Doxycycline post-exposure prophylaxis in Seattle is linked to a halving of syphilis diagnoses overall and a reduction of cases by a third in transgender people. Despite very low uptake, women also experienced a significant drop in syphilis cases, likely partly explained by reduced syphilis transmission within the communities where doxyPEP is being used.
In the study published in the journal of Clinical Infectious Diseases, Dr Timothy Menza and colleagues from Public Health – Seattle and King County and the University of Washington add more population-level evidence suggesting that the use of doxyPEP can significantly lower syphilis diagnoses. They estimate that doxyPEP use was associated with 52% fewer syphilis cases overall, with reductions of 53% in men, 47% in women and 33% in transgender and non-binary people.
DoxyPEP contains a single antibiotic called doxycycline dosed at 200mg once within 72 hours after condomless sex. The antibiotic helps prevent some of the major sexually transmitted bacterial infections – syphilis, chlamydia and to a lesser extent (due to increasing prevalence of resistance) gonorrhoea. It is mainly offered to sexually active gay and bisexual men and transgender people at a higher risk of infection. However, while it has been effective at reducing the burden of syphilis in areas where it was implemented, it is not fail-proof and it’s possible that not taking it in time may be one of the reasons for failure.
The Centres for Disease Control and Prevention (CDC) defines ‘in time’ as within 72 hours after risky exposure; however, the bacterium may already be spreading in the body within the first 24 hours. Even though doxycycline may still reach levels high enough to fight the bacterium, a single dose, especially if taken a little late, may not be able to completely rid the body of all syphilis bacteria.
In a previous small study, genital and rectal concentrations of doxycycline remained above effective levels for up to three days after dosing. However, blood concentrations were substantially lower, suggesting that if the bacterium had already spread beyond local tissues before doxyPEP was taken, suppression might be less effective. In fact, in cases where doxyPEP fails, it may slow the bacterium, mask the infection’s typical early symptoms and delay positive test results, allowing it to progress into the latent (dormant) stage unnoticed. However, it is not yet clear how often this happens in real-world practice. It is also unclear whether this risk is clinically important compared to the overall benefits of doxyPEP.
While doxycycline post-exposure prophylaxis is now increasingly used for prevention, due to the risk of late-dosing, doxyPrEP (doxycycline pre-exposure prophylaxis) has been considered as a potential alternative. This might involve taking half the dose (100mg) on a more regular (perhaps daily) basis. While the idea sounds plausible there are potential downsides to it. Since syphilis can usually be treated with antibiotics, using them more frequently for prevention raises questions about the balance of benefits and risks. Like all medications, doxycycline can cause side effects, and there are concerns about the impact of repeated use on the gut microbiome and other aspects of health. Additionally, increased use of antibiotics may contribute to the development of resistance, which could limit treatment options in the future.
The study
Researchers analysed surveillance data to examine how syphilis diagnoses changed following the introduction of doxyPEP in King County, the area which includes the city of Seattle. The city’s sexual health clinic was one of the sites where the DoxyPEP trial was conducted which ended in May 2022. The clinic started by offering doxyPEP to all present and past trial participants as an extension to the trial and by March 2023 they were offering it to non-trial participants too.
Using syphilis diagnoses data from the period between 2017 and 2025, they modelled the number of total syphilis cases expected in the county and then compared it to the actual rates after doxyPEP was introduced. Using this method, they could estimate the reduction in the number of syphilis cases that doxyPEP use was possibly associated with.
Over the period of eight and a half years – including just over two years with doxyPEP available – 9951 syphilis cases were recorded, averaging 98 cases per month. Overall, 7851 cases were in men (77 cases per month on average), 1829 in women (18 per month), and 271 in transgender and non-binary people (three per month).
The data did not include reliable information on sexual orientation, so analyses grouped all men together, which may mask differences in doxyPEP use and effectiveness between heterosexual men and gay and bisexual men.
Syphilis diagnoses before and after doxyPEP
Before doxyPEP was introduced, there were 6135 syphilis cases. Case numbers were stable between 2018 and 2020, but began to rise from 2021, increasing by around three cases per month.
After doxyPEP was introduced, case numbers declined, falling by an average of 6.7 per month. Based on pre-existing trends, the researchers estimated that there would have been around 5952 cases without doxyPEP. The observed number (2921) was lower, suggesting that doxyPEP use was associated with a reduction of about 52% in all syphilis cases.
Reductions were seen across three main groups but were largest in men. Among men, cases declined by an average of 4.5 per month, translating into an estimated reduction of about 53%. Among women, cases declined by around two per month (47% reduction). In transgender and non-binary people, declines were smaller, at around 0.1 cases per month, revealing a reduction of about 33%.
In contrast, in pregnant people in the period between 2017 and 2024, syphilis cases rose from 13 to 48, paralleled by a rise in syphilis cases in newborns from 0 to 23. However, in 2025 from January through June, cases stabilised and remained similar to previous years.
Concluding thoughts
A similar principle to herd immunity may be at work through sexual networks. When enough people are protected against infection, overall transmission can fall, indirectly reducing the risk for those who are not using doxyPEP. This may help explain the similar scale of reduction in women in this study, even though they are rarely prescribed doxyPEP. However, this indirect effect does not appear to extend to pregnant people and newborns. This may reflect differences in how these groups are connected within sexual networks, or it may be that any impact in this population takes longer to become apparent, as suggested by the stabilisation of cases in early 2025.
It is encouraging that the 53% reduction in syphilis cases observed in this study is consistent with findings from San Francisco, where a 51% decline was reported among gay and bisexual men and transgender women following the introduction of doxyPEP.
It’s important to note that the present study is observational, in other words it only tracks and records changes; it cannot conclude that all the reduction in cases was only due to doxyPEP or determine what part of the reduction was caused directly by it. Furthermore, it’s possible that a part of the reduction comes indirectly from the community-level protection that forms as more people use doxyPEP.
While the findings of the study align with other reports regarding the effectiveness of doxyPEP, they do not distinguish between subgroups such as heterosexual men and gay men where the effect of the implementation may differ; for example, heterosexual men are much less likely to use doxyPEP and analysing all men together may lead to overestimation of doxyPEP’s effect for heterosexual men or underestimation of the effect for gay and bisexual men.
