Surgical site infections (SSIs) remain a critical issue, accounting for 22% of healthcare-associated infections and costing over $10 billion direct cost annually in the United States alone. SSIs in spine surgery often result in catastrophic complications due to proximity to the spinal cord, nerve roots, and spinal implants, which lead to neurological impairment, infected non-union, and permeant disability. Ultimately this result in further indirect costs from inability to return to work and life-long medical aid. Systemic antibiotics are currently the standard prophylaxis for spine surgeries; however, they usually fail to achieve high surgical-site tissue levels of antibiotics for a prolonged period to prevent infections while also leading to antibiotic-induced organ toxicity and antibiotic resistance. In most cases, multiple operations are often required to address an SSI after spine surgery related to infection of the surgical site hardware, implants, bone and soft tissue.
Polymeric nanospheres are a promising delivery system. However hydrophilic antibiotics like vancomycin, a key prophylactic antibiotic for SSI prevention, exhibits poor encapsulation efficiency (<30%) due to poor drug-polymer interactions. Hydrophobic Ion Pairing (HIP), a technique used to modify the solubility of charged hydrophilic molecules by pairing them ionically with oppositely charged hydrophobic molecules to form drug-complexes, could enhance the interaction with polymer matrices.
HIP complexes of vancomycin with counter-ions (DOSS, SDS, and Sodium Linoleate) were prepared in acidic medium where the primary amine groups of vancomycin are protonated. We characterized these vancomycin complexes via FTIR and LogP (octanol/water) to assess lipophilicity, then encapsulated them in PLGA, PLA, and PCL using a double emulsion-solvent evaporation method. All investigated counter-ions successfully formed vancomycin-HIP complex precipitates, as confirmed by FTIR spectra, with maximum complexation of 96.2%, 95.8%, and 66.6% for DOSS, SDS, and Sodium Linoleate respectively at drug: counter-ion mole ratio of 1:2. Furthermore, all complexes showed statistically significant increases in LogP; -0.89±0.25, -0.69±0.19, and -0.975±0.05, for vancomycin-: DOSS, SDS, and Linoleate respectively compared to vancomycin HCl (-3.29±0.02). This LogP shift signifies an increase in affinity for hydrophobic environments typical of polymer drug encapsulation, which enhanced loading efficiency compared to vancomycin-HCl. Notably, we achieved a 2.7-fold increase in encapsulation efficiency of Vancomycin-DOSS in PLGA (64.7%±0.4), and 5.5- and 5.6-fold in PLA (46.7±5.9) and PCL (47.8±6.9) compared to Vancomycin-HCl, a significant improvement in polymeric antibiotic drug delivery systems. The resulting nanospheres (~300 nm) as determined with SEM exhibit smooth, spherical particles with relatively narrow size distributions suitable for systemic, and or localized application at spinal fusion sites as a viable alternative to systemic antibiotics and non-degradable carriers.
These findings serve as a critical step in the development of an antibiotic drug delivery system and a transformative approach to SSI prevention. This is the first application of HIP for polymeric system delivery of vancomycin for spine surgeries. The improved (2.7x) encapsulation efficiency and enhanced lipophilicity will provide sustained release to maintain therapeutic levels that aligns with the most at risk time points for SSI after surgery. Future research includes further in vitro studies to validate sustained release kinetics over 21 days and testing of antimicrobial efficacy against prevalent pathogens like S. aureus (45% of spinal SSIs) and P. aeruginosa (notorious for drug resistance), which will be validated by our established in vivo mouse model for infected spine fusions. This novel antibiotic prophylaxis of this proposal could be extended to other ionizable hydrophilic antibiotics or molecules suggesting broader potential impact.