Use of tetracyclines in sexually transmitted infection (STI) prevention and treatment has evolved since the 1940s.^1,2,3 Most recently, doxycycline—a broad-spectrum tetracycline antimicrobial—has been recommended for use by the United States (US) Centers for Disease Control and Prevention (CDC) as post-exposure prophylaxis (doxy PEP) to prevent bacterial STIs.³ With the anticipation of expanded use of doxycycline in STI care, there is concern for the potential development of antimicrobial resistance (AR) among bacterial STIs and other bacterial pathogens.

Ceftriaxone (a third-generation cephalosporin) is the sole recommended and last remaining antibiotic for empiric treatment of gonorrhea.² Fortunately, there have been no resistance-related ceftriaxone treatment failures identified in the US to date.¹ It is possible that the introduction of doxy PEP may facilitate development of resistance to tetracyclines and other antimicrobial agents among circulating Neisseria gonorrhoeae (GC). GC genomic sequencing data from Europe have shown associations between the presence of tetracycline-resistance mutations and other resistance-associated mutations.⁴ Another global study found that GC strains with decreased susceptibility or resistance to ceftriaxone typically exhibit dual resistance to tetracyclines.⁵ Limited data from clinical trials show a higher proportion of GC isolates with tetracycline resistance among doxy PEP groups.^6,7 Monitoring for the development of antimicrobial-resistant GC is imperative so as to ensure efficacy of recommended treatment regimens.

National sentinel surveillance projects have provided valuable insight into AR trends among GC isolates in the US. CDC’s Gonococcal Isolate Surveillance Project (GISP) has monitored trends in antimicrobial-resistant GC among male gonococcal urethral isolates collected at STI clinics in the US since 1986. Enhanced GISP (eGISP) and Strengthening the US Response to Resistant Gonorrhea (SURRG) expanded antimicrobial-resistant GC surveillance within the last decade by monitoring trends among genital and extragenital isolates collected from patients attending STI clinics (eGISP and SURRG) and high-gonorrhea morbidity non-STI clinic sites (SURRG).^8,9

In anticipation of expanded use of doxy PEP, we describe the epidemiology of tetracycline resistance among GC isolates in the US. Specifically, we used available data from three sentinel surveillance programs in the US (GISP, eGISP and SURRG) to examine:

Our analysis using national sentinel surveillance data shows that TetR among GC isolates has remained stable since 1987, currently at about 20% of sampled GC isolates. Interestingly, the proportion of isolates demonstrating TetHLR has increased over time, now representing a majority of identified TetR. TetHLR increased across US census regions and anatomic sites of infection. Further, though TetR varied by sex/sex of sex partner(s), as consistent with published data,^10,15 TetHLR increased among all sex/sex of sex partner(s) groups.

TetHLR among GC isolates was first described during the mid-1980s in the US, with the emergence of the conjugative plasmid-encoded TetM determinant.¹² High and increasing proportions of TetHLR have been described in other countries, with selection pressure from doxycycline use and introduction of gonococcal lineages from other regions considered potential contributing factors.^16,17,18 A recently published analysis of publicly-available US GC genomic sequence data from 2018 through 2024 has similarly shown an increasing proportion of isolates carrying the TetM gene as well as expansion of tetM-carrying lineages.¹⁹

Mechanisms of TetR (chromosomally encoded vs plasmid encoded resistance) may be associated with differences in co-resistance or reduced susceptibility to other antimicrobial agents. In one study, ceftriaxone—our last remaining empiric GC treatment—was noted to have higher MICs among GC isolates with chromosomally encoded TetR.²⁰ Though the proportion of GC isolates exhibiting decreased susceptibility to ceftriaxone remains low in the US,^9,10 ongoing antimicrobial-resistant GC surveillance remains crucial. Alongside phenotypic AR surveillance, expanding molecular surveillance, including whole genome sequencing (WGS) capacity, will be important. Paired phenotypic and genetic data can improve our understanding of genetic determinants of AR, including the identification of novel mutations. Further, through WGS, GC strain diversity can be tracked across sexual networks, geographical regions and time. These data can help to identify outbreaks, provide insight into changing AR patterns and inform the development of molecular assays for improved antimicrobial-resistant GC detection. Development and implementation of robust PCR-based tests for plasmid-mediated TetR would allow for improved estimates of TetHLR prevalence through the testing of remnant clinical specimens. As doxycycline use expands, a robust surveillance system that includes both phenotypic and molecular surveillance will be critical to understand TetR/TetHLR and other AR patterns and inform our collective public health response to antimicrobial-resistant GC.

