In Vitro Activity and Microbiological Efficacy of Gepotidacin from a Phase 2, Randomized, Multicenter, Dose-Ranging Study in Patients with Acute Bacterial Skin and Skin Structure Infections

• Published in: Antimicrobial agents and chemotherapy Vol. 64; no. 3
• Main Authors: Scangarella-Oman, Nicole E, Ingraham, Karen A, Tiffany, Courtney A, Tomsho, Lynn, Van Horn, Stephanie F, Mayhew, David N, Perry, Caroline R, Ashton, Theresa C, Dumont, Etienne F, Huang, Jianzhong, Brown, James R, Miller, Linda A
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 21-02-2020
• Subjects: Acenaphthenes - pharmacology; Anti-Bacterial Agents - pharmacology; Clinical Therapeutics; Clinical Trials, Phase II as Topic; Gram-Positive Bacteria - drug effects; Heterocyclic Compounds, 3-Ring - pharmacology; Humans; Methicillin-Resistant Staphylococcus aureus - drug effects; Methicillin-Resistant Staphylococcus aureus - genetics; Microbial Sensitivity Tests; Multicenter Studies as Topic; Mutation - genetics; Randomized Controlled Trials as Topic; Skin - microbiology; Skin Diseases, Infectious - microbiology; Staphylococcus aureus - drug effects; Staphylococcus aureus - genetics; MSSA; GSK2140944; ABSSSI; S. aureus; gepotidacin; skin infection; MRSA; antibacterial agent
• ISSN: 0066-4804; 1098-6596; 1098-6596
• DOI: 10.1128/AAC.01302-19

A phase 2 study of gepotidacin demonstrated the safety and efficacy of 3 gepotidacin doses (750 mg every 12 h [q12h], 1,000 mg q12h, and 1,000 mg every 8 h [q8h]) in hospitalized patients with suspected/confirmed Gram-positive acute bacterial skin and skin structure infections (ABSSSIs). Evaluating microbiology outcomes and responses were secondary endpoints. Pretreatment isolates recovered from infected lesions underwent susceptibility testing per Clinical and Laboratory Standards Institute guidelines.
accounted for 78/102 (76%) of Gram-positive isolates; 54/78 (69%) were methicillin-resistant
(MRSA), and 24/78 (31%) were methicillin-susceptible
(MSSA). Posttherapy microbiological success (culture-confirmed eradication of the pretreatment pathogen or presumed eradication based on a clinical outcome of success) for
was 90% for the gepotidacin 750-mg q12h group, 89% for the 1,000-mg q12h, and 73% in the 1000-mg q8h group. For 78
isolates obtained from pretreatment lesions, gepotidacin MIC
/MIC
values were 0.25/0.5 μg/ml against both MRSA and MSSA. Isolates recovered from the few patients with posttreatment cultures showed no significant reduction in gepotidacin susceptibility (≥4-fold MIC increase) between pretreatment and posttreatment isolates. Two of the 78
isolates from pretreatment lesions had elevated gepotidacin MICs and had mutations known to occur in quinolone-resistant
(GyrA S84L, ParC S80Y, and ParE D422E) or to confer elevated MICs to novel bacterial topoisomerase inhibitors (GyrA D83N, both isolates; ParC V67A, one isolate). This first report of microbiological outcomes and responses of gepotidacin in patients with ABSSSIs supports further evaluation of gepotidacin as a novel first-in-class antibacterial agent. (This study has been registered at ClinicalTrials.gov under identifier NCT02045797.).