Degradable Hydrophilic Poly(ethylene glycol) Microspheres for the Sustained Delivery of Peptide-Based Antibiotics for Local Anti-infective Therapies

Bacterial infections related to medical implants, especially periprosthetic joint infection (PJI), pose a significant clinical challenge. Systemic antibiotic therapy faces limitations, including bacterial resistance, systemic toxicity, and inadequate drug penetration at infection sites. This study investigates a drug delivery strategy using dry, sterile, and hydrophilic degradable microspheres (DrugMic) for extemporaneous antibiotic loading. DrugMic consists of polyethylene glycol (PEG) hydrogels cross-linked with a hydrolyzable cross-linker composed of PEG and varying proportions of lactide and caprolactone. Following microsphere synthesis and e-beam sterilization, extemporaneous antibiotic loading was achieved by rapid mixing of the antibiotic solutions with the sterile microspheres. The study focuses on polymyxins and glycopeptides (vancomycin and teicoplanin) because of their key role in combating the Gram-negative and Gram-positive pathogens increasingly prevalent in PJI, all of which were efficiently loaded through ionic and hydrophobic interactions. The subsequent in vitro drug release lasted between 2 days and 2 weeks, depending on the compositing and degradation rate of the microsphere. Drug release was mainly influenced by antibiotic lipophilicity and degree of microsphere cross-linking. DrugMic protects antibiotics by avoiding exposure to harsh processing conditions such as organic solvents, high temperatures, mechanical shear, and terminal sterilization, which can degrade antibiotics by radiolysis. A rabbit pharmacokinetic study confirmed sustained teicoplanin release after extemporaneous loading onto sterile DrugMic. The DrugMic appears to be a promising degradable platform for the local treatment of PJI with antibiotics that are effective against multidrug-resistant Gram-positive and Gram-negative bacteria.