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Steady-state concentrations of flucloxacillin in porcine vertebral cancellous bone and intervertebral disc following oral and intravenous administration assessed by microdialysis



Flucloxacillin is a frequently used antibiotic in the treatment of spondylodiscitis. We assessed steady-state concentrations and time above minimal inhibitory concentration (fT > MIC) of flucloxacillin in the intervertebral disc, vertebral cancellous bone, subcutaneous tissue and plasma, after intravenous and oral administration.


Sixteen pigs were randomized into two groups; Group Peroral (Group PO) and Group Intravenous (Group IV) received 1 g flucloxacillin every 6 h for 24 h orally or intravenously. Microdialysis was used for sampling in the compartments of interest. A flucloxacillin target of 50% fT > MIC was applied for three MIC targets: 0.125, 0.5 and 2.0 μg/mL.


Intravenous administration resulted in significantly longer fT > MIC for all targets. Target attainment was only reached for the low target of 0.125 μg/mL in Group IV in vertebral cancellous bone, subcutaneous tissue, and plasma (intervertebral disc 47%). In Group IV, mean fT > MIC values in the investigated compartments were in the range of 47–67% of the dosing interval for 0.125 μg/mL, 20–35% for 0.5 μg/mL, and 0–15% for 2.0 μg/mL. In Group PO, mean fT > MIC values for 0.125 μg/mL were in the range of 1–33%. No pigs reached a concentration of 0.5 μg/mL in any of the investigated compartments in Group PO.


Administration of 1 g flucloxacillin every 6 h resulted in surprisingly low steady-state fT > MIC after intravenous and oral administration. However, intravenous administration resulted in significantly higher concentrations across compartments compared to oral administration. Sufficient target tissue concentrations for treatment of spondylodiscitis may require a dose increase or alternative dosing regimens.

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  1. Lener S et al (2018) Management of spinal infection: a review of the literature. Acta Neurochir (Wien) 160(3):487–496

    Article  Google Scholar 

  2. Cottle L, Riordan T (2008) Infectious spondylodiscitis. J Infect 56(6):401–412

    Article  Google Scholar 

  3. Gouliouris T, Aliyu SH, Brown NM (2010) Spondylodiscitis: update on diagnosis and management. J Antimicrob Chemother 65(Suppl 3):iii11–iii24

    CAS  PubMed  Google Scholar 

  4. Giordan E et al (2019) Outcomes and risk factors for spontaneous spondylodiscitis: case series and meta-analysis of the literature. J Clin Neurosci 68:179–187

    CAS  Article  Google Scholar 

  5. Hopkinson N, Patel K (2016) Clinical features of septic discitis in the UK: a retrospective case ascertainment study and review of management recommendations. Rheumatol Int 36(9):1319–1326

    Article  Google Scholar 

  6. Preiss H, Kriechling P, Montrasio G, Huber T, Janssen I, Moldovan A, Lipsky BA, Uçkay I (2020) Oral flucloxacillin for treating osteomyelitis: a narrative review of clinical practice. J Bone Joint Infect 5(1):16–24

    Article  Google Scholar 

  7. Bue M et al (2018) Vancomycin concentrations in the cervical spine after intravenous administration: results from an experimental pig study. Acta Orthop 89(6):683–688

    Article  Google Scholar 

  8. Hanberg P et al (2016) Pharmacokinetics of single-dose cefuroxime in porcine intervertebral disc and vertebral cancellous bone determined by microdialysis. Spine J 16(3):432–438

    Article  Google Scholar 

  9. Flecknell P (2002) Replacement, reduction and refinement. Altex 19(2):73–78

    PubMed  Google Scholar 

  10. Bendtsen MAF et al (2021) Flucloxacillin bone and soft tissue concentrations assessed by microdialysis in pigs after intravenous and oral administration. Bone Joint Res 10(1):60–67

    Article  Google Scholar 

  11. Ferrero MMA et al (1993) Plasma and bone concentrations of cefuroxime and flucloxacillin—Oral versus parenteral administration in 20 arthroplasties. Acta Orthop Scand 64(5):525–529

    Article  Google Scholar 

  12. Ferrero MMA et al (1994) Relationship between plasma and bone concentrations of cefuroxime and flucloxacillin. Biopharm Drug Dispos 15(7):599–608

    Article  Google Scholar 

  13. Torkington MS et al (2017) Bone penetration of intravenous flucloxacillin and gentamicin as antibiotic prophylaxis during total hip and knee arthroplasty. Bone Joint J 99(3):358–364

    Article  Google Scholar 

  14. Kho CM et al (2017) A review on microdialysis calibration methods: the theory and current related efforts. Mol Neurobiol 54(5):3506–3527

