Tibial bone and soft-tissue concentrations following combination therapy with vancomycin and meropenem – evaluated by microdialysis in a porcine model

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.

Comparison of Intravenous Microdialysis and Standard Plasma Sampling for Monitoring of Vancomycin and Meropenem Plasma Concentrations—An Experimental Porcine Study

“…Theoretically, co-administration could influence protein binding, the diffusion across the microdialysis membrane, and sampling of the two molecules due to potential interactions. Nonetheless, the vancomycin and meropenem setup simulates relevant treatment regimens of various infectious disease, e.g., osteomyelitis and central nervous system infections [ 28 , 29 ]. Finally, the applied descriptive statistics is restricted to the actual data.…”

Concentrations of co-administered vancomycin and meropenem in the internal dead space of a cannulated screw and in cancellous bone adjacent to the screw – Evaluated by microdialysis in a porcine model

“…2017/15-0201-01184). The study adhered to the ARRIVE guidelines, and in order to comply with the 3R's and reduce the number of animals used for research, the reference data for the interventions in the present study was acquired from a recent publication with a different purpose on the same pigs [16] . All chemical analyses were performed at the Department of Forensic Medicine, Aarhus University Hospital.…”

“…A separate 25 mm (Ø 2 mm) drillhole was then made into cancellous bone approximately 2-4 mm parallel to the cannulated screw. An identical cancellous bone drillhole (without screw intervention) in the contralateral proximal tibia was also created [16] . Microdialysis catheters were introduced into the cannulated screw and the cancellous bone drillholes and fastened to the skin with single sutures to prevent displacement during sampling.…”

“…Quantification of unbound vancomycin and meropenem concentrations in the microdialysate samples was done using UHPLC and tandem mass spectrometry (MS) as previously described [16] . The method showed acceptable levels of precision (CV < 15%) in the quantification ranges of [0.1-20 μg/mL].…”

“…A p-value less than 0.05 was considered significant. The pharmacokinetic parameters and statistical analyses were performed using Stata (v. 16.1, StataCorp LLC, College Station, TX, USA), while T > MIC values were calculated in Microsoft Excel (v. 16.54, Microsoft Corporation).…”