Pharmacodynamic Evaluation of Zoliflodacin Treatment of Neisseria gonorrhoeae Strains With Amino Acid Substitutions in the Zoliflodacin Target GyrB Using a Dynamic Hollow Fiber Infection ModelShow others and affiliations
2022 (English)In: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 13, article id 874176
Article in journal (Refereed) Published
Abstract [en]
Novel antimicrobials for effective treatment of uncomplicated gonorrhea are essential, and the first-in-class, oral spiropyrimidinetrione DNA gyrase B inhibitor zoliflodacin appears promising. Using our newly developed Hollow Fiber Infection Model (HFIM), the pharmacodynamics of zoliflodacin was examined. A clinical zoliflodacin-susceptible N. gonorrhoeae strain, SE600/18 (harbouring a GyrB S467N amino acid substitution; MIC = 0.25 mg/L), and SE600/18-D429N (zoliflodacin-resistant mutant with a second GyrB substitution, D429N, selected in the HFIM experiments; zoliflodacin MIC = 2 mg/L), were examined. Dose-range experiments, simulating zoliflodacin single oral dose regimens of 0.5, 1, 2, 3, and 4 g, were performed for SE600/18. For SE600/18-D429N, dose-range experiments, simulating zoliflodacin single oral 2, 3, 4, and 6 g doses, and zoliflodacin oral dose-fractionation experiments with 4, 6, and 8 g administered as q12 h were performed. Both strains grew well in the untreated HFIM growth control arms and mostly maintained growth at 1010-1011 CFU/ml for 7 days. Zoliflodacin 3 and 4 g single dose oral regimens successfully eradicated SE600/18 and no growth was recovered during the 7-days experiments. However, the single oral 0.5, 1, and 2 g doses failed to eradicate SE600/18, and zoliflodacin-resistant populations with a GyrB D429N substitution were selected with all these doses. The zoliflodacin-resistant SE600/18-D429N mutant was not eradicated with any examined treatment regimen. However, this in vitro-selected zoliflodacin-resistant mutant was substantially less fit compared to the zoliflodacin-susceptible SE600/18 parent strain. In conclusion, the rare clinical gonococcal strains with GyrB S467N substitution are predisposed to develop zoliflodacin resistance and may require treatment with zoliflodacin ≥3 g. Future development may need to consider the inclusion of diagnostics directed at identifying strains resistant or predisposed to resistance development at a population level and to strengthen surveillance (phenotypically and genetically), and possibly also at the patient level to guide treatment.
Place, publisher, year, edition, pages
Frontiers Media S.A., 2022. Vol. 13, article id 874176
Keywords [en]
Neisseria gonorrhoeae, antimicrobial treatment, gyrB, hollow fiber infection model, mutant, pharmacodynamics, pharmacokinetics, zoliflodacin
National Category
Infectious Medicine
Identifiers
URN: urn:nbn:se:oru:diva-98849DOI: 10.3389/fphar.2022.874176ISI: 000796239800001PubMedID: 35496288Scopus ID: 2-s2.0-85128950080OAI: oai:DiVA.org:oru-98849DiVA, id: diva2:1655948
Note
Funding agencies:
Global Antibiotic Research and Development Partnership (GARDP), Geneva, Switzerland
Örebro County Council Research Committee, Örebro, Sweden
Foundation for Medical Research at Örebro University Hospital, Örebro, Sweden
2022-05-042022-05-042024-01-17Bibliographically approved