Tibial bone and soft-tissue concentrations following combination therapy with vancomycin and meropenem - evaluated by microdialysis in a porcine model : should patients with open fractures have higher doses of antibiotics?

Sofus Ørbæk Vittrup; Pelle Hanberg; Martin Bruun Knudsen; Sara Kousgaard Tøstesen; Josephine Olsen Kipp; Jakob Hansen; Nis Pedersen Jørgensen; Maiken Stilling; Mats Bue

doi:10.1302/2046-3758.112.BJR-2021-0321.R1

Tibial bone and soft-tissue concentrations following combination therapy with vancomycin and meropenem - evaluated by microdialysis in a porcine model : should patients with open fractures have higher doses of antibiotics?

Bone Joint Res. 2022 Feb;11(2):112-120. doi: 10.1302/2046-3758.112.BJR-2021-0321.R1.

Authors

Sofus Ørbæk Vittrup^{1

2}, Pelle Hanberg^{1

2}, Martin Bruun Knudsen¹, Sara Kousgaard Tøstesen^{1

2}, Josephine Olsen Kipp^{1

2}, Jakob Hansen³, Nis Pedersen Jørgensen⁴, Maiken Stilling^{1

2

5}, Mats Bue^{1

2

5}

Affiliations

¹ Aarhus Denmark Microdialysis Research (ADMIRE), Orthopaedic Research Laboratory, Aarhus University Hospital, Aarhus, Denmark.
² Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
³ Department of Forensic Medicine, Aarhus University Hospital, Aarhus, Denmark.
⁴ Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
⁵ Department of Orthopaedic Surgery, Aarhus University Hospital, Aarhus, Denmark.

PMID: 35176868
PMCID: PMC8882321
DOI: 10.1302/2046-3758.112.BJR-2021-0321.R1

Abstract

Aims: Prompt and sufficient broad-spectrum empirical antibiotic treatment is key to preventing infection following open tibial fractures. Succeeding co-administration, we dynamically assessed the time for which vancomycin and meropenem concentrations were above relevant epidemiological cut-off (ECOFF) minimal inhibitory concentrations (T > MIC) in tibial compartments for the bacteria most frequently encountered in open fractures. Low and high MIC targets were applied: 1 and 4 µg/ml for vancomycin, and 0.125 and 2 µg/ml for meropenem.

Methods: Eight pigs received a single dose of 1,000 mg vancomycin and 1,000 mg meropenem simultaneously over 100 minutes and 10 minutes, respectively. Microdialysis catheters were placed for sampling over eight hours in tibial cancellous bone, cortical bone, and adjacent subcutaneous adipose tissue. Venous blood samples were collected as references.

Results: Across the targeted ECOFF values, vancomycin displayed longer T > MIC in all the investigated compartments in comparison to meropenem. For both drugs, cortical bone exhibited the shortest T > MIC. For the low MIC targets and across compartments, mean T > MIC ranged between 208 and 449 minutes (46% to 100%) for vancomycin and between 189 and 406 minutes (42% to 90%) for meropenem. For the high MIC targets, mean T > MIC ranged between 30 and 446 minutes (7% to 99%) for vancomycin and between 45 and 181 minutes (10% to 40%) for meropenem.

Conclusion: The differences in the T > MIC between the low and high targets illustrate how the interpretation of these results is highly susceptible to the defined MIC target. To encompass any trauma, contamination, or individual tissue differences, a more aggressive dosing approach may be considered to achieve longer T > MIC in all the exposed tissues, and thereby lower the risk of acquiring an infection after open tibial fractures. Cite this article: Bone Joint Res 2022;11(2):112-120.

Keywords: Antibiotic prophylaxis; Cortical bone; Meropenem; Microdialysis; Open fracture; Open tibial fractures; Vancomycin; antibiotics; catheters; infections; porcine model; soft-tissues; subcutaneous adipose tissue; tibial bone; vancomycin.