Pharmacodynamic Evaluation of Zoliflodacin Treatment of Neisseria gonorrhoeae Strains With Amino Acid Substitutions in the Zoliflodacin Target GyrB Using a Dynamic Hollow Fiber Infection Model

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 exa...

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Vydané v:Frontiers in pharmacology Ročník 13; s. 874176
Hlavní autori: Jacobsson, Susanne, Golparian, Daniel, Oxelbark, Joakim, Franceschi, Francois, Brown, David, Louie, Arnold, Drusano, George, Unemo, Magnus
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: Switzerland Frontiers Media S.A 14.04.2022
Predmet:
antimicrobial treatment
gyrB
hollow fiber infection model
mutant
Neisseria gonorrhoeae
pharmacodynamics
pharmacokinetics
Pharmacology
zoliflodacin
gyrB
Neisseria gonorrhoeae
zoliflodacin
pharmacodynamics
pharmacokinetics
hollow fiber infection model
mutant
antimicrobial treatment
ISSN:1663-9812, 1663-9812
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Shrnutí: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 10 10 –10 11  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.
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Edited by: Mukhlesur Rahman, University of East London, United Kingdom
Sheeba Santhini Manoharan-Basil, Institute of Tropical Medicine Antwerp, Belgium
This article was submitted to Experimental Pharmacology and Drug Discovery, a section of the journal Frontiers in Pharmacology
Reviewed by: Junping Peng, Institute of Pathogen Biology (CAMS), China
ISSN:1663-9812
1663-9812
DOI:10.3389/fphar.2022.874176