In Vitro Activity and Microbiological Efficacy of Gepotidacin (GSK2140944): A Phase 2, Randomized, Multicenter, Dose-Ranging Study in Patients With Acute Bacterial Skin and Skin Structure Infections

Abstract

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 Clinical and Laboratory Standards Institute (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. Sixty‐seven percent (82/122) of subjects had ≥1 Gram‐positive aerobic pathogen from their lesion specimen and were included in the modified microbiological ITT population (mMITT; table). Seventy‐six percent (78/102) of isolates were S. aureus [54 methicillin‐resistant Staphylococcus aureus (MRSA) (69%), 24 methicillin‐sensitive Staphylococcus aureus (MSSA) (31%)] and 24% (24/102) were other pathogens. [Table Presented] Against the 78 S. aureus isolates recovered from baseline lesion specimens, GEP MIC50/MIC90s were; 0.25/0.5 μ g/mL, respectively with similar MICs for MRSA and MSSA (figure). 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. au‐reus 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.