Doxycycline use for bacterial sexually transmitted infections (STIs) increased in recent years due to changes in treatment guidelines, the shortage of benzathine penicillin for treatment of syphilis, and adoption of doxycycline post-exposure prophylaxis. While this increased use is expected to select for doxycycline resistance, particularly in Neisseria gonorrhoeae, the impact has been unclear. Here, we analyzed over 14,000 publicly available N. gonorrhoeae genome sequences from 2018-2024 generated through the US Centers for Disease Control and Prevention N. gonorrhoeae surveillance system, assessed the distribution of tetM, a plasmid-borne gene that confers high-level (MIC ≥ 16µg/mL) tetracycline resistance, and evaluated the spatial, temporal, and evolutionary dynamics of its spread. The proportion of Neisseria gonorrhoeae carrying tetM increased from below 10% in 2020 to over 35% in 2024.

Phylogenetic analysis revealed four major clades that have rapidly expanded. Two of these lineages also carry penA alleles that increase resistance to ceftriaxone. The strength of selection for tetracycline resistance, as indicated by its increased proportion and the growth of major tetM-carrying lineages, suggests a favorable environment for N. gonorrhoeae strains spreading globally that carry tetM and resistance to multiple other antibiotics used in gonorrhea treatment.

The authors have declared no competing interest.

This work was supported by NIH R01 AI132606 and R01 AI153521 to Y.H.G

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The data required to reproduce this analysis is publicly available through the NCBI Pathogen Detection database with detailed instructions available in the Supplementary Appendix.