Flucloxacillin bone and soft tissue concentrations assessed by microdialysis in pigs after intravenous and oral administration.

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.

Local Vancomycin Concentrations after Intra-articular Injection into the Knee Joint: An Experimental Porcine Study.

Intra-articular injection of vancomycin may be an important antimicrobial prophylactic supplement to systemic administration in the prevention of prosthetic joint infections. In eight female pigs, 500 mg of diluted vancomycin was given by intra-articular injection into the knee joint. Microdialysis was used for dense sampling of vancomycin concentrations over 12 hours in the synovial fluid of the knee joint, and in the adjacent femoral and tibial cancellous bone and subcutaneous tissue. Venous blood samples were obtained as reference. The mean (standard deviation [SD]) peak drug concentration of vancomycin in the synovial fluid of the knee joint was 5,277 (5,668) µg/mL. Only one pig failed to reach a peak drug concentration above 1,000 µg/mL. The concentration remained high throughout the sampling interval with a mean (SD) concentration of 337 (259) µg/mL after 690 minutes. For all extraarticular compartments, the pharmacokinetic parameters (area under the concentration time-curve, peak drug concentration, and time to peak drug concentration) were comparable. The highest extraarticular mean (SD) peak drug concentration of 4.4 (2.3) µg/mL was found in subcutaneous tissue. An intra-articular injection of 500 mg diluted vancomycin was found to provide significant prophylactic mean concentrations for at least 12 hours in the synovial fluid of the knee joint. Correspondingly, the adjacent tissue and plasma concentrations were low but remained stable, signifying low risk of systemic toxic side effects and a slow release or uptake from the synovium to the systemic circulation.

Microdialysis for the Assessment of Intervertebral Disc and Vertebral Cancellous Bone Metabolism in a Large Porcine Model.

BACKGROUND/AIM: It remains challenging to evaluate the in vivo pathophysiological biochemical characteristics in spine tissue, due to lack of an applicable model and feasible methods. The aim of this study was to apply microdialysis for the assessment of basic metabolites from the C3-C4 intervertebral disc, C3 vertebral cancellous bone and subcutaneous adipose tissue in a large porcine model. MATERIALS AND METHODS: In 7 pigs, glucose, pyruvate, lactate and glycerol concentrations were evaluated in an 8-hour sampling period. RESULTS: The mean lactate/pyruvate (L/P) ratios for the intervertebral disc and vertebral cancellous bone were comparable and exceeded the ischemic cut-off value of 25 for the entire sampling interval. For subcutaneous adipose tissue, the L/P ratio was below the ischemic cut-off. CONCLUSION: This exploratory study confirms previous findings of ischemia in bone and the intervertebral disc. This encourages new microdialysis study designs in spine tissue employing large porcine models to create new knowledge and a greater understanding of the metabolism and pathogenesis in spine tissue.

Local concentrations of gentamicin obtained by microdialysis after a controlled application of a GentaColl sponge in a porcine model.

Local treatment with gentamicin may be an important tool in the prevention and treatment of surgical site infections in high-risk procedures and patients. The aim of this study was to evaluate the pharmacokinetic profile of gentamicin in bone and surrounding tissue, released from a controlled application of a GentaColl sponge in a porcine model. In eight female pigs, a GentaColl sponge of 10 × 10 cm (1.3 mg gentamicin/cm2 ) was placed in a cancellous bone cavity in the proximal tibia. Microdialysis was used for sampling of gentamicin concentrations over 48 hours from the cavity with the implanted GentaColl sponge, cancellous bone parallel to the cavity over and under the epiphyseal plate, cortical bone, the intramedullary canal, subcutaneous tissue, and the joint cavity of the knee. Venous blood samples were obtained as reference. The main finding was a mean peak drug concentration (95% CI) of gentamicin in the cancellous bone cavity containing the implanted GentaColl sponge of 11 315 (9049-13 581) µg/mL, persisting above 1000 µg/mL until approximately 40 hours after application. Moreover, the concentrations were low (<1 µg/mL) in the surrounding tissues as well as in plasma. The mean peak gentamicin concentration from the cancellous bone cavity after a controlled application of a GentaColl sponge was high and may be adequate for the prevention of biofilm formation. However, high MIC strains and uncontrolled application of the GentaColl sponge may jeopardize this conclusion.

Vancomycin concentrations in the cervical spine after intravenous administration: results from an experimental pig study.

Background and purpose - Vancomycin may be an important drug for intravenous perioperative antimicrobial prophylaxis in spine surgery. We assessed single-dose vancomycin intervertebral disc, vertebral cancellous bone, and subcutaneous adipose tissue concentrations using microdialysis in a pig model. Material and methods - 8 female pigs received 1,000 mg of vancomycin intravenously as a single dose over 100 minutes. Microdialysis probes were placed in the C3-C4 intervertebral disc, C3 vertebral cancellous bone, and subcutaneous adipose tissue, and vancomycin concentrations were obtained over 8 hours. Venous blood samples were obtained as reference. Results - Ranging from 0.24 to 0.60, vancomycin tissue penetration, expressed as the ratio of tissue to plasma area under the concentration-time curve from 0 to the last measured value, was incomplete for all compartments. The lowest penetration was found in the intervertebral disc. The time to a mean clinically relevant minimal inhibitory concentration (MIC) of 4 µg/mL was 3, 17, 25, and 156 min for plasma, subcutaneous adipose tissue, vertebral cancellous bone, and the intervertebral disc, respectively. In contrast to the other compartments, a mean MIC of 8 µg/mL was not reached in the intervertebral disc. An approximately 3-times longer elimination rate was observed in the intervertebral disc in comparison with all the other compartments (p < 0.001), and the time to peak drug concentration was higher for all tissues compared with plasma Interpretation - Preoperative administration of 1,000 mg of vancomycin may provide adequate vancomycin tissue concentrations with a considerable delay, though tissue penetration was incomplete. However, in order also to achieve adequate intervertebral disc concentrations in all individuals and accommodating a potentially higher MIC target, supplemental application of vancomycin may be necessary.