1532. Human Target Attainment Probabilities for Delafloxacin against Escherichia coli and Pseudomonas aeruginosa
Session: Poster Abstract Session: Preclinical Study with New Antibiotics and Antifungals
Friday, October 6, 2017
Room: Poster Hall CD
Posters
  • IDWeek 2017 - Poster 1532 - DLX Human Target Attainment Final.pdf (389.4 kB)
  • Background: Delafloxacin (DLX) is a broad-spectrum fluoroquinolone antibiotic under FDA review for the treatment of ABSSSI. Previous studies determined DLX bacterial stasis and 1‑log10 bacterial reduction free AUC0‑24 / MIC (fAUC0‑24/MIC) targets for Escherichia coli (EC) and Pseudomonas aeruginosa (PA) in a mouse thigh infection model. The resulting PK/PD targets were used to predict DLX target attainment probabilities (TAP) in humans.

    Methods: Monte Carlo simulations were used to estimate TAP with DLX 300 mg IV, q12hr. Human DLX plasma pharmacokinetics were determined in patients with ABSSSI in a Phase 3 clinical trial. Individual AUC values were analyzed and determined to be log-normally distributed. The parameters of the AUC distribution were used to simulate random values for fAUC24, which then were combined with random MIC values based on 2014-2015 US distributions of skin and soft tissue isolates of EC (n=108) and PA (n=40), to calculate PK/PD TAPs.

    Results:

    DLX fAUC0‑24/MIC targets for bacterial stasis and 1‑log10 bacterial reduction for EC were 14.5 and 26.2, and for PA were 3.81 and 5.02, respectively. The Monte Carlo simulations for EC predicted TAPs of 98.7% for stasis at an MIC of 0.25 μg/mL, and 99.3% for 1‑log10 bacterial reduction at an MIC of 0.12 μg/mL. The simulations for PA predicted TAPs of 97.3% for stasis and 86.5% for 1‑log10 bacterial reduction at an MIC of 1 μg/mL.

    E. coli

    MIC (ug/mL)

    Target

    0.008

    0.015

    0.03

    0.06

    0.12

    0.25

    0.5

    1

    Stasis

    100

    100

    100

    100

    100

    97.8

    50.4

    2.0

    1-Log Kill

    100

    100

    100

    100

    99.3

    60.4

    5.8

    0.0

    P. aeruginosa

    MIC (ug/mL)

    Target

    0.03

    0.06

    0.12

    0.25

    0.5

    1

    2

    4

    5

    Stasis

    100

    100

    100

    100

    100

    97.3

    45.9

    1.7

    0.5

    1-Log Kill

    100

    100

    100

    100

    100

    86.5

    17.8

    0.3

    0.1

    Conclusion: DLX 300 mg IV, q12hr, should achieve fAUC24/MIC ratios that are adequate to treat ABSSSI caused by most contemporary isolates of EC and PA. For EC, isolates with DLX MICs ≤0.25 μg/mL comprised 73% of all isolates. For PA, isolates with DLX MICs ≤1 μg/mL comprised 88% of all isolates. Similar results would be expected for TAP with oral DLX 450 mg, q12hr.

    Randall Hoover, Ph.D., Melinta Therapeutics, New Haven, CT, Andrea Marra, PhD, Pharmacology, Melinta Therapeutics, New Haven, CT, Erin Duffy, PhD, Melinta Therapeutics, New Haven, CT and Sue K. Cammarata, MD, Melinta Therapeutics, Inc., New Haven, CT

    Disclosures:

    R. Hoover, Melinta Therapeutics: Consultant , Consulting fee

    A. Marra, Melinta Therapeutics: Employee , Salary

    E. Duffy, Melinta Therapeutics: Employee , Salary

    S. K. Cammarata, Melinta Therapeutics: Employee , Salary

    Findings in the abstracts are embargoed until 12:01 a.m. PDT, Wednesday Oct. 4th with the exception of research findings presented at the IDWeek press conferences.