title: In vitro activities of the novel bicyclolides modithromycin (EDP-420, EP-013420, S-013420) and EDP-322 against MDR clinical Neisseria gonorrhoeae isolates and international reference strains.
abstract: OBJECTIVE
  New antimicrobials are essential to prevent gonorrhoea becoming an untreatable infection. Herein, the in vitro activities of the novel bicyclolides modithromycin (EDP-420, EP-013420, S-013420) and EDP-322 against Neisseria gonorrhoeae strains were investigated and compared with antimicrobials currently or previously recommended for treatment of gonorrhoea.
  
  
  METHODS
  MICs (mg/L) were determined using an agar dilution method (modithromycin and EDP-322) or Etest (seven antimicrobials) for a large geographically, temporally and genetically diverse collection of clinical N. gonorrhoeae isolates (n = 225) and international reference strains (n = 29), including diverse MDR and XDR isolates.
  
  
  RESULTS
  The MIC range, modal MIC, MIC50 and MIC90 of modithromycin and EDP-322 were 0.004-256, 0.25, 0.25 and 1 mg/L and 0.008-16, 0.5, 0.5 and 1 mg/L, respectively. The activities of modithromycin and EDP-322 were mainly superior to those of azithromycin and additional antimicrobials investigated. In general, there was no cross-resistance with other antimicrobials.
  
  
  CONCLUSIONS
  Modithromycin and EDP-322 exhibited high levels of in vitro activities against N. gonorrhoeae, including isolates resistant to azithromycin, cefixime, ceftriaxone, spectinomycin, ampicillin, tetracycline and ciprofloxacin. However, some cross-resistance with high-level azithromycin resistance (MIC = 4096 mg/L) was observed. Modithromycin and EDP-322 could be effective options for treatment of gonorrhoea, particularly for cases resistant to extended-spectrum cephalosporins and as a part of an antimicrobial combination therapy regimen. Nevertheless, it is important to detail the in vitro selection, in vivo emergence and mechanisms of resistance, pharmacokinetics/pharmacodynamics in humans and optimal dosing, and perform appropriate randomized controlled clinical trials.
authors.affiliation: WHO Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
authors.forename: Susanne
authors.initials: S
authors.lastname: Jacobsson
authors.affiliation: WHO Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Golparian
authors.affiliation: Enanta Pharmaceuticals, Inc., Watertown, MA, USA.
authors.forename: Ly T
authors.initials: LT
authors.lastname: Phan
authors.affiliation: National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ohnishi
authors.affiliation: WHO Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Fredlund
authors.affiliation: Enanta Pharmaceuticals, Inc., Watertown, MA, USA.
authors.forename: Yat Sun
authors.initials: YS
authors.lastname: Or
authors.affiliation: WHO Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden magnus.unemo@orebroll.se.
authors.forename: Magnus
authors.initials: M
authors.lastname: Unemo
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial; D006069:Gonorrhea / Q000382:microbiology; D006801:Humans; D018942:Macrolides / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D009344:Neisseria gonorrhoeae / Q000187:drug effects* / Q000302:isolation & purification
chemical_list: D000900:Anti-Bacterial Agents; D001952:Bridged-Ring Compounds; C520838:EDP 420; D018942:Macrolides
keywords: N. gonorrhoeae; antimicrobial resistance; gonorrhoea; treatment