Genomic surveillance meets clinical practice: rule-based individualized treatment prediction for gonorrhoea using SensiTyper

Extensively drug-resistant (XDR) Neisseria gonorrhoeae strains threaten the current empirical gonorrhoea treatment. We designed and analytically validated SensiTyper, a rule-based framework that predicts antimicrobial susceptibility from whole-genome sequencing data and generates susceptibility-guided individualized treatment recommendations. SensiTyper was applied to 13,701 gonococcal genomes from 68 countries in 1928-2024, including cultured isolates and clinical molecular samples, and benchmarked predictions against previous genomic and phenotypic data. Susceptibility predictions for ceftriaxone, ciprofloxacin, spectinomycin, and zoliflodacin had 98.9-100% sensitivity and specificity. Azithromycin susceptibility predictions had 92.5% sensitivity and 97.1% specificity, and gepotidacin susceptibility prediction 100% sensitivity, but 0% specificity, illustrating that low-level phenotypic gepotidacin resistance is not caused by the only known resistance determinants (GyrA A92T plus ParC D86N). The SensiTreat module integrates antimicrobial susceptibility profiles into sequential treatment logic, providing susceptibility-guided individualized treatment recommendations while also enabling alternative stewardship strategies prioritizing, e.g., ciprofloxacin. SensiTyper flags XDR isolates for expert follow-up, test-of-cure and comprehensive contact tracing. In conclusion, SensiTyper is a robust and adaptable approach for gonococcal antimicrobial susceptibility prediction, individualized gonorrhoea treatment and antimicrobial stewardship.