Eradication of Staphylococcus aureus in Implant-Associated Osteomyelitis by an Injectable In Situ-Forming Depot Antibiotics Delivery System

Author:

Fuglsang-Madsen Albert Juan1ORCID,Henriksen Nicole Lind12,Chávez Elizabeth Serrano1,Kvich Lasse Andersson3,Birch Julie Knippel Melsted2,Hartmann Katrine Top2,Eriksen Thomas2,Bjarnsholt Thomas34ORCID,Gottlieb Hans5,Andresen Thomas Lars1,Jensen Louise Kruse2,Henriksen Jonas Rosager1,Hansen Anders Elias1ORCID

Affiliation:

1. Department of Health Technology, Technical University of Denmark , Kongens Lyngby , Denmark

2. Department of Veterinary and Animal Sciences, University of Copenhagen , Frederiksberg , Denmark

3. Costerton Biofilm Centre, Institute of Immunology and Microbiology, University of Copenhagen , Copenhagen , Denmark

4. Department of Clinical Microbiology, University of Copenhagen , Copenhagen , Denmark

5. Department of Orthopedic Surgery, Herlev Hospital , Herlev , Denmark

Abstract

Abstract Background Bone infections with Staphylococcus aureus are notoriously difficult to treat and have high recurrence rates. Local antibiotic delivery systems hold the potential to achieve high in situ antibiotic concentrations, which are otherwise challenging to achieve via systemic administration. Existing solutions have been shown to confer suboptimal drug release and distribution. Here we present and evaluate an injectable in situ-forming depot system termed CarboCell. The CarboCell technology provides sustained and tuneable release of local high-dose antibiotics. Methods CarboCell formulations of levofloxacin or clindamycin with or without antimicrobial adjuvants cis-2-decenoic acid or cis-11-methyl-2-dodecenoic acid were tested in experimental rodent and porcine implant-associated osteomyelitis models. In the porcine models, debridement and treatment with CarboCell-formulated antibiotics was carried out without systemic antibiotic administration. The bacterial burden was determined by quantitative bacteriology. Results CarboCell formulations eliminated S. aureus in infected implant rat models. In the translational implant-associated pig model, surgical debridement and injection of clindamycin-releasing CarboCell formulations resulted in pathogen-free bone tissues and implants in 9 of 12 and full eradication in 5 of 12 pigs. Conclusions Sustained release of antimicrobial agents mediated by the CarboCell technology demonstrated promising therapeutic efficacy in challenging translational models and may be beneficial in combination with the current standard of care.

Funder

Novo Nordisk Foundation

Innovation Fund Denmark

Publisher

Oxford University Press (OUP)

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