Characterization of isolates from two phase 3 uncomplicated urinary tract infection trials (EAGLE-2 and EAGLE-3) that show an apparent ≥4-fold increase in gepotidacin MIC between baseline and post-baseline visits

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Abstract Background and objectives Effective therapies for the treatment of uncomplicated urinary tract infections (uUTIs) are increasingly limited due to rising multidrug resistance, necessitating the development of novel antimicrobials. Gepotidacin is a first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA gyrase and topoisomerase IV through a distinct binding site, a unique mechanism of action, and with well-balanced inhibition for most pathogens. Gepotidacin was recently approved by the FDA and MHRA for the treatment of uUTIs and by the FDA for uncomplicated urogenital gonorrhoea. This study investigated the development of resistance to gepotidacin among isolates from two Phase 3 uUTI clinical trials (EAGLE-2 [NCT04020341]/EAGLE-3 [NCT04187144]). Methods Post-baseline isolates exhibiting a reproducible ≥4-fold increase in minimum inhibitory concentration (MIC) and non-distinct multi-locus sequence typing/pulsed-field gel electrophoresis results underwent single nucleotide polymorphism/insertion-deletion analysis. Results Across both studies, initial MIC testing showed 58/1045 (5.6%) patients with pathogen(s) demonstrating an apparent ≥4-fold increase in post-baseline gepotidacin MIC. Analyses identified only one patient with multiple Escherichia coli isolate pairs displaying potential development of resistance to gepotidacin. While the post-baseline isolates did not meet the putative direct descendancy criteria, we have conservatively considered this a case of possible development of resistance due to the rarity of the gepotidacin target-specific mutation (ParC D79G) in the on-therapy and test-of-cure E. coli isolates. Conclusions Collectively, results from the Phase 3 trials indicate a low incidence of resistance development to gepotidacin, with only one potential case among gepotidacin-treated patients (1/1045; 0.096%). Further research is warranted to elucidate the mechanisms underlying elevated post-baseline gepotidacin MICs.

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