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Population Pharmacokinetics of Flucloxacillin In Bone and Soft Tissue- Standard Dosing is Not Sufficient to Achieve Therapeutic Concentrations.
Öbrink-Hansen, Kristina; Pham, Anh Duc; Bue, Mats; Hanberg, Pelle; Bendtsen, Mathias; Slater, Josefine; Friberg, Lena E; Thorsted, Anders; Stilling, Maiken.
Afiliación
  • Öbrink-Hansen K; Department of Infectious Diseases, Department of Medicine, Regional Hospital Unit West Jutland, Gl Landevej 61, 7400, Herning, Denmark. Kristina.Obrink.Hansen@auh.rm.dk.
  • Pham AD; Department of Infectious Diseases, Aarhus University Hospital, Palle Juul-Jensens Blvd 99, 8200, Aarhus N, Denmark. Kristina.Obrink.Hansen@auh.rm.dk.
  • Bue M; Department of Pharmacy, Uppsala University, Box 580, 751 23, Uppsala, Sweden.
  • Hanberg P; Leiden Academic Centre for Drug Research, Leiden University, Einstein weg 55, 2333, CC, Leiden, The Netherlands.
  • Bendtsen M; Department of Clinical Medicine, Aarhus University Hospital, Palle Juul-Jensens Blvd 82, 8200, Aarhus N, Denmark.
  • Slater J; Aarhus Microdialysis Research Group, Aarhus University Hospital, Palle Juul-Jensens Blvd 99, 8200, Aarhus N, Denmark.
  • Friberg LE; Department of Orthopedic Surgery, Aarhus University Hospital, Palle Juul-Jensens Blvd 99, 8200, Aarhus N, Denmark.
  • Thorsted A; Department of Clinical Medicine, Aarhus University Hospital, Palle Juul-Jensens Blvd 82, 8200, Aarhus N, Denmark.
  • Stilling M; Aarhus Microdialysis Research Group, Aarhus University Hospital, Palle Juul-Jensens Blvd 99, 8200, Aarhus N, Denmark.
Pharm Res ; 39(7): 1633-1643, 2022 Jul.
Article en En | MEDLINE | ID: mdl-35233728
PURPOSE: Flucloxacillin is a ß-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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Floxacilina / Antibacterianos Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Pharm Res Año: 2022 Tipo del documento: Article País de afiliación: Dinamarca Pais de publicación: Estados Unidos
Texto completo
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Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Floxacilina / Antibacterianos Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Pharm Res Año: 2022 Tipo del documento: Article País de afiliación: Dinamarca Pais de publicación: Estados Unidos