Microbiological Analysis from a Phase 2 Randomized Study in Adults Evaluating Single Oral Doses of Gepotidacin in the Treatment of Uncomplicated Urogenital Gonorrhea Caused by Neisseria gonorrhoeae

Antimicrob Agents Chemother. 2018 Nov 26;62(12):e01221-18. doi: 10.1128/AAC.01221-18. Print 2018 Dec.

Abstract

We evaluated microbiological correlates for the successful treatment of Neisseria gonorrhoeae isolates from a phase 2 study of gepotidacin, a novel triazaacenaphthylene antibacterial, for therapy of uncomplicated urogenital gonorrhea. Culture, susceptibility testing, genotypic characterization, and frequency of resistance (FoR) were performed for selected isolates. Microbiological success was defined as culture-confirmed eradication of N. gonorrhoeae Against 69 baseline urogenital isolates, gepotidacin MICs ranged from ≤0.06 to 1 µg/ml (MIC90 = 0.5 µg/ml). For gepotidacin, the ratio of the area under the free-drug concentration-time curve to the MIC (fAUC/MIC) was associated with therapeutic success. Success was 100% (61/61) at fAUC/MICs of ≥48 and decreased to 63% (5/8) for fAUC/MICs of ≤25. All 3 isolates from microbiological failures were ciprofloxacin resistant, had a baseline gepotidacin MIC of 1 µg/ml, and carried a preexisting ParC D86N mutation, a critical residue for gepotidacin binding. In a test-of-cure analysis, the resistance to gepotidacin emerged in 2 isolates (MICs increased ≥32-fold) with additional GyrA A92T mutations, also implicated in gepotidacin binding. Test-of-cure isolates had the same sequence type as the corresponding baseline isolates. For 5 selected baseline isolates, all carrying a ParC D86N mutation, the in vitro FoR to gepotidacin was low (10-9 to 10-10); the resistant mutants had the same A92T mutation as the 2 isolates in which resistance emerged. Five participants with isolates harboring the ParC D86N mutation were treatment successes. In summary, fAUC/MICs of ≥48 predicted 100% microbiological success, including 3 isolates with the ParC D86N mutation (fAUC/MICs ≥ 97). Pharmacokinetic/pharmacodynamic determinations may help to evaluate new therapies for gonorrhea; further study of gepotidacin is warranted. (This study has been registered at ClinicalTrials.gov under identifier NCT02294682.).

Keywords: Neisseria gonorrhoeae; microbiology; urogenital gonorrhea.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acenaphthenes / blood
  • Acenaphthenes / pharmacokinetics*
  • Acenaphthenes / pharmacology
  • Administration, Oral
  • Adult
  • Anti-Bacterial Agents / blood
  • Anti-Bacterial Agents / pharmacokinetics*
  • Anti-Bacterial Agents / pharmacology
  • Area Under Curve
  • Bacterial Typing Techniques
  • Blood Culture
  • Ciprofloxacin / therapeutic use
  • DNA Topoisomerase IV / genetics*
  • DNA Topoisomerase IV / metabolism
  • Drug Administration Schedule
  • Drug Resistance, Bacterial / genetics*
  • Female
  • Gene Expression
  • Gonorrhea / blood
  • Gonorrhea / drug therapy*
  • Gonorrhea / microbiology
  • Gonorrhea / pathology
  • Heterocyclic Compounds, 3-Ring / blood
  • Heterocyclic Compounds, 3-Ring / pharmacokinetics*
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Humans
  • Male
  • Microbial Sensitivity Tests
  • Mutation
  • Neisseria gonorrhoeae / drug effects*
  • Neisseria gonorrhoeae / enzymology
  • Neisseria gonorrhoeae / genetics
  • Neisseria gonorrhoeae / isolation & purification
  • Treatment Outcome

Substances

  • Acenaphthenes
  • Anti-Bacterial Agents
  • Heterocyclic Compounds, 3-Ring
  • Ciprofloxacin
  • gepotidacin
  • DNA Topoisomerase IV

Associated data

  • ClinicalTrials.gov/NCT02294682