1482. Microbiological Analysis from a Phase II Study Evaluating Gepotidacin (GSK2140944) in the Treatment of Uncomplicated Urinary Tract Infections

BACKGROUND: Gepotidacin (GEP), a first in class novel triazaacenaphthylene bacterial topoisomerase inhibitor, inhibits bacterial replication and has in vitro activity against key pathogens, including drug-resistant strains, associated with a range of infections. METHODS: This phase IIa single-center study evaluated the safety, tolerability, pharmacokinetics, and efficacy of oral GEP 1,500 mg BID for 5 days in female subjects with acute cystitis. Clean catch mid-stream urine specimens were obtained for quantitative culture by standard methods. Susceptibility testing by CLSI broth microdilution and gradient diffusion (fosfomycin only) was conducted. Inclusion in the microbiological intent-to-treat population (micro-ITT) required growth of a qualifying baseline uropathogen (≥ 10(5) CFU/mL). Microbiological success was defined as culture-confirmed eradication (no growth, <10(3) CFU/mL) of the qualifying baseline uropathogen. RESULTS: Of 22 participants, 8 (36%) had a baseline qualifying uropathogen (5 E. coli, 1 S. saprophyticus, 1 K. pneumoniae, and 1 C. koseri) and were included in the micro-ITT. GEP MICs against the 8 qualifying uropathogens ranged from 0.06 to 4 µg/mL. Two E. coli isolates were multidrug-resistant (defined as resistance to ≥3 antibiotic classes) due to resistance to ampicillin, trimethoprim-sulfamethoxazole and ciprofloxacin/levofloxacin or cefazolin. One additional E. coli isolate was ampicillin-resistant. Of the 8 participants in the micro-ITT, 7 (88%), and 6 (75%) were microbiological successes at the Test of Cure (TOC) and Follow-up Visits, respectively. The one microbiological failure at TOC (E. coli) was due to an unreportable (out of stability) urine specimen. For the 4 participants with available steady-state PK, qualifying Enterobacteriaceae uropathogens and who were microbiological successes at TOC, plasma fAUC24h/MICs ranged from 7 to 90.5 and urine AUC24h/MICs from 1292 to 121,698. The participant with the lowest plasma fAUC/MIC (7) and urine AUC24h/MIC (1292) had a K. pneumoniae with a gepotidacin MIC of 4 µg/mL. CONCLUSION: This first report of microbiological efficacy in the treatment of acute cystitis supports further clinical study of GEP as a first-in-class, novel mechanism of action antibacterial. DISCLOSURES: All authors: No reported disclosures.