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Population Pharmacokinetics of Flucloxacillin In Bone and Soft Tissue– Standard Dosing is Not Sufficient to Achieve Therapeutic Concentrations

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Abstract

Purpose

Flucloxacillin is a β-lactam penicillin commonly used in the treatment of bone and soft tissue infections. In a recent porcine study, we found surprisingly low time for which the free concentration was maintained above the minimal inhibitory concentration (fT>MIC) in bone and soft tissue, following flucloxacillin oral (PO) and intravenous (IV) administration at 1g every 6h (q6h). In addition to plasma, sampling was obtained from subcutaneous tissue, knee joint, cancellous bone and cortical bone, using microdialysis. To identify flucloxacillin dosing regimens that result in theoretically therapeutic concentrations, we developed a population pharmacokinetic (PK) model for the porcine data, and combined it with a human flucloxacillin population PK model for simulations.

Methods

A four-compartment model was developed, and various dosing regimens and modes of administration were simulated. Predicted concentrations were compared to %fT>MIC (0.5 mg/L and 2 mg/L).

Results

Continuous infusion (CI) resulted in higher %fT>MIC compared to intermittent administration. For intermittent IV dosing (4, 8 and 12g/24h), fT>MIC (0.5 mg/L) was ≥70% in plasma, and ranged between 42-96% in the sampled tissue in a typical individual. By applying CI, 4g/day was sufficient to achieve ≥98% fT>MIC (0.5 mg/L) in all sampled tissues. For MIC 2 mg/L, ≥50% fT>MIC was only achieved in plasma at CI 8 and 12g/24h and IV 3g q6h.

Conclusions

To reach efficacious flucloxacillin bone and tissue concentrations, dose increment or continuous infusion needs to be considered.

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Funding

This work was supported by the Novo Nordisk Foundation (Grant number: NNF18OC0033304), Sofus Carl Emil Friis Foundation (No grant number), Aase & Ejnar Danielsens Foundation (Grant number: 19-10-0025), Augustinus Foundation (Grant number: 19-0320) and Direktør Emil Hertz og Hustru Inger Hertz Foundation (No grant number).

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Authors and Affiliations

  1. Department of Infectious Diseases, Department of Medicine, Regional Hospital Unit West Jutland, Gl Landevej 61, 7400, Herning, Denmark

    Kristina Öbrink-Hansen

  2. Department of Infectious Diseases, Aarhus University Hospital, Palle Juul-Jensens Blvd 99, 8200, Aarhus N, Denmark

    Kristina Öbrink-Hansen

  3. Department of Pharmacy, Uppsala University, Box 580, 751 23, Uppsala, Sweden

    Anh Duc Pham, Lena E. Friberg & Anders Thorsted

  4. Leiden Academic Centre for Drug Research, Leiden University, Einstein weg 55, 2333, CC, Leiden, The Netherlands

    Anh Duc Pham

  5. Department of Clinical Medicine, Aarhus University Hospital, Palle Juul-Jensens Blvd 82, 8200, Aarhus N, Denmark

    Mats Bue, Pelle Hanberg, Mathias Bendtsen, Josefine Slater & Maiken Stilling

  6. Aarhus Microdialysis Research Group, Aarhus University Hospital, Palle Juul-Jensens Blvd 99, 8200, Aarhus N, Denmark

    Mats Bue, Pelle Hanberg, Mathias Bendtsen, Josefine Slater & Maiken Stilling

  7. Department of Orthopedic Surgery, Aarhus University Hospital, Palle Juul-Jensens Blvd 99, 8200, Aarhus N, Denmark

    Mats Bue, Pelle Hanberg & Maiken Stilling

Authors
  1. Kristina Öbrink-Hansen
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  2. Anh Duc Pham
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  3. Mats Bue
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  8. Anders Thorsted
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  9. Maiken Stilling
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Contributions

Kristina Öbrink-Hansen contributed to the conception and design of the study; contributed to the interpretation of data; provided critical review and final approval of the manuscript. Anh Duc Pham contributed to the design of the study; contributed to data analyses and interpretation; provided critical review and final approval of the manuscript. Mats Bue contributed to the conception and design of the study; contributed to the interpretation of data; provided critical review and final approval of the manuscript. Pelle Hanberg contributed to the conception and design of the study; contributed to the interpretation of data; provided critical review and final approval of the manuscript. Mathias Bendtsen contributed to the conception and design of the study; contributed to the interpretation of data; provided critical review and final approval of the manuscript. Josefine Slater contributed to the conception and design of the study; contributed to the interpretation of data; provided critical review and final approval of the manuscript. Lena E. Friberg contributed to the design of the study; contributed to data analyses and interpretation; provided critical review and final approval of the manuscript. Anders Thorsted contributed to the design of the study; contributed to data analyses and interpretation; provided critical review and final approval of the manuscript. Maiken Stilling contributed to the conception and design of the study; contributed to the interpretation of data; provided critical review and final approval of the manuscript.

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Correspondence to Kristina Öbrink-Hansen.

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Öbrink-Hansen, K., Pham, A.D., Bue, M. et al. Population Pharmacokinetics of Flucloxacillin In Bone and Soft Tissue– Standard Dosing is Not Sufficient to Achieve Therapeutic Concentrations. Pharm Res 39, 1633–1643 (2022). https://doi.org/10.1007/s11095-022-03197-y

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