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
Early efficacy Day 2-3
Post therapy Day 12-18
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.
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