Determination of frequency of spontaneous resistance for gepotidacin and levofloxacin against a collection of gram-positive and gram-negative organisms.

Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antimicrobial recently approved by the Food and Drug Administration (FDA) and Medicines and Healthcare products Regulatory Agency for the treatment of uncomplicated urinary tract infections (uUTI) and by the FDA for uncomplicated urogenital gonorrhea. Gepotidacin selectively inhibits type II topoisomerases involved in bacterial DNA replication by a distinct binding site and novel mechanism of action, conferring in vitro activity against most uropathogens, including those resistant to current antimicrobials. This study evaluated the potential of gepotidacin to select for spontaneous resistance in Citrobacter freundii, Enterobacter cloacae species complex, Klebsiella aerogenes, Klebsiella pneumoniae, Proteus mirabilis, Providencia rettgeri, Enterococcus faecalis, and Staphylococcus saprophyticus clinical isolates. Mutant frequencies ranged from 6.1 × 10-8 to <2.5 × 10-10 at 4× gepotidacin MIC concentrations, and no mutant isolates were recovered at 10× gepotidacin MIC concentrations. No target gene-specific (gyrA, gyrB, parC, parE) cross-resistance was observed with any of the comparators tested. As gepotidacin target site mutations in gyrA/B were only found in Enterococcus faecalis, repressor inactivation or activator dysregulation mutations in efflux pumps were identified as possible mechanisms of reduced susceptibility in the Gram-negative isolates. Further investigation is needed into the relevance of these resistance mechanisms, the clinical significance of these findings, and whether there are any potential fitness costs of decreased gepotidacin susceptibility.