ABSTRACT

Zoliflodacin (previously ETX0914, AZD0914) refers to a first-in-class Spiropyrimidinetrione antibiotic developed to fight the growing global threat of antimicrobial-resistant Neisseria gonorrhoeae. This review summarizes evidence from around 30 main studies highlighting the drug’s mode of action, antimicrobial activity, pharmacokinetics and pharmacodynamics, clinical efficacy, safety profile, and resistance patterns. Zoliflodacin works specifically by inhibiting bacterial DNA gyrase subunit B (GyrB) and presents an antibacterial activity through a different mechanism as compared to fluoroquinolones and is associated with a lack of cross-resistance seen in currently used anti-gonococcal therapies. In vitro experiments show strong activity against multidrug resistant gonococcal isolates that showed MIC₅₀ values from 0.03 to 0.125 µg/mL and MIC₉₀ values from 0.06 to 0.25 µg/mL in different geographical regions. Pharmacokinetic and pharmacodynamic analyses validate dose at 3 g of oral dosage, reportedly showing high probability of being reached in MIC distributions. Clinical evidence from Phase 3 randomized, non-inferiority trials demonstrates Zoliflodacin to be non-inferior to ceftriaxone plus azithromycin for uncomplicated urogenital gonorrhoea, with Cure rates at extragenital sites were comparable between groups; however, the study was not powered to establish non-inferiority at these anatomical sites. Genomic and phenotypic monitoring demonstrated high level of GyrB-target conservation and a very low prevalence of resistance-associated mutations. In summary, the evidence obtained supports Zoliflodacin as an orally effective therapeutic alternative for gonorrhoea in the face of increasing antimicrobial resistance.