title: In Vitro Activity of Delafloxacin against Clinical Neisseria gonorrhoeae Isolates and Selection of Gonococcal Delafloxacin Resistance.
abstract: We evaluated the in vitro activity of delafloxacin against a panel of 117 Neisseria gonorrhoeae strains, including 110 clinical isolates collected from 2012 to 2015 and seven reference strains, compared with the activities of seven antimicrobials currently or previously recommended for treatment of gonorrhea. We examined the potential for delafloxacin to select for resistant mutants in ciprofloxacin-susceptible and ciprofloxacin-resistant N. gonorrhoeae We characterized mutations in the gyrA, gyrB, parC, and parE genes and the multidrug-resistant efflux pumps (MtrC-MtrD-MtrE and NorM) by PCR and sequencing and by whole-genome sequencing. The MIC50, MIC90, and MIC ranges of delafloxacin were 0.06 μg/ml, 0.125 μg/ml, and ≤0.001 to 0.25 μg/ml, respectively. The frequency of spontaneous mutation ranged from 10(-7) to <10(-9) The multistep delafloxacin resistance selection of 30 daily passages resulted in stable resistant mutants. There was no obvious cross-resistance to nonfluoroquinolone comparator antimicrobials. A mutant with reduced susceptibility to ciprofloxacin (MIC, 0.25 μg/ml) obtained from the ciprofloxacin-susceptible parental strain had a novel Ser91Tyr alteration in the gyrA gene. We also identified new mutations in the gyrA and/or parC and parE genes and the multidrug-resistant efflux pumps (MtrC-MtrD-MtrE and NorM) of two mutant strains with elevated delafloxacin MICs of 1 μg/ml. Although delafloxacin exhibited potent in vitro activity against N. gonorrhoeae isolates and reference strains with diverse antimicrobial resistance profiles and demonstrated a low tendency to select for spontaneous mutants, it is important to establish the correlation between these excellent in vitro data and treatment outcomes through appropriate randomized controlled clinical trials.
authors.affiliation: Neisseria Reference Laboratory, Department of Global Health, University of Washington, Seattle, Washington, USA sogeo@uw.edu.
authors.forename: Olusegun O
authors.identifier: 0000-0002-8504-2319
authors.initials: OO
authors.lastname: Soge
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Salipante
authors.affiliation: Environmental & Occupational Health Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: David
authors.initials: D
authors.lastname: No
authors.affiliation: Melinta Therapeutics, New Haven, Connecticut, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Duffy
authors.affiliation: Environmental & Occupational Health Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Marilyn C
authors.initials: MC
authors.lastname: Roberts
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000890:Anti-Infective Agents / Q000494:pharmacology; D004351:Drug Resistance; D024841:Fluoroquinolones / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D009344:Neisseria gonorrhoeae / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D024841:Fluoroquinolones; C477891:delafloxacin