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Pharmacodynamic Eva...
Pharmacodynamic Evaluation of Dosing, Bacterial Kill, and Resistance Suppression for Zoliflodacin Against Neisseria gonorrhoeae in a Dynamic Hollow Fiber Infection Model
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- Jacobsson, Susanne, 1974- (author)
- Örebro universitet,Institutionen för medicinska vetenskaper,Region Örebro län,WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
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- Golparian, Daniel, 1984- (author)
- Örebro universitet,Institutionen för medicinska vetenskaper,WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
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- Oxelbark, Joakim, 1970- (author)
- Örebro universitet,Institutionen för hälsovetenskaper,Region Örebro län,Division of Clinical Chemistry, Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
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- Alirol, Emilie (author)
- Global Antibiotic Research and Development Partnership (GARDP), Geneva, Switzerland
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- Franceschi, Francois (author)
- Global Antibiotic Research and Development Partnership (GARDP), Geneva, Switzerland
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- Gustafsson, Tomas N. (author)
- Umeå universitet,Institutionen för klinisk mikrobiologi
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- Brown, David (author)
- Institute for Therapeutic Innovation, College of Medicine, University of Florida, Orlando, FL, United States
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- Louie, Arnold (author)
- Institute for Therapeutic Innovation, College of Medicine, University of Florida, Orlando, FL, United States
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- Drusano, George (author)
- Institute for Therapeutic Innovation, College of Medicine, University of Florida, Orlando, FL, United States
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- Unemo, Magnus, 1970- (author)
- Örebro universitet,Institutionen för medicinska vetenskaper,Region Örebro län,WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
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(creator_code:org_t)
- 2021-05-21
- 2021
- English.
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In: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 12
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Infektionsmedicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Infectious Medicine (hsv//eng)
Keyword
- Neisseria gonorrhoeae
- antimicrobial treatment
- hollow fiber infection model
- pharmacodynamics
- pharmacokinetics
- zoliflodacin
Publication and Content Type
- ref (subject category)
- art (subject category)
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Jacobsson, Susan ...
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Golparian, Danie ...
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Oxelbark, Joakim ...
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Alirol, Emilie
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Franceschi, Fran ...
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Gustafsson, Toma ...
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Brown, David
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Louie, Arnold
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Drusano, George
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Unemo, Magnus, 1 ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Infectious Medic ...
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Frontiers in Pha ...
- By the university
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Örebro University
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Umeå University