CARBOHYDRATE-ESTER DEPOT ENABLES PROLONGED LOCAL GENTAMICIN AND CLINDAMYCIN EXPOSURE BEYOND CURRENT STANDARDS

Aim To investigate the targeted and systemic in vivo pharmacokinetics of gentamicin and clindamycin released from a carbohydrate-ester based dual antibiotic (gentamicin/clindamycin) sustained-release depot formulation (CC-G/C). Method 2.5 mL of CC-G/C comprising clindamycin and gentamicin was injected via 21G needles into a ~1 cm³ bone void in the proximal tibias and the adjacent soft tissue of pigs. Following bilateral injection, microdialysis was employed in two pigs to sample the concentrations of gentamicin and clindamycin from the adjacent soft tissues over 12 hours (n=4). Simultaneous plasma samples were obtained as a reference (n=2). Samples from bone, tissue, plasma and CC-G/C depots were collected from pigs on days 1, 3, and 7 (n=3 pigs per timepoint). Antibiotic concentrations in bone, tissue and plasma were quantified by LC-MS/MS and depots by LC-UVvis/ELSD. Results Microdialysis indicated high and consistent soft tissue levels (> 300±100 µg/mL clindamycin and > 70±30 µg/mL gentamicin) for both antibiotics during the initial 12 hours, with minimal systemic spillover (< 0.07±0.02 µg/mL). On day 1, average tissue concentrations of gentamicin and clindamycin reached 700±200 µg/g and 3700±700 µg/g in trabecular bone, respectively, and 400±100 µg/g and 1900±500 µg/g in bone void. Over the 7-day study period, levels of both antibiotics in bone declined, with half-lives of 2.6 days for clindamycin and 1.9 days for gentamicin, effectively reaching 80±20 µg/g and 700±100 µg/g at day 7. For the void, levels remained high (>300µg/mg) throughout the study. The on- to off-target ratio (AUC tissue /AUC plasma ) was 3000 for gentamicin and 100,000 for clindamycin. Analysis of recovered CC-G/C depots demonstrated an accumulated release of both gentamicin and clindamycin of 27-46 % of the entire depot on day 1 and 58-82% on day 7. Conclusion CC-G/C facilitates high and sustained in vivo concentrations of gentamicin and clindamycin in trabecular bone and bone voids for up to the 7 days investigated, with minimal systemic exposure. These findings support the potential of CC-G/C as a promising carbohydrate-ester based drug delivery technology for managing orthopedic infections by achieving local antibiotic levels sufficient to eradicate bacterial biofilms and persister cells.