Antibacterial Activity of Oritavancin and Daptomycin Against Clinical Isolates of Vancomycin-Resistant Enterococcus faecium in In Vitro Pharmacokinetic/Pharmacodynamic Models
Bibliographic record
Abstract
Background. The lack of new therapies to treat infections caused by vancomycin-resistant Enterococcus (VRE) has led to clinical use of daily high-dose daptomycin (hd DAP QD) regimens (≥10 mg/kg) to optimize outcomes. The long-acting lipoglycopeptide oritavancin (ORI) exhibits in vitro activity against VRE, although its safety and efficacy in treating clinical VRE infections have not been established. This study tested simulated human dosing regimens of a single 1200 mg dose of ORI (ORI SD) and hd DAP QD against clinical isolates of vancomycin-resistant Enterococcus faecium (VREfm) in an in vitro pharmacokinetic/pharmacodynamic model (IVPM) over 72 hours. Methods. Inocula (106 CFU/ml) of VREfm (VanA) clinical isolates B7181440 (ORI MIC = 0.06 µg/ml; DAP MIC = 1 µg/ml) and B7231527 (ORI MIC = 0.5 µg/ml; DAP MIC = 4 µg/ml) were exposed to simulated free drug (ƒd) plasma concentrations associated with ORI SD (3 hour infusion targeting a free peak [ƒCmax] of 20.7 µg/ml based on 85% plasma protein binding [PPB]; α, β and γ T½ of 2.3 hours, 13.4 hours, and 245 hours, respectively) or hd DAP QD (12 mg/kg; bolus dose targeting a ƒCmax of 15.6 µg/ml based on 91.5% PPB and T½ of 8h) over 72h in one-compartment IVPMs. ORI and DAP concentrations in the IVPM were determined by fluorescence polarization and bioassay, respectively. Results presented are from two independent experiments performed in duplicate. MICs were determined by broth microdilution following CLSI M7-A10 guidelines. Results. ƒd levels associated with hd DAP QD exhibited rapid bactericidal activity (≥3-log reduction in CFU/ml) within 3h against both VREfm isolates whereas ORI SD exerted bactericidal activity over 24 hours (figure). Sustained bactericidal activity was observed with hd DAP QD over 24 hours; however, both VRE isolates exhibited subsequent regrowth at 48 hours coincident with 2- to 16-fold increases in DAP MICs. In contrast, no regrowth of either VREfm isolate occurred with the ORI SD as bacterial counts remained below the limit of detection (< 67 CFU/ml) between 24 and 72 hours. Conclusion. The sustained bactericidal activity of ORI SD against VanA VREfm at simulated human exposures in the IVPM warrants further study of ORI as a treatment option for clinical VRE infections. Disclosures. A. Belley, The Medicines Company: Employee and Shareholder, Salary D. Lalonde Seguin, The Medicines Company: Research Contractor, Salary F. Arhin, The Medicines Company: Employee, Salary G. Moeck, The Medicines Company: Employee, Salary
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".