Dual therapy is associated with synchronous gonococcal susceptible-zone MIC dynamics: Norway, 2013-2025

Neisseria gonorrhoeae has repeatedly overcome every antibiotic class deployed against it. Antimicrobial resistance surveillance systems that focus on resistance prevalence may contribute to delayed realisation that a bacterial population is adapting to empiric treatment regimes. As new antibiotics zoliflodacin and gepotidacin will soon be launched in Norway, this study aimed to explore how surveillance might detect subtle gonococcal minimum inhibitory concentration (MIC) shifts, by focusing on the susceptible-zone, using the dual therapy era as a 'natural experiment'. We also aimed to map the population antibiotic co-resistance landscapes that will confront the new antimicrobial agents.

In this retrospective, population-based, descriptive study, the recently introduced 'susceptible isolate pressure indicator' ratio (SIPI) was applied to 13 years of per-isolate Norwegian gonococcal surveillance data (2013-2025; n = 8,230 isolates) to characterise susceptible-zone MIC dynamics during and after the dual therapy era. Annual Kendall τ-b correlations between full MIC distributions of the dual therapy agents and legacy antibiotics were plotted to characterise the evolving cross-resistance landscape.

Ceftriaxone and azithromycin SIPI trajectories moved in close synchrony throughout the dual-therapy period and diverged after the 2020 treatment policy change. Divergence timing differed by anatomical site. Male anal and pharyngeal isolates followed distinct trajectories. Post-dual therapy, ceftriaxone and azithromycin SIPI trends were consistent with model predictions for changing selective pressure.

Susceptible-zone MIC distributions may contain resistance emergence information not captured by conventional surveillance metrics. The SIPI ratio may offer an innovative framework for monitoring future treatment policy decisions.