Abstract
Objectives
Resistance in Neisseria gonorrhoeae to all gonorrhoea therapeutic antimicrobials has emerged. Novel therapeutic antimicrobials are imperative and the first-in-class spiropyrimidinetrione zoliflodacin appears promising. Zoliflodacin could be introduced in dual antimicrobial therapies to prevent the emergence and/or spread of resistance. We investigated the in vitro activity of and selection of resistance to zoliflodacin alone and in combination with six gonorrhoea therapeutic antimicrobials against N. gonorrhoeae.
Methods
The international gonococcal reference strains WHO F (WT) and WHO O, WHO V and WHO X (strains with different AMR profiles) were examined. Zoliflodacin was evaluated alone or combined with ceftriaxone, cefixime, spectinomycin, gentamicin, tetracycline, cethromycin or sitafloxacin in chequerboard assays, time–kill curve analysis and selection-of-resistance studies.
Results
Zoliflodacin alone or in combination with all six antimicrobials showed rapid growth inhibition against all examined strains. The time–kill curve analysis indicated that tetracycline or cethromycin combined with zoliflodacin can significantly decrease the zoliflodacin kill rate in vitro. The frequency of selected zoliflodacin-resistance mutations was low when evaluated as a single agent and further reduced for all antimicrobial combinations. All resistant mutants contained the GyrB mutations D429N, K450T or K450N, resulting in zoliflodacin MICs of 0.5–4 mg/L.
Conclusions
Zoliflodacin, alone or in combination with sexually transmitted infection therapeutic antimicrobials, rapidly kills gonococci with infrequent resistance emergence. Zoliflodacin remains promising for gonorrhoea oral monotherapy and as part of dual antimicrobial therapy with low resistance emergence potential. A Phase III trial evaluating efficacy and safety of zoliflodacin for uncomplicated gonorrhoea treatment is planned in 2019.
Resistance in Neisseria gonorrhoeae to all gonorrhoea therapeutic antimicrobials has emerged. Novel therapeutic antimicrobials are imperative and the first-in-class spiropyrimidinetrione zoliflodacin appears promising. Zoliflodacin could be introduced in dual antimicrobial therapies to prevent the emergence and/or spread of resistance. We investigated the in vitro activity of and selection of resistance to zoliflodacin alone and in combination with six gonorrhoea therapeutic antimicrobials against N. gonorrhoeae.
Methods
The international gonococcal reference strains WHO F (WT) and WHO O, WHO V and WHO X (strains with different AMR profiles) were examined. Zoliflodacin was evaluated alone or combined with ceftriaxone, cefixime, spectinomycin, gentamicin, tetracycline, cethromycin or sitafloxacin in chequerboard assays, time–kill curve analysis and selection-of-resistance studies.
Results
Zoliflodacin alone or in combination with all six antimicrobials showed rapid growth inhibition against all examined strains. The time–kill curve analysis indicated that tetracycline or cethromycin combined with zoliflodacin can significantly decrease the zoliflodacin kill rate in vitro. The frequency of selected zoliflodacin-resistance mutations was low when evaluated as a single agent and further reduced for all antimicrobial combinations. All resistant mutants contained the GyrB mutations D429N, K450T or K450N, resulting in zoliflodacin MICs of 0.5–4 mg/L.
Conclusions
Zoliflodacin, alone or in combination with sexually transmitted infection therapeutic antimicrobials, rapidly kills gonococci with infrequent resistance emergence. Zoliflodacin remains promising for gonorrhoea oral monotherapy and as part of dual antimicrobial therapy with low resistance emergence potential. A Phase III trial evaluating efficacy and safety of zoliflodacin for uncomplicated gonorrhoea treatment is planned in 2019.
| Original language | English |
|---|---|
| Pages | 3521–3529 |
| Number of pages | 9 |
| Volume | 74 |
| No. | 12 |
| Specialist publication | Journal of Antimicrobial Chemotherapy |
| DOIs | |
| Publication status | Published - Dec 2019 |
ASJC Scopus subject areas
- Pharmacology
- Microbiology (medical)
- Infectious Diseases
- Pharmacology (medical)
Access to Document
- Foerster_et_al_In_vitro_antimicrobial_combination_testing_and_evolution_of_resistance_to_the_first-in-class_spiropyrimidinetrione_zoliflodacin_Journal_of_Antimicrobial_Chemotherapy_2019
This is a pre-copyedited, author-produced version of an article accepted for publication in Journal of Antimicrobial Chemotherapy following peer review. The version of record Sunniva Foerster, George Drusano, Daniel Golparian, Michael Neely, Laura J V Piddock, Emilie Alirol, Magnus Unemo, In vitro antimicrobial combination testing of and evolution of resistance to the first-in-class spiropyrimidinetrione zoliflodacin combined with six therapeutically relevant antimicrobials for Neisseria gonorrhoeae, Journal of Antimicrobial Chemotherapy, Volume 74, Issue 12, December 2019, Pages 3521–3529, https://doi.org/10.1093/jac/dkz376 is available online at: https://academic.oup.com/jac/article/74/12/3521/5561459