There is concern that GC infections at extragenital sites, particularly oropharyngeal infections, are harder to eradicate compared to genital infections and may facilitate the development of antimicrobial-resistant GC.^21,22 Our data suggest potential differences in TetR and TetHLR by anatomic site; however, interpretation is limited as the contribution of isolates by sex/sex of sex partner(s) groups varied by anatomic site of infection. Differences in gonorrhea screening recommendations by population and potential differences in screening protocols/practices across participating jurisdictions may have contributed to selection bias.² Further investigation is needed to better understand the role of extragenital GC infections in the development of antimicrobial-resistant GC, including in the context of increased doxycycline use for STI prevention.

Efficacy of doxycycline in preventing gonorrhea has varied among doxy PEP clinical trials, in part due to geographic differences in prevalence of pre-existing gonococcal TetR.^6,7,23 Modeling has demonstrated that a higher prevalence of TetHLR prior to introduction of doxy PEP attenuates the benefit of doxy PEP in reducing the burden of gonococcal infections in a population.²⁴ Our analysis shows that tetracycline-resistant GC is circulating in the US and that most identified resistant isolates are now demonstrating high-level resistance, including among populations for which doxy PEP is recommended.³ As doxy PEP implementation expands, ongoing evaluations of real-world effectiveness of doxy PEP in preventing GC and continued surveillance of TetHLR prevalence will be important to understand the potential impact of TetHLR prevalence on doxy PEP. It is important that doxy PEP complement other established preventative measures and STI screening continues as recommended.^3,25

Though our analysis is strengthened by use of a large, population-based sample identified through national sentinel surveillance, there are limitations to consider. Sampling methods for eGISP and SURRG did not allow for interpretation of percentage of TetR or TetHLR as prevalence.^8,9 Urethral GC isolates collected from men through GISP and eGISP were limited to men with symptomatic urethritis, which may have introduced bias if gonococcal strain types differentially cause symptomatic or asymptomatic infections. Known challenges in isolating GC through culture, particularly at extragenital sites, may limit our sample from representing all circulating strains of GC infections in the US;^26,27,28 this may have affected our findings if sensitivity of GC culture varies among gonococcal strains. Our sample is largely limited to public STI clinics and biased towards areas with high GC morbidity; findings may not all be generalizable to populations outside of these settings. Estimates of antimicrobial-resistant GC through GISP have been shown to be nationally representative of men in the US who are reported with urogenital gonorrhea;²⁹ similar evaluations of antimicrobial-resistant GC estimates through eGISP and SURRG are needed. As discussed, our interpretation of differences in TetR and TetHLR patterns by anatomic site is limited due to differential contribution of isolates by sex/sex of sex partner(s) groups across anatomic sites of infection, and future analyses examining patterns of TetR and TetHLR by additional stratifications will be important. Data collection practices for sex and sex of sex partner(s) variables differed by project and project site and may affect observed differences across sex/sex of sex partner(s) groups. Future national and regional estimates may be enhanced by additional data on sex of sex of partner(s). Finally, our estimates are based on GC isolates collected through US national surveillance and thus, do not represent global TetR patterns, as demonstrated through a recent systematic review of global estimates of tetracycline-resistant GC.³⁰

In sum, our analysis showed that while the overall level of TetR has remained stable over time, a growing proportion of GC isolates collected through national surveillance are demonstrating TetHLR. This increase in TetHLR was observed across US census regions and across sex/sex of sex partner(s) groups. As doxycycline use in STI care expands, enhanced surveillance methods will be imperative to both monitor and better understand the downstream impact on antimicrobial-resistant GC.