title: High in vitro susceptibility to the novel spiropyrimidinetrione ETX0914 (AZD0914) among 873 contemporary clinical Neisseria gonorrhoeae isolates from 21 European countries from 2012 to 2014.
abstract: Resistance in Neisseria gonorrhoeae against all antimicrobials available for the treatment of gonorrhea has emerged. The first gonococcal strains with high-level resistance to ceftriaxone, the last option for first-line empirical antimicrobial monotherapy, were recently described. Consequently, new treatment options are essential. In this study, the in vitro activity of the novel spiropyrimidinetrione ETX0914 (AZD0914), a DNA topoisomerase II inhibitor, was investigated among contemporary consecutive clinical N. gonorrhoeae isolates obtained in 21 European countries and compared to the activities of antimicrobials currently or previously recommended for treatment. Consecutive clinical N. gonorrhoeae isolates (n = 873) cultured in 21 European countries from 2012 to 2014 were examined for their susceptibility to ETX0914. The MICs of ETX0914 were determined using the agar dilution method. For comparison, the MICs of ceftriaxone, cefixime, azithromycin, and ciprofloxacin were determined using Etest or the agar dilution method. For ETX0914, the MIC range, modal MIC, MIC50, and MIC90 were ≤0.002 to 0.25 mg/liter, 0.125 mg/liter, 0.064 mg/liter, and 0.125 mg/liter, respectively. The MIC values were substantially lower than those of the fluoroquinolone ciprofloxacin and most other antimicrobials examined. No cross-resistance with any other examined antimicrobial was observed. In conclusion, the in vitro susceptibility to the novel spiropyrimidinetrione ETX0914 (AZD0914) among 873 contemporary clinical isolates from 21 European countries was high, and no cross-resistance to antimicrobials currently or previously used for gonorrhea treatment was indicated. Additional studies investigating the in vitro and in vivo induction and mechanisms of ETX0914 resistance in gonococci, pharmacokinetics/pharmacodynamics in modeling/simulations and in humans, and performance in randomized controlled gonorrhea treatment trials are essential.
authors.affiliation: WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden magnus.unemo@orebroll.se.
authors.forename: Magnus
authors.initials: M
authors.lastname: Unemo
authors.affiliation: WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Ringlander
authors.affiliation: Sexually Transmitted Bacteria Reference Unit, Public Health England, Colindale, London, United Kingdom.
authors.forename: Catherine
authors.initials: C
authors.lastname: Wiggins
authors.affiliation: WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Fredlund
authors.affiliation: WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
authors.forename: Susanne
authors.initials: S
authors.lastname: Jacobsson
authors.affiliation: Sexually Transmitted Bacteria Reference Unit, Public Health England, Colindale, London, United Kingdom.
authors.forename: Michelle
authors.initials: M
authors.lastname: Cole
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017963:Azithromycin / Q000494:pharmacology; D001463:Barbiturates / Q000494:pharmacology*; D020682:Cefixime / Q000494:pharmacology; D002443:Ceftriaxone / Q000494:pharmacology; D002939:Ciprofloxacin / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D005060:Europe; D024841:Fluoroquinolones / Q000494:pharmacology; D006801:Humans; D007555:Isoxazoles; D008826:Microbial Sensitivity Tests; D009025:Morpholines; D009344:Neisseria gonorrhoeae / Q000187:drug effects*; D023303:Oxazolidinones; D013141:Spiro Compounds / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D001463:Barbiturates; D024841:Fluoroquinolones; D007555:Isoxazoles; D009025:Morpholines; D023303:Oxazolidinones; D013141:Spiro Compounds; D002939:Ciprofloxacin; D002443:Ceftriaxone; D017963:Azithromycin; D020682:Cefixime; C000599190:zoliflodacin