    CAS  Article  Google Scholar 

  15. Hanberg P et al (2019) Single-dose pharmacokinetics of meropenem in porcine cancellous bone determined by microdialysis: an animal study. Bone Joint Res 8(7):313–322

    Article  Google Scholar 

  16. Bue M et al (2018) Bone and subcutaneous adipose tissue pharmacokinetics of vancomycin in total knee replacement patients. Acta Orthop 89(1):95–100

    Article  Google Scholar 

  17. Joukhadar C, Muller M (2005) Microdialysis: current applications in clinical pharmacokinetic studies and its potential role in the future. Clin Pharmacokinet 44(9):895–913

    CAS  Article  Google Scholar 

  18. European Committee on Antimicrobial Susceptibility Testing 2020 Accessed 14 Apr 2020

  19. Wayne PA (2020) Principles and procedures for the development of epidemiological cutoff values for antifungal susceptibility testing. CLSI supplement M57. Clinical and Laboratory Standards Institute Accessed 8 Nov 2020

  20. Clinical and Laboratory Institute Accessed 14 Apr 2020

  21. Ulldemolins M et al (2010) Flucloxacillin dosing in critically ill patients with hypoalbuminaemia: special emphasis on unbound pharmacokinetics. J Antimicrob Chemother 65(8):1771–1778

    CAS  Article  Google Scholar 

  22. Weis S et al (2019) Cefazolin versus anti-staphylococcal penicillins for the treatment of patients with Staphylococcus aureus bacteraemia. Clin Microbiol Infect 25(7):818–827

    CAS  Article  Google Scholar 

  23. Landersdorfer CB et al (2007) Population pharmacokinetics at two dose levels and pharmacodynamic profiling of flucloxacillin. Antimicrob Agents Chemother 51(9):3290–3297

    CAS  Article  Google Scholar 

  24. Bue M et al (2018) Single-dose bone pharmacokinetics of vancomycin in a porcine implant-associated osteomyelitis model. J Orthop Res 36(4):1093–1098

    CAS  PubMed  Google Scholar 

  25. Jensen LK et al (2017) Suppurative inflammation and local tissue destruction reduce the penetration of cefuroxime to infected bone implant cavities. J Comp Pathol 157(4):308–316

    CAS  Article  Google Scholar 

  26. Vertebral osteomyelitis and discitis in adults 2020 Accessed 9 Nov 2020

  27. Li HK et al (2019) Oral versus intravenous antibiotics for bone and joint infection. N Engl J Med 380(5):425–436

    CAS  Article  Google Scholar 

  28. Cyriac JM, James E (2014) Switch over from intravenous to oral therapy: a concise overview. J Pharmacol Pharmacother 5(2):83–87

    Article  Google Scholar 

  29. Sutherland R, Croydon EA, Rolinson GN (1970) Flucloxacillin, a new isoxazolyl penicillin, compared with oxacillin, cloxacillin, and dicloxacillin. Br Med J 4(5733):455–460

    CAS  Article  Google Scholar 

  30. Wallenburg E et al (2021) A meta-analysis of protein binding of flucloxacillin in healthy volunteers and hospitalized patients. Clin Microbiol Infect 28(3):446-e1

    Article  Google Scholar 

  31. Roberts S et al (2006) Histology and pathology of the human intervertebral disc. J Bone Joint Surg Am 88(Suppl 2):10–14

    PubMed  Google Scholar 

  32. Alini M et al (2008) Are animal models useful for studying human disc disorders/degeneration? Eur Spine J 17(1):2–19

    Article  Google Scholar 

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The authors wish to thank Sofus Carl Emil Friis Foundation, Aase & Ejnar Danielsen’s Foundation, the Augustinus Foundation, Direktør Emil Hertz og hustru Inger Hertz Foundation, and the Novo Nordisk Foundation for supporting this study financially. No competing interests were declared.

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Authors and Affiliations



MAFB: Drafted the manuscript. Acquisition, analysis and interpretation of data. PH: Designed the study. Interpretation of data. Critical revision. JS: Acquisition of data. Critical revision. JH: Responsible for chemical analysis of drug levels. Critical revision. KÖ-H: Designed the study. Interpretation of data. Critical revision. MS: Designed the study. Interpretation of data. Critical revision. Supervision of research. Approval of final version to publish. MB: Designed the study. Interpretation of data. Critical revision. Supervision of research. Approval of final version to publish.

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Correspondence to Mathias A. F. Bendtsen.

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Bendtsen, M.A.F., Hanberg, P., Slater, J. et al. Steady-state concentrations of flucloxacillin in porcine vertebral cancellous bone and intervertebral disc following oral and intravenous administration assessed by microdialysis. Eur Spine J 31, 1508–1514 (2022).

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  • Flucloxacillin
  • Bone
  • Infection
  • Spondylodiscitis
  • Animal model