Gepotidacin (GSK2140944) In Vitro Activity against Gram-positive and Gram-negative Bacteria (MBC/MIC, Kill Kinetics, Checkerboard, PAE/SME tests) [PublishAheadOfPrint]

Gepotidacin is a first in class, novel triazaacenaphthylene antibiotic that inhibits bacterial DNA replication and has in vitro activity against susceptible and drug-resistant pathogens. Reference in vitro methods were used to investigate the minimum inhibitory (MIC) and minimum bactericidal concentration (MBC) activity of gepotidacin and comparator agents against Staphylococcus aureus Streptococcus pneumoniae and Escherichia coli. Gepotidacin in vitro activity was also evaluated using time-kill kinetics, broth microdilution checkerboard methods for synergy testing, and for postantibiotic and subinhibitory effects. MIC₉₀ values for gepotidacin when tested against 50 S. aureus (including MRSA) and 50 S. pneumoniae (including penicillin-nonsusceptible) isolates were 0.5 μg/mL and for E. coli (n=25) was 4 μg/mL. Gepotidacin was bactericidal when tested against S. aureus, S. pneumoniae, and E. coli with minimum bactericidal concentration/MIC ratios of ≤4 against 98, 98, and 88% of isolates tested, respectively. Time-kill curves indicated that the bactericidal activity for gepotidacin was observed at 4 or 10x MIC concentrations at 24 hours for all isolates. For S. aureus, regrowth was observed in the presence of gepotidacin and the resulting gepotidacin MICs were 2- to 128-fold higher than baseline gepotidacin MICs. Checkerboard analysis of gepotidacin combined with other antimicrobials demonstrated no occurrences of antagonism with agents from multiple antimicrobial classes. The most common interaction when testing gepotidacin was indifference (fractional inhibitory concentration index >0.5-<2; 82.7% for gram-positive isolates and 82.6% for gram-negative isolates). The postantibiotic effect (PAE) for gepotidacin was short when tested against S. aureus (≤0.6 hours against MRSA and MSSA) and the PAE- sub-MIC effect (SME) was extended in length (>8 hours; 3 isolates at 1/2x MIC). The PAE for levofloxacin was modest (0.0-2.4 hours), and the PAE-SME observed varied from 1.2 to >9 hours at 1/2x MIC. These in vitro data indicate that gepotidacin is a bactericidal agent that exhibits a modest PAE and an extended PAE-SME when tested against gram-positive and -negative bacteria and merits further study for potential use in treating infections caused by these pathogens.

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