15 % oleic acid, 5 % soy phosphatidylcholine, 10 % cetyltrimethylammonium bromide (CTAB) in medium-chain triglycerides (MCT) at a concentration of 250 mg/ml, 20 % benzyl alcohol, and 50 % PG-4 caprate. SEDDS 2 comprised 10 % soy phosphatidylcholine in MCT at a concentration of 53 mg/ml, 10 % CTAB, 20 % benzyl alcohol, and 60 % PG-4 caprate. SEDDS were characterized regarding droplet size, polydispersity index (PDI), zeta potential, and stability. Cytotoxicity was evaluated on Caco-2, HeLa, and SW620 cells. Antimicrobial activity was assessed by agar diffusion studies and time-kill assays with Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Candida albicans . Both formulations showed a droplet size below 200 nm with a PDI <0.4, a positive zeta potential, and robust thermodynamic stability. They exhibited low toxicity profiles while maintaining full antimicrobial efficacy on all tested pathogens. Compared to unformulated daptomycin, SEDDS 1 and 2 lowered the minimum inhibitory concentration (MIC) 5- and 8- fold for S. aureus and 10- and 30- fold for S. epidermidis , respectively. Bacterial killing time was 10 5 -fold shortened with SEDDS 1 and 10 6 -fold with SEDDS 2. Furthermore, HIP and SEDDS enhanced antibacterial activity against Candida albicans and Pseudomonas aeruginosa . According to these results, ion pairing of daptomycin with ELA and incorporation into SEDDS is a promising approach to improve the antimicrobial activity of this drug.