Pharmacodynamics of Flucloxacillin in a Neutropenic Murine Thigh Infection Model: A Piece of the Puzzle towards Evidence-Based Dosing
Abstract
:1. Introduction
2. Results
2.1. Pharmacokinetics
2.2. Plasma Protein Binding
2.3. Determination of the PK/PD Index and the Magnitude of the Index Correlated with Efficacy
2.4. MIC Distribution
2.5. Monte Carlo Simulations
3. Discussion
4. Materials and Methods
4.1. Bacteria, Media, and Antibiotics for Animal Experiments
4.2. Animals
4.3. Thigh and Lung Infection Model in Neutropenic Mice
4.4. Measurement of Flucloxacillin Concentrations in Plasma
4.5. Flucloxacillin Pharmacokinetics in Mice
4.6. Pharmacodynamic and Statistical Analysis
4.7. Determination of Minimum Inhibitory Concentrations (MIC) and Wild-Type Distribution
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Model | Bootstrap | 95% Percentiles | |||
---|---|---|---|---|---|
Parameters | Estimate | Rel. SE (%) | Median | 2.5% | 97.5% |
Ka (h−1) | 9.78 | 28 | 9.59 | 6.09 | 19.48 |
V (L) | 0.511 | 17 | 0.51 | 0.31 | 0.70 |
KM (mg/L) | 7.51 | 18 | 7.36 | 3.99 | 10.67 |
Vmax (mg/h) | 98.8 | 4 | 98.34 | 45.65 | 131.45 |
Variability on KM (%) | 41.2 | 60 | 40.7 | 4.1 | 69.5 |
Additive error (mg/L) | 0.0477 | 4 | 0.048 | 0.047 | 0.049 |
Proportional error (%) | 42.5 | 16 | 40.0 | 22.4 | 56.8 |
Isolates | Stasis | 1-log Kill | 2-log Kill |
---|---|---|---|
%fT > 0.25xMIC | |||
S. aureus ATCC29213 | 13.38 | 15.71 | 19.73 |
S. aureus MUP4421 | 13.77 | 15.29 | 19.18 |
S. aureus MUP1621 | 11.42 | 12.41 | 30.60 |
S. aureus MUP2723 | 9.92 | 14.90 | 20.64 |
S. aureus MUP3297 | 13.44 | 17.20 | 22.21 |
S. aureus MUP3199 | 13.53 | 14.41 | 15.47 |
S. aureus MUP2396 | 12.79 | 15.10 | 18.58 |
S. aureus SA2704 | 11.91 | 12.50 | 13.95 |
S. aureus-average | 12.52 | 14.69 | 20.05 |
S. aureus-median | 13.09 | 15.00 | 19.46 |
S. aureus-SD | 1.34 | 1.60 | 5.04 |
S. agalactiae | 19.55 | 22.13 | n.a. |
%fT > MIC | |||
S. pyogenes | 9.39 | 10.41 | 11.34 |
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Roelofsen, E.E.; de Winter, B.C.M.; van der Spek, H.; Snijders, S.; Koch, B.C.P.; van den Berg, S.; Muller, A.E. Pharmacodynamics of Flucloxacillin in a Neutropenic Murine Thigh Infection Model: A Piece of the Puzzle towards Evidence-Based Dosing. Antibiotics 2022, 11, 1049. https://doi.org/10.3390/antibiotics11081049
Roelofsen EE, de Winter BCM, van der Spek H, Snijders S, Koch BCP, van den Berg S, Muller AE. Pharmacodynamics of Flucloxacillin in a Neutropenic Murine Thigh Infection Model: A Piece of the Puzzle towards Evidence-Based Dosing. Antibiotics. 2022; 11(8):1049. https://doi.org/10.3390/antibiotics11081049
Chicago/Turabian StyleRoelofsen, Eveline E., Brenda C. M. de Winter, Heleen van der Spek, Susan Snijders, Birgit C. P. Koch, Sanne van den Berg, and Anouk E. Muller. 2022. "Pharmacodynamics of Flucloxacillin in a Neutropenic Murine Thigh Infection Model: A Piece of the Puzzle towards Evidence-Based Dosing" Antibiotics 11, no. 8: 1049. https://doi.org/10.3390/antibiotics11081049
APA StyleRoelofsen, E. E., de Winter, B. C. M., van der Spek, H., Snijders, S., Koch, B. C. P., van den Berg, S., & Muller, A. E. (2022). Pharmacodynamics of Flucloxacillin in a Neutropenic Murine Thigh Infection Model: A Piece of the Puzzle towards Evidence-Based Dosing. Antibiotics, 11(8), 1049. https://doi.org/10.3390/antibiotics11081049