Antimicrobial and pharmaceutical properties of antimicrobial-loaded calcium sulfate composites for resistant Gram-negative diabetic foot osteomyelitis

Background: Diabetic foot osteomyelitis (DFO) results in limb amputation, reduced quality of life, and early mortality, with antimicrobial resistant (AMR) organisms becoming an increasing problem within DFO management. Here we report the antimicrobial and pharmaceutical properties of antimicrobial-loaded calcium sulfate composites for the targeted treatment of AMR DFO.

Methods: Calcium sulphate alpha-hemihydrate (Stimulan® Rapid Cure) beads containing 120 mg gentamicin, 500 mg ciprofloxacin, or 200 mg (2.5 MU) colistin were tested against Pseudomonas aeruginosa (NCTC6750 and an extensively drug-resistant clinical isolate from DFO) and Escherichia coli (NCTC8196) over time using an adapted EUCAST disk-diffusion methodology. Antimicrobial synergy, drug-release and dose uniformity testing were undertaken to further characterise these composites.

Results: Setting times were 5, 10, and 30 minutes for gentamicin, colistin, and ciprofloxacin, respectively. Ciprofloxacin was released continuously and zones of inhibition (ZOI) remained consistent against all species, including the ciprofloxacin resistant P. aeruginosa, over a ten-week period. Gentamicin and colistin underwent burst-release with subsequent drug-release and ZOIs decreasing rapidly over a 3-week period. No synergy was observed between any antimicrobial combination. Ciprofloxacin bead content was more uniform (10.7% variation) than gentamicin and colistin (48.0% and 133.6% variation, respectively).

Conclusions: Gentamicin, colistin and ciprofloxacin calcium sulfate beads may provide useful targeted therapies for AMR DFO. Future work should focus on different mixing methods for making calcium sulfate beads to determine effects on dose uniformity. More work is required to understand the clinical utility of ciprofloxacin in these composites, particularly considering the available pharmaceutical formulations.