LAUSR

Background Mycoplasma genitalium has rapidly developed resistance to first-line azithromycin and second-line moxifloxacin. Third-line pristinamycin is difficult to source and only 80% effective. Consequently, there is an urgent need for alternative therapies, and to protect new antimicrobials against development and/or spread of resistance. Resistance-guided therapy and combination with other antimicrobials are important tools. Gepotidacin is a novel, first-in-class triazaacenaphthylene topoisomerase II inhibitor inhibiting DNA replication by a mechanism distinct from fluoroquinolones. Limited studies have shown activity against fluoroquinolone susceptible M. genitalium strains Methods We determined the gepotidacin minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) in 54 M . genitalium isolates by the Vero-cell culture method. Macrolide resistance was present in 31 isolates, fluoroquinolone resistance in 18 (33%) isolates; 17 had dual resistance. Synergy testing was performed for gepotidacin and doxycycline by checkerboard titration for four macrolide or dual resistant isolates. Results Gepotidacin was active against all 54 M . genitalium isolates with median and modal MIC of 0.125 mg/L and MIC90 at 0.25 mg/L (range ≤0.016–0.5 mg/L). No difference in MIC between macrolide resistant and susceptible isolates (p=0.24) or between fluoroquinolone and dual-resistant and susceptible isolates (p=0.2) was demonstrated. Gepotidacin MBC was available for 45 M . genitalium isolates with a median MIC of 0.064 and a median MBC of 0.125 mg/L and all isolates had ≤4 fold difference between MIC and MBC suggesting bactericidal effect. Checkerboard titrations showed synergistic or additive effect with a Fractional Inhibitory Concentration Index (ΣFIC) of 0.5 for two isolates (one macrolide resistant and one dual resistant) and additive effect (ΣFIC at 0.62 and 0.75) for a macrolide and a dual resistant isolate, respectively. Conclusion Gepotidacin warrants further evaluation in clinical treatment trials for M. genitalium. Combination therapy with doxycycline should be clinically studied to assess effect and potential protection against development and/or spread of resistance. Disclosure No significant relationships.