Background: Post-exposure prophylaxis with doxycycline (doxyPEP) has been shown to reduce cases of bacterial sexually transmitted infections; however, due to pre-existing tetracycline resistance in Neisseria gonorrhoeae, routine use of doxyPEP may select in the near term for lineages with tetracycline or multi-drug resistance.
Methods: We analyzed genomes and minimum inhibitory concentrations (MICs) from 5,439 N. gonorrhoeae isolates to identify lineages with chromosomally-mediated tetracycline resistance (MIC≥2 µg/ml) and tetM-mediated high-level resistance (MIC >8 µg/ml). We examined co-resistance to ceftriaxone, azithromycin, and ciprofloxacin. Lastly, we described the prevalence of these lineages among demographic groups in the United States in 1,041 isolates sequenced by CDC’s Gonococcal Isolate Surveillance Program (GISP).
Results: Tetracycline resistance has been acquired throughout the N. gonorrhoeae phylogeny. The presence of tetM is associated with high-level tetracycline resistance; 97.6% (957/984) of isolates with tetracycline MIC >8 µg/ml encode tetM, and only 6.6% (68/1025) encoding tetM have a reported MIC≤8 µg/ml. Co-resistance to other antimicrobials is most common in isolates with chromosomally-mediated tetracycline resistance. MICs to ceftriaxone, azithromycin, and ciprofloxacin are significantly higher in isolates with tetracycline MICs=2-8 µg/ml compared to isolates that are not resistant to tetracycline and to isolates with high-level tetracycline resistance (p< 0.0001). Ceftriaxone reduced susceptibility (MIC≥0.125 µg/mL) was rare in GISP isolates (n=2), but global data suggest that reduced susceptibility is most often acquired by strains with chromosomally-mediated tetracycline resistance, including the emerging lineage encoding the penA 60 allele. The proportion of isolates with tetracycline resistance is not significantly different between men who have sex with men (27.3%, 94/344) and men who have sex with women (21.9%, 130/593).
Conclusion: The near-term impact of doxyPEP on N. gonorrhoeae antimicrobial resistance and circulating lineages will be influenced by the strength of selection for high-level tetracycline resistance. If doxyPEP use selects for all tetracycline resistant lineages, there is potential for increased resistance to other antimicrobials as well. However, if doxyPEP use primarily selects for lineages with tetM-mediated resistance, we may observe reduced resistance to other antimicrobials due to limited co-resistance in these lineages. Genomic surveillance among doxyPEP users is needed to distinguish between these outcomes and monitor for de novo resistance acquisition.
