Novel Pharmacokinetic/Pharmacodynamic Parameters Quantify the Exposure–Effect Relationship of Levofloxacin against Fluoroquinolone-Resistant Escherichia coli
Abstract
:1. Introduction
2. Results
2.1. Characterisation of Bacterial Strains
2.2. In Vitro Infection Model Experiments
2.3. Pharmacokinetic/Pharmacodynamic Metrics
2.4. Exposure–Effect Relationship
2.4.1. Stratification per E.coli Strain
2.4.2. Stratification for Static and Dynamic Exposure
3. Discussion
4. Materials and Methods
4.1. Characterisation of Bacterial Strains
4.1.1. Genotypic Resistance
4.1.2. Antimicrobial Susceptibility Testing
4.2. In Vitro Infection Model Experiments
4.3. Pharmacokinetic/Pharmacodynamic Metrics
4.4. Exposure–effect Relationship
4.4.1. Stratification per E. coli Strain
4.4.2. Stratification for Static and Dynamic Exposure
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Sequence Type | Mutations in QRDR | Acquired Fluoroquinolone Resistance | Minimal Inhibitory Concentration (mg/L) | |
---|---|---|---|---|
gyrA | parC | |||
58 | Ser-83→Leu | WT | - | 8 |
88 | Ser-83→Leu | WT | qnrS1 | 2 |
167 | Ser-83→Leu Asp-87→Asn | Ser-80→Ile | - | 8 |
Parameter (unit) | Estimate (RSE, %) | ||
---|---|---|---|
Sequence Type 58 | Sequence Type 88 | Sequence Type 167 | |
cumAUC50 (mg·h·L−1) | 158 (9.45) | 28.6 (7.85) | 49.4 (7.54) |
Hill | 1.02 (5.49) | 1.25 (5.37) | 0.961 (6.62) |
cumAUCreg, static (mg·h·L−1) | 3132 (36.5) | 330 (22.9) | 1679 (20.3) |
cumAUCreg, dynamic (mg·h·L−1) | 248 (34.6) | 373 (34.9) | 473 (39.2) |
cumAUCreg,static/cumAUCreg,dynamic ratio | 12.6 | 0.885 | 3.55 |
Proportional residual variability, % CV | 4.00 (11.8) | 4.33 (11.7) | 3.33 (11.3) |
Sequence Type 58 | Sequence Type 88 | Sequence Type 167 | ||||
---|---|---|---|---|---|---|
CLVX = 1-fold MIC | Time (h) | Effect | Time (h) | Effect | Time (h) | Effect |
Dominance of killing process (Higher impact of Emax term) | ≤1.10 | ≤0.0539 | ≤0.80 | ≤0.358 | ≤2.20 | ≤0.320 |
Intersection of killing and regrowth trajectories | 13.3 | 0.610 | 8.7 | 0.630 | 10.1 | 0.803 |
Dominance of regrowth process (Higher impact of inhibition term) | ≥90.0 | ≥0.179 | ≥41.0 | ≥0.252 | ≥31.4 | ≥0.541 |
CLVX = 2-fold MIC | ||||||
Dominance of killing process (Higher impact of Emax term) | ≤8.70 | ≤0.560 | ≤5.30 | ≤0.503 | ≤13.1 | ≤0.737 |
Intersection of killing and regrowth trajectories | 26.2 | 0.863 | 15.3 | 0.866 | 29.9 | 0.892 |
Dominance of regrowth process (Higher impact of inhibition term) | ≥60.0 | ≥0.697 | ≥29.5 | ≥0.732 | ≥66.0 | ≥0.750 |
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Seeger, J.; Guenther, S.; Schaufler, K.; Heiden, S.E.; Michelet, R.; Kloft, C. Novel Pharmacokinetic/Pharmacodynamic Parameters Quantify the Exposure–Effect Relationship of Levofloxacin against Fluoroquinolone-Resistant Escherichia coli. Antibiotics 2021, 10, 615. https://doi.org/10.3390/antibiotics10060615
Seeger J, Guenther S, Schaufler K, Heiden SE, Michelet R, Kloft C. Novel Pharmacokinetic/Pharmacodynamic Parameters Quantify the Exposure–Effect Relationship of Levofloxacin against Fluoroquinolone-Resistant Escherichia coli. Antibiotics. 2021; 10(6):615. https://doi.org/10.3390/antibiotics10060615
Chicago/Turabian StyleSeeger, Johanna, Sebastian Guenther, Katharina Schaufler, Stefan E. Heiden, Robin Michelet, and Charlotte Kloft. 2021. "Novel Pharmacokinetic/Pharmacodynamic Parameters Quantify the Exposure–Effect Relationship of Levofloxacin against Fluoroquinolone-Resistant Escherichia coli" Antibiotics 10, no. 6: 615. https://doi.org/10.3390/antibiotics10060615
APA StyleSeeger, J., Guenther, S., Schaufler, K., Heiden, S. E., Michelet, R., & Kloft, C. (2021). Novel Pharmacokinetic/Pharmacodynamic Parameters Quantify the Exposure–Effect Relationship of Levofloxacin against Fluoroquinolone-Resistant Escherichia coli. Antibiotics, 10(6), 615. https://doi.org/10.3390/antibiotics10060615