Background: Peri and postoperative antibiotics are key adjuvant treatment tools in the management of periprosthetic joint infection (PJI). The aim of this study was to evaluate the effect of rifampicin on the area under the moxifloxacin concentration-time curve from 0 to 24 hours (AUC 0-24 ) in the synovial fluid of the knee joint, tibial bone, and adjacent subcutaneous tissue under steady-state conditions using microdialysis in a porcine model.Methods: Twenty female pigs were randomized to receive oral treatment with moxifloxacin monotherapy (Group A, n = 10) of 400 mg once daily for 3 days or a combination therapy (Group B, n = 10) of 400 mg of moxifloxacin once daily for 3 days and 450 mg of rifampicin twice daily for 7 days. Microdialysis was used for sampling the synovial fluid of the knee joint, tibial cancellous and cortical bone, and adjacent subcutaneous tissues. Plasma samples were taken as a reference. Measurements were obtained for 24 hours.Results: Coadministration of moxifloxacin and rifampicin resulted in reductions of the moxifloxacin AUC 0-24 in all targeted tissue compartments by 67% to 85% (p < 0.05). The corresponding change in plasma was 20% (p = 0.49). For both groups, the tissue penetration (the ratio of tissue free fraction AUC 0-24 to plasma free fraction AUC 0-24 [fAUC tissue /fAUC plasma ]) was incomplete in all investigated compartments. The highest moxifloxacin tissue penetration was in the knee joint synovial fluid: 0.59 (Group A) and 0.24 (Group B). The lowest tissue penetration was in the cortical bone: 0.17 (Group A) and 0.03 (Group B). Conclusions:We found a significant reduction of the moxifloxacin concentration, expressed as the AUC 0-24 , in tissues relevant to acute PJI treatment when coadministered with rifampicin.Clinical Relevance: The concentrations within the targeted tissue compartments were reduced significantly more than the concentrations in plasma, which may be particularly important as plasma concentrations are used in clinical practice to assess moxifloxacin treatment sufficiency. Joint replacement alleviates pain and enhances joint function for numerous patients every year. Although infection related to arthroplasty procedures is rare (European intercountry range, 1% to 3%) 1 , the number of procedures is rising, and infections result in high morbidity rates and expenditures associated with their treatment 2,3 . Current treatment protocols for acute periprosthetic joint infection (PJI) include surgical debridement, antibiotics, and implant retention (DAIR) 4 . Periand postoperative antibiotics are key adjuvant treatment tools, and the optimal selection, mode of administration, and duration of treatment are dependent on multiple factors 4,5 .Quinolones combined with rifampicin are recommended internationally as the first-line antibiotic therapy in acute staphylococcal PJI, the most prevalent type of PJI 4,6 . In comparison to older quinolones, moxifloxacin exhibits lower epidemiological cutoff values (ECOFFs) for staphylococci and a lower potential for antibiotic-...

Similar to CD4 T cells, precursor CD8 T cells are thought to depend on a co-stimulatory signal through CD28 for proliferation and differentiation into effector cells. CD46 is another co-stimulatory receptor that promotes differentiation of CD4 T-helper cells type 1 (Th1 cells) into a regulatory phenotype with a switch from IFN-γ towards IL-10-secretion over time. Whether CD46 exerts a similar function on CD8 T cells remains to be fully elucidated. Here, we demonstrate that CD46 co-stimulation induced secretion of IFN-γ as well as expansion of IFN-γ-secreting CD8 T cells. In contrast to CD46 co-stimulation of CD4 T cells, CD8 T cells did not differentiate into a regulatory IL-10-secreting phenotype. This demonstrates that CD46 is a co-stimulatory receptor on CD8 T cells, and that it exerts separate functions during CD4 and CD8 T-cell differentiation.

