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

• Published in: Pharmaceutical research Vol. 39; no. 7; pp. 1633 - 1643
• Main Authors: Öbrink-Hansen, Kristina, Pham, Anh Duc, Bue, Mats, Hanberg, Pelle, Bendtsen, Mathias, Slater, Josefine, Friberg, Lena E., Thorsted, Anders, Stilling, Maiken
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-07-2022; Springer; Springer Nature B.V
• Subjects: Analysis; Antibiotics; Beta lactamases; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Bone surgery; Cancellous bone; Care and treatment; Catheters; Clinical medicine; Continuous infusion; Cortical bone; Dialysate; Dosage; Dosage and administration; Drug dosages; Flucloxacillin; General anesthesia; Health aspects; Hospitals; Infection; Infections; Infectious diseases; Intravenous administration; Medical Law; Medical research; Medicine; Medicine, Experimental; Methicillin; Microdialysis; Minimum inhibitory concentration; Orthopedics; Ostomy; Penicillin; Pharmacokinetics; Pharmacology/Toxicology; Pharmacy; Plasma; Population; Population pharmacokinetic model; Research Paper; β-Lactam antibiotics; Population pharmacokinetic model; Flucloxacillin; Microdialysis; Continuous infusion
• ISSN: 0724-8741; 1573-904X; 1573-904X
• DOI: 10.1007/s11095-022-03197-y

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 (
f
T>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 %
f
T>MIC (0.5 mg/L and 2 mg/L).
Results
Continuous infusion (CI) resulted in higher %
f
T>MIC compared to intermittent administration. For intermittent IV dosing (4, 8 and 12g/24h),
f
T>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%
f
T>MIC (0.5 mg/L) in all sampled tissues. For MIC 2 mg/L, ≥50%
f
T>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.