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

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.

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

“…The WHO Global Action Plan to Control the Spread and Impact of Antimicrobial Resistance in N. gonorrhoeae ( WHO, 2012 ) and WHO Global Action Plan on Antimicrobial Resistance ( WHO, 2015 ) stress that new antimicrobials for treatment of urogenital and extragenital gonorrhea are imperative. Currently, solely two new antimicrobials, zoliflodacin ( Jacobsson et al, 2014 ; Alm et al, 2015 ; Basarab et al, 2015 ; Foerster et al, 2015 ; Unemo et al, 2015 ; Taylor et al, 2018 ; Foerster et al, 2019 ; O’Donnell et al, 2019 ; Unemo et al, 2019 ; Bradford et al, 2020 ; Jacobsson et al, 2021 ) and gepotidacin ( Jacobsson et al, 2018 ; Scangarella-Oman et al, 2018 ; Taylor et al, 2018 ), are in later stages of clinical development for treatment of uncomplicated gonorrhea.…”

“…No clinical N. gonorrhoeae isolates with zoliflodacin resistance have been reported when international gonococcal populations from the last decade have been examined ( Jacobsson et al, 2014 ; Unemo et al, 2015 ; Unemo et al, 2019 ; Bradford et al, 2020 ; Le et al, 2021 ). However, in static in vitro laboratory experiments zoliflodacin-resistant mutants have been selected; all containing substitutions of amino acids D429 or K450 of GyrB ( Alm et al, 2015 ; Foerster et al, 2015 ; Foerster et al, 2019 ; Jacobsson et al, 2021 ). No clinical isolate with amino acid substitution in GyrB K450 and only one single clinical isolate with a GyrB D429V substitution has been found ( Jacobsson et al, 2014 ; Alm et al, 2015 ; Unemo et al, 2015 ; Unemo et al, 2019 ; Bradford et al, 2020 ; Le et al, 2021 ; Adamson et al, 2021 ).…”

“…No N. gonorrhoeae isolates with in vitro resistance to zoliflodacin were found ( Taylor et al, 2018 ). To provide further understanding of the findings of the zoliflodacin phase 2 RCT ( Taylor et al, 2018 ), we developed, optimized and quality assured a dynamic in vitro hollow fiber infection model (HFIM) to simulate gonococcal infections and the pharmacokinetic (PK)/pharmacodynamic (PD) of antimicrobials acting against N. gonorrhoeae infections ( Jacobsson et al, 2021 ), using geographically, phenotypically and genomically diverse WHO N. gonorrhoeae reference strains ( Unemo et al, 2015 ) . This HFIM for N. gonorrhoeae was used to study the PK/PD of zoliflodacin treatment against N. gonorrhoeae strains with full susceptibility to zoliflodacin and no gyrB mutations ( Jacobsson et al, 2021 ).…”

“…To provide further understanding of the findings of the zoliflodacin phase 2 RCT ( Taylor et al, 2018 ), we developed, optimized and quality assured a dynamic in vitro hollow fiber infection model (HFIM) to simulate gonococcal infections and the pharmacokinetic (PK)/pharmacodynamic (PD) of antimicrobials acting against N. gonorrhoeae infections ( Jacobsson et al, 2021 ), using geographically, phenotypically and genomically diverse WHO N. gonorrhoeae reference strains ( Unemo et al, 2015 ) . This HFIM for N. gonorrhoeae was used to study the PK/PD of zoliflodacin treatment against N. gonorrhoeae strains with full susceptibility to zoliflodacin and no gyrB mutations ( Jacobsson et al, 2021 ). Further understanding of the microbiological cures and failures of the treatments in the zoliflodacin phase 2 RCT ( Taylor et al, 2018 ), the zoliflodacin concentration-dependent killing of N. gonorrhoeae , and importance of also examining suppression of resistance emergence was provided ( Jacobsson et al, 2021 ).…”

Fascinating Molecular and Immune Escape Mechanisms in the Treatment of STIs (Syphilis, Gonorrhea, Chlamydia, and Herpes Simplex)

“…Three years later, an in vitro study of 1209 consecutive clinical N. gonorrhoeae isolates did not reveal any cross-resistance to ciprofloxacin, azithromycin, cefixime, and ceftriaxone [ 135 ]. Patients should take at least 2 g of a single oral dose treatment of zoliflodacin to obtain effective N. gonorrhoeae suppression [ 136 ]. Additionally, studies revealed that the conventional therapeutic dose of 2 g does not induce cardiac arrhythmias and is well tolerated [ 137 ].…”