Aims Flucloxacillin is commonly administered intravenously for perioperative antimicrobial prophylaxis, while oral administration is typical for prophylaxis following smaller traumatic wounds. We assessed the time, for which the free flucloxacillin concentration was maintained above the minimum inhibitory concentration ( fT > MIC) for methicillin-susceptible Staphylococcus aureus in soft and bone tissue, after intravenous and oral administration, using microdialysis in a porcine model. Methods A total of 16 pigs were randomly allocated to either intravenous (Group IV) or oral (Group PO) flucloxacillin 1 g every six hours during a 24-hour period. Microdialysis was used for sampling in cancellous and cortical bone, subcutaneous tissue, and the knee joint. In addition, plasma was sampled. The flucloxacillin fT > MIC was evaluated using a low MIC target (0.5 μg/ml) and a high MIC target (2.0 μg/ml). Results Intravenous administration resulted in longer fT > MIC (0.5 μg/ml) compared to oral administration, except for cortical bone. In Group IV, all pigs reached a concentration of 0.5 μg/ml in all compartments. The mean fT > MIC (0.5 μg/ml) was 149 minutes (95% confidence interval (CI) 119 to 179; range 68 to 323) in subcutaneous tissue and 61 minutes (95% CI 29 to 94; range 0 to 121) to 106 minutes (95% CI 76 to 136; range 71 to 154) in bone tissue. In Group PO, 0/8 pigs reached a concentration of 0.5 μg/ml in all compartments. For the high MIC target (2.0 μg/ml), fT > MIC was close to zero minutes in both groups across compartments. Conclusion Although intravenous administration of flucloxacillin 1 g provided higher fT > MIC for the low MIC target compared to oral administration, concentrations were surprisingly low, particularly for bone tissue. Achievement of sufficient bone and soft tissue flucloxacillin concentrations may require a dose increase or continuous administration. Cite this article: Bone Joint Res 2021;10(1):60–67.

Abstract. Introduction. Systemic perioperative vancomycin may not provide sufficient prophylactic target-site concentrations in the prevention of prosthetic joint infections. Intraosseous vancomycin potentially provides high target-site concentrations. The objective of the present study was to evaluate the local bone and tissue concentrations following tibial intraosseous vancomycin administration in a porcine model. Methods. Eight pigs received 500 mg diluted vancomycin (50 mg/mL) through an intraosseous cannula into the proximal tibial cancellous bone. No tourniquet was applied. Microdialysis was applied for sampling of vancomycin concentrations in adjacent tibial cancellous bone, in cortical bone, in the intramedullary canal of the diaphysis, in the synovial fluid of the knee joint, and in the subcutaneous tissue. Plasma samples were obtained as a systemic reference. Samples were collected for 12 h. Results. High vancomycin concentrations were found in the tibial cancellous bone with a mean peak drug concentration of 1236 (range 28–5295) µg/mL, which remained high throughout the sampling period. The mean (standard deviation) peak drug concentration in plasma was 19 (2) µg/mL, which was obtained immediately after administration. Peak drug concentration, time to peak drug concentration, and area under the concentration–time curve were within the same range in the intramedullary canal, the synovial fluid of the knee, and the subcutaneous tissue. Conclusion. Tibial intraosseous administration of vancomycin provided high concentrations in tibial cancellous bone throughout a 12 h period but with an unpredictable and wide range of peak concentration. The systemic absorption was high and immediate, thus mirroring an intravenous administration. Low mean concentrations were found in all the remaining compartments.

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Co-administration of meropenem and vancomycin has been suggested as a systemic empirical antibiotic treatment of pyogenic spondylodiscitis. The aim of this study was, in an experimental porcine model, to evaluate the percentage of an 8-h dosing interval of co-administered meropenem and vancomycin concentrations above the relevant minimal inhibitory concentrations (MICs) (%T>MIC) in spinal tissues using microdialysis. Eight female pigs (Danish Landrace breed, weight 78–82 kg) received a single-dose bolus infusion of 1000 mg of meropenem and 1000 mg vancomycin simultaneously before microdialysis sampling. Microdialysis catheters were applied in the third cervical (C3) vertebral cancellous bone, the C3–C4 intervertebral disc, paravertebral muscle, and adjacent subcutaneous tissue. Plasma samples were obtained for reference. The main finding was that for both drugs, the %T>MICs were highly reliant on the applied MIC target, but were heterogeneous across all targeted tissues, ranging from 25–90% for meropenem, and 10–100% for vancomycin. For both MIC targets, the highest %T>MIC was demonstrated in plasma, and the lowest %T>MIC was demonstrated in the vertebral cancellous bone for meropenem, and in the intervertebral disc for vancomycin. When indicated, our findings may suggest a more aggressive dosing approach of both meropenem and vancomycin to increase the spinal tissue concentrations to treat the full spectrum of potentially encountered bacteria in a spondylodiscitis treatment setting.

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