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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 (doxy-PEP). 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 conferring high-level (MIC ≥ 16μg/mL) tetracycline resistance, and evaluated the spatial, temporal, and evolutionary dynamics of its spread (Supplementary Appendix). The mean estimated proportion of isolates in this collection carrying tetM increased from below 10% in 2020 to >30% in the first quarter of 2024 (Figure 1A), with the highest prevalence in Health and Human Services Region 10 (Supplementary Appendix), consistent with a recent report from Seattle1. The increase in tetM prevalence in 2020 coincides with the shift away from azithromycin and towards doxycycline for treatment of chlamydia2, and the increase starting in the summer of 2022 coincides with the reporting of the DoxyPEP trial’s results3.

pplementary Appendix), consistent with a recent report from Seattle1. The increase in tetM prevalence in 2020 coincides with the shift away from azithromycin and towards doxycycline for treatment of chlamydia2, and the increase starting in the summer of 2022 coincides with the reporting of the DoxyPEP trial’s results3. Over the study period, the number of large tetM-carrying lineages increased from one to four (Figure 1B). The major tetM lineage before 2020 accounted for 41% of tetM-carrying isolates, with the remainder sporadic isolates and small lineages. In contrast, the four major tetM lineages after 2020 together account for 83% of tetM-carrying isolates, indicating substantial expansion of these lineages. Of the four major lineages, two carry variants in penA, which encodes PBP2, the main target of ceftriaxone, that increase ceftriaxone resistance: A501V and mosaic penA 34 (Figure 1B; Supplementary Appendix)4. These results suggest that widespread use of doxycycline for the treatment and prevention of STIs may be contributing to reshaping of the gonococcal population in the US.

ch encodes PBP2, the main target of ceftriaxone, that increase ceftriaxone resistance: A501V and mosaic penA 34 (Figure 1B; Supplementary Appendix)4. These results suggest that widespread use of doxycycline for the treatment and prevention of STIs may be contributing to reshaping of the gonococcal population in the US. Extremely drug-resistant N. gonorrhoeae lineages carrying both tetM and penA alleles such as mosaic penA 60 associated with a ceftriaxone MIC of 0.5–1 μg/mL, together with resistance to fluoroquinolones and macrolides, have been spreading globally5. The strength of selection in the US for tetM, as indicated by its increasing proportion and the expansion of major tetM-carrying lineages, suggests a favorable environment for these highly drug-resistant strains to spread within the US and highlights the need for continued surveillance.