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 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.
Highlights
In 2016, Neisseria gonorrhoeae was estimated to cause 87 million new global gonorrhea cases among adults each year (Rowley et al, 2016), an increase of 12% compared to the 78 million estimated cases in 2012 (Newman et al, 2015)
The antibiotic was administered to the hollow fiber infection model (HFIM) by a syringe pump, and peristaltic pumps isovolumetrically replaced drug-containing broth medium with drug-free medium to simulate the plasma halflife and free drug concentration–time profiles for zoliflodacin reported in humans throughout the study
One N. gonorrhoeae reference strain that is susceptible to zoliflodacin and other modern antimicrobials (WHO F) and one XDR reference strain susceptible to zoliflodacin but resistant to ceftriaxone, cefixime, and ciprofloxacin (WHO X) were examined
Summary
In 2016, Neisseria gonorrhoeae was estimated to cause 87 million new global gonorrhea cases among adults each year (Rowley et al, 2016), an increase of 12% compared to the 78 million estimated cases in 2012 (Newman et al, 2015). In addition to the increasing incidence internationally, the emergence and spread of antimicrobial resistance (AMR) in N. gonorrhoeae globally seriously threatens the management and control of gonorrhea (Wi et al, 2017; Day et al, 2018; Unemo et al, 2019). This development prompted the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) to categorize N. gonorrhoeae as a priority 2 (high) pathogen and an urgent threat, respectively (WHO, 2017; CDC, 2019).
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