TY - JOUR
T1 - Population Pharmacokinetics of Flucloxacillin In Bone and Soft Tissue– Standard Dosing is Not Sufficient to Achieve Therapeutic Concentrations
AU - Öbrink-Hansen, Kristina
AU - Pham, Anh Duc
AU - Bue, Mats
AU - Hanberg, Pelle
AU - Bendtsen, Mathias
AU - Slater, Josefine
AU - Friberg, Lena E.
AU - Thorsted, Anders
AU - Stilling, Maiken
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2022/7
Y1 - 2022/7
N2 - 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.
AB - 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.
KW - Continuous infusion
KW - Flucloxacillin
KW - Microdialysis
KW - Population pharmacokinetic model
UR - http://www.scopus.com/inward/record.url?scp=85125997421&partnerID=8YFLogxK
U2 - 10.1007/s11095-022-03197-y
DO - 10.1007/s11095-022-03197-y
M3 - Journal article
C2 - 35233728
AN - SCOPUS:85125997421
SN - 0724-8741
VL - 39
SP - 1633
EP - 1643
JO - Pharmaceutical Research
JF - Pharmaceutical Research
IS - 7
ER -