Physicochemical and Antimicrobial Properties of Thermosensitive Chitosan Hydrogel Loaded with Fosfomycin.

Luke J Tucker,Dhanush L Amarasekara,Christine S Grant,Santanu Kundu,Lauren B Priddy,Amol V Janorkar,Nicholas C Fitzkee,Anandavalli Varadarajan,Malley A Gautreaux

doi:10.3390/md19030144

Luke J Tucker, Dhanush L Amarasekara + Show 7 more

Open Access

https://doi.org/10.3390/md19030144

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Abstract

Thermosensitive chitosan hydrogels—renewable, biocompatible materials—have many applications as injectable biomaterials for localized drug delivery in the treatment of a variety of diseases. To combat infections such as Staphylococcus aureus osteomyelitis, localized antibiotic delivery would allow for higher doses at the site of infection without the risks associated with traditional antibiotic regimens. Fosfomycin, a small antibiotic in its own class, was loaded into a chitosan hydrogel system with varied beta-glycerol phosphate (β-GP) and fosfomycin (FOS) concentrations. The purpose of this study was to elucidate the interactions between FOS and chitosan hydrogel. The Kirby Bauer assay revealed an unexpected concentration-dependent inhibition of S. aureus, with reduced efficacy at the high FOS concentration but only at the low β-GP concentration. No effect of FOS concentration was observed for the planktonic assay. Rheological testing revealed that increasing β-GP concentration increased the storage modulus while decreasing gelation temperature. NMR showed that FOS was removed from the liquid portion of the hydrogel by reaction over 12 h. SEM and FTIR confirmed gels degraded and released organophosphates over 5 days. This work provides insight into the physicochemical interactions between fosfomycin and chitosan hydrogel systems and informs selection of biomaterial components for improving infection treatment.

Highlights

Chitosan (CH) is the deacetylated derivative of chitin with a degree of deacetylation of at least 50% and is regularly used in the food industry as an edible, renewably sourced food preservative
The addition of FOS increased the zone of inhibition (ZOI), as all groups containing FOS showed enhanced antimicrobial efficacy over those without FOS (Figure 1)
It has been previously established that CH and FOS are effective in inhibiting S. aureus growth independently [2,9]

Summary

Introduction

Chitosan (CH) is the deacetylated derivative of chitin with a degree of deacetylation of at least 50% and is regularly used in the food industry as an edible, renewably sourced food preservative. CH has shown antimicrobial effects against bacterial strains including. Escherichia coli and Staphylococcus aureus (S. aureus) [1,2]. CH hydrogels are produced by combining acid-solubilized CH with beta-glycerol phosphate (β-GP), the neutralizing, biocompatible salt that makes CH solutions thermosensitive [3]. Once the CH solution is chilled, the β-GP stabilizes the CH through ion and hydrogen bonding [4]. As hydrogen bonds are weak, physiological temperatures (37 ◦ C) are sufficient to break them, allowing the CH to precipitate and forming a hydrogel [4]. The gels can be modified to create a composite material, or loaded with antibiotic or chemotherapy drug, for a variety of applications [5]

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