Pharmacodynamic Evaluation of Dosing, Bacterial Kill, and Resistance Suppression for Zoliflodacin Against Neisseria gonorrhoeae in a Dynamic Hollow Fiber Infection Model

Antimicrobial resistance in Neisseria gonorrhoeae is threatening the treatment and control of gonorrhea globally, and new treatment options are imperative. Utilizing our dynamic in vitro hollow fiber infection model (HFIM), we examined the pharmacodynamics of the first-in-class spiropyrimidinetrione...

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Vydáno v:Frontiers in pharmacology Ročník 12; s. 682135
Hlavní autoři: Jacobsson, Susanne, Golparian, Daniel, Oxelbark, Joakim, Alirol, Emilie, Franceschi, Francois, Gustafsson, Tomas N., Brown, David, Louie, Arnold, Drusano, George, Unemo, Magnus
Médium: Journal Article
Jazyk:angličtina
Vydáno: Switzerland Frontiers Media S.A 21.05.2021
Témata:
antimicrobial treatment
hollow fiber infection model
Neisseria gonorrhoeae
pharmacodynamics
pharmacokinetics
Pharmacology
zoliflodacin
pharmacokinetics
hollow fiber infection model
Neisseria gonorrhoeae
zoliflodacin
pharmacodynamics
antimicrobial treatment
ISSN:1663-9812, 1663-9812
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Shrnutí:Antimicrobial resistance in Neisseria gonorrhoeae is threatening the treatment and control of gonorrhea globally, and new treatment options are imperative. Utilizing our dynamic in vitro hollow fiber infection model (HFIM), we examined the pharmacodynamics of the first-in-class spiropyrimidinetrione (DNA gyrase B inhibitors), zoliflodacin, against the N. gonorrhoeae reference strains World Health Organization F (susceptible to all relevant antimicrobials) and WHO X (extensively drug resistant, including resistance to ceftriaxone) over 7 days. Dose-range experiments with both strains, simulating zoliflodacin single oral dose regimens of 0.5–8 g, and dose-fractionation experiments with WHO X, simulating zoliflodacin oral dose therapy with 1–4 g administered as q12 h and q8 h for 24 h, were performed. A kill-rate constant that reflected a rapid bacterial kill during the first 6.5 h for both strains and all zoliflodacin doses was identified. In the dose-range experiments, the zoliflodacin 2–8 g single-dose treatments successfully eradicated both WHO strains, and resistance to zoliflodacin was not observed. However, zoliflodacin as a single 0.5 g dose failed to eradicate both WHO strains, and a 1 g single dose failed to eradicate WHO X in one of two experiments. The zoliflodacin 1 g/day regimen also failed to eradicate WHO X when administered as two and three divided doses given at q12 h and q8 h in the dose-fractionation studies, respectively. All failed regimens selected for zoliflodacin-resistant mutants. In conclusion, these data demonstrate that zoliflodacin should be administered at >2 g as a single oral dose to provide effective killing and resistance suppression of N. gonorrhoeae . Future studies providing pharmacokinetic data for zoliflodacin (and other gonorrhea therapeutic antimicrobials) in urogenital and extragenital infection sites, particularly in the pharynx, and evaluation of gonococcal strains with different gyrB mutations would be important.
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Present Address: Emilie Alirol, Medicines for Malaria Venture, Geneva, Switzerland
Chris Kenyon, Institute of Tropical Medicine Antwerp, Belgium
Reviewed by: Pio Maria Furneri, University of Catania, Italy
This article was submitted to Experimental Pharmacology and Drug Discovery, a section of the journal Frontiers in Pharmacology
Edited by: Priyia Pusparajah, Monash University Malaysia, Malaysia
ISSN:1663-9812
1663-9812
DOI:10.3389/fphar.2021.682135