2237. In vitro Activity and Microbiological Efficacy of Gepotidacin (GSK2140944): A Phase II, Randomized, Multicenter, Dose-Ranging Study in Patients with Acute Bacterial Skin and Skin Structure Infections
Session: Poster Abstract Session: New Antibiotics in Development
Saturday, October 29, 2016
Room: Poster Hall
Posters
  • T-GSK0659 ID Week Gepotidacin microbiology poster_For print_updated_Final.pdf (547.3 kB)
  • Background: Gepotidacin (GEP), a first in class novel triazaacenaphthylene bacterial topoisomerase inhibitor (BTI), inhibits bacterial replication and has in vitro activity against key pathogens, including drug-resistant strains, associated with a range of conventional and biothreat infections.

    Methods: This phase 2 study evaluated the safety, tolerability, pharmacokinetics, and efficacy of 3 IV/oral doses of GEP in subjects with acute bacterial skin and skin structure infections (ABSSSIs) suspected to be caused by Gram positive pathogens and requiring hospitalization. Pre-treatment specimens of the infected lesion were obtained for culture by standard methods and susceptibility testing by CLSI broth microdilution for protocol-defined pathogens. As part of an exploratory endpoint, microbiological success was defined as culture confirmed eradication of the baseline pathogen, or derived from clinical outcome in the absence of a post-therapy specimen.

    Results: 67% (82/122) of subjects had at least 1 Gram-positive aerobic pathogen from their lesion specimen and were included in the modified microbiological ITT population (mMITT). 76% (78/102) of isolates were S. aureus [54 MRSA (69%), 24 MSSA (31%)] and 24% (24/102) were other pathogens.

    Summary of Microbiological Response for S. aureus (mMITT):

    Microbiological success n/N (%) by GEP IV/Oral dose

    Timepoint

    750mg/1500mg BID

    1000mg/2000mg BID

    1000mg/2000mg TID

    Early efficacy Day 2-3

    24/39 (62%)

    19/28 (68%)

    9/11 (82%)

    Post therapy Day 12-18

    35/39 (90%)

    25/28 (89%)

    8/11 (73%)

    Frequency distribution of GEP MICs against S. aureus recovered from baseline lesion specimens:

    Against the 78 S. aureus isolates recovered from baseline lesion specimens, GEP MIC50 /MIC90s  were; 0.25/0.5 µg/mL, respectively with similar MICs for MRSA and MSSA. In the few subjects with post-baseline lesion specimens, there was no reduction in susceptibility (≥4-fold MIC increase) to GEP between baseline and post-baseline. Two pre-treatment S. aureus isolates with elevated GEP MICs were found to contain mutations in the BTI binding pocket.

    Conclusion: This first report of microbiological efficacy in treatment of ABSSSI supports further clinical study of GEP as a first-in-class, novel mechanism of action antibacterial.

     

    Nicole Scangarella-Oman, MS1, Karen Ingraham, MS1, Courtney Tiffany, BS1, Caroline Perry, PhD1, Teri Ashton, PhD2, Etienne Dumont, MD1, Jianzhong Huang, PhD1 and Linda Miller, PhD1, (1)GlaxoSmithKline, Collegeville, PA, (2)GlaxoSmithKline, Research Triangle Park, NC

    Disclosures:

    N. Scangarella-Oman, GlaxoSmithKline: Employee and Shareholder , Salary

    K. Ingraham, GlaxoSmithKline: Employee , Research support

    C. Tiffany, GlaxoSmithKline: Employee , Salary and Stock

    C. Perry, GlaxoSmithKline: Employee and Shareholder , Salary

    T. Ashton, GlaxoSmithKline: Employee and Shareholder , Salary

    E. Dumont, GlaxoSmithKline: Employee and Shareholder , Salary

    J. Huang, GlaxoSmithKline: Employee and Shareholder , Salary

    L. Miller, GlaxoSmithKline: Employee , Salary

    Findings in the abstracts are embargoed until 12:01 a.m. CDT, Wednesday Oct. 26th with the exception of research findings presented at the IDWeek press conferences.