|Titel på arbejdet
|Bone, intervertebral disc and subcutaneous adipose tissue pharmacokinetics of vancomycin obtained by microdialysis
|Mats Høy Bue
|Afdeling / Sted
|Ortopædkirurgisk afdeling, Regionshospitalet Horsens
|Abstract / Summary
The prevention and treatment of bone, intervertebral disc and implant-associated bone infections remain a major challenge for clinicians. Treatment failure can have devastating complications for both the patients and the healthcare system. Treatment failure rates remain high, which may be a consequence of incomplete antimicrobial bone and intervertebral disc penetration.
The majority of orthopaedic infections are caused by Staphylococcus aureus, with an increasing incidence of methicillin-resistant Staphylococcus aureus (MRSA) infections. Vancomycin is effective against these bacteria and may become an important drug in some orthopaedic settings.
The evaluation of vancomycin bone and intervertebral disc pharmacokinetics is, however, a challenging task. At present, bone and intervertebral disc pharmacokinetics of vancomycin have mainly been investigated using bone and disc tissue samples and discectomy. These methods suffer from methodological limitations, which makes it hard to assess the pharmacokinetic profile of the investigated drugs. The pharmacokinetic tool, microdialysis, has shown promising evolvement for sampling of various antimicrobials in bone and the intervertebral disc. The advantages of serially sampling the extracellular and unbound fraction of drug make the method attractive compared to the existing methods.
The objective of this PhD project was to apply microdialysis for sampling of vancomycin in different orthopaedically relevant settings. The project consisted of three studies, one of which was a clinical study and two of which were experimental studies: two mimicking perioperative settings and one evaluating the infectious situation. Vancomycin was administered and sampled in the same way in all three studies: a single dose of 1,000 mg being given intravenously over 100 min, and concentrations were sampled over 8 hours. The quantification of drug was performed with ultra-high performance liquid chromatography with ultraviolet detection. Data were analysed by non-compartmental analysis.
In the clinical study, Study I, the penetration of vancomycin to bone and subcutaneous adipose tissue was found to be incomplete and delayed in male patients undergoing total knee replacement surgery. To evaluate the effect of infection on vancomycin bone penetration, Study II found that the Staphylococcus aureus implant-associated osteomyelitis reduced vancomycin bone penetration, especially to the implant cavity. In Study III, the vancomycin penetration to the vertebral cancellous bone and the intervertebral disc were also found to be incomplete and delayed.
In conclusion, microdialysis was successfully applied for the assessment of vancomycin concentrations in healthy and infected bone and in the intervertebral disc. In all three studies, clinical as well as experimental, an incomplete and delayed penetration of vancomycin to bone and the intervertebral disc was found. The lowest penetration ratios were found in cortical bone, the implant cavity, and the intervertebral disc. Overall, these results suggest that a single dose of 1,000 mg of vancomycin may not penetrate adequately to healthy bone, infected bone or the intervertebral disc.