Pharmacodynamic Evaluation of Dosing, Bacterial Kill, and Resistance Suppression for Zoliflodacin Against Neisseria gonorrhoeae in a Dynamic Hollow Fiber Infection Model
Susanne Jacobsson, Daniel Golparian, Joakim Oxelbark, Emilie Alirol, Francois Franceschi, Tomas N. Gustafsson, David Brown, Arnold Louie, George Drusano, Magnus Unemo.
Frontiers in Pharmacology, 21 May, 2021. https://doi.org/10.3389/fphar.2021.682135
Abstract
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 7days. Dose-range experiments with both strains, simulating zoliflodacin single oral dose regimens of 0.5–8g, and dose-fractionation experiments with WHO X, simulating zoliflodacin oral dose therapy with 1–4g administered as q12h and q8h for 24h, were performed. A kill-rate constant that reflected a rapid bacterial kill during the first 6.5h for both strains and all zoliflodacin doses was identified. In the dose-range experiments, the zoliflodacin 2–8g single-dose treatments successfully eradicated both WHO strains, and resistance to zoliflodacin was not observed. However, zoliflodacin as a single 0.5g dose failed to eradicate both WHO strains, and a 1g single dose failed to eradicate WHO X in one of two experiments. The zoliflodacin 1g/day regimen also failed to eradicate WHO X when administered as two and three divided doses given at q12h and q8h 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 >2g 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.