Sexually transmitted infections (STIs) have risen sharply worldwide over the past two decades. Europe is no exception, according to recent surveys. The three most common bacterial STIs are Chlamydia trachomatis, which causes chlamydia; Treponema pallidum, the cause of syphilis; and Neisseria gonorrhoeae, which causes gonorrhea. The risk of acquiring one or more of these pathogens through unprotected sex is particularly high among men who have sex with men (MSM) and transgender women.

With the rise in infections, interest in drug-based prevention strategies has also grown. Particularly in the US and Europe, the use of doxycycline as post-exposure prophylaxis (doxy-PEP) against syphilis, chlamydia, and, to some extent, gonorrhea, became established years ago in at-risk populations.

However, its use remains off-label, and recommendations for antibiotic STI prophylaxis with doxycycline currently exist only for the high-risk groups mentioned above. These recommendations are based primarily on the findings of three large randomized controlled trials conducted between 2018 and 2022, which confirmed the efficacy and safety of doxycycline as STI prophylaxis in HIV-positive individuals and HIV pre-exposure prophylaxis (PrEP) users.

Evidence From Randomized Trials

These studies showed a significant reduction in syphilis, chlamydia, and gonorrhea infections among MSM and transgender women when doxycycline prophylaxis was administered within 72 hours of potential exposure. These trials formed the basis for the first clinical guidelines on doxy-PEP issued by the CDC in 2024.

The CDC recommends offering MSM and transgender women who had a bacterial STI within the last 12 months a prescription for a single 200-mg dose of doxycycline to self-administer, ideally within 24 hours after oral, vaginal, or anal intercourse. The number of single doses prescribed should be sufficient for the period until the next appointment with the prescribing clinician, and ongoing need should be reassessed every 3-6 months.

The German STI Society has already issued a significantly more limited recommendation in an earlier statement. It explicitly points to the still-uncertain effects on promoting microbial resistance that broader use outside defined risk groups could bring, and advocates doxy-PEP only under narrowly defined criteria and after careful consideration in individual cases.

This is also because data on its effectiveness in other populations are lacking: In a single additional study that examined the effectiveness of doxycycline PEP compared to standard treatment in cisgender women, no significant reduction in bacterial STIs was observed — however, only about 30% of participants in the doxy-PEP group actually used the prophylaxis. Ongoing studies should improve the evidence base; no new results from those trials are yet available. Overall, the evidence is insufficient to recommend doxy-PEP for other population groups.

Rising Demand for Doxy-PrEP

This is even more true for the second possible option of antibiotic STI prophylaxis: doxy-PrEP. Physicians in HIV specialty practices and STI treatment centers are increasingly confronted with requests for drug prophylaxis — analogous to HIV PrEP — not only after high-risk sexual encounters but also beforehand.

Previous studies have shown that a daily dose of 100 mg doxycycline offers good protection against bacterial STIs. Within professional circles, demand for doxy-PrEP is viewed very critically: for example, DSTIG’s 2023 statement clearly opposes daily preventative doxycycline use. Nevertheless, both post-exposure and, increasingly, pre-exposure doxycycline prophylaxis strategies have already gained traction in the MSM community, as reports indicate. That is not surprising: Smaller pilot studies in recent years suggest doxy-PrEP could prevent roughly two thirds of infections.

There are currently no real alternatives available: Doxycycline is the only antibiotic with sufficient data for prophylactic use against bacterial STIs, and vaccines against syphilis, gonorrhea and chlamydia have long been under development but are not expected to reach the market for some time. Immunization with the four-component meningococcal B vaccine provides only some protection against gonorrhea.

Resistance Risks and Uncertainty

It remains unclear what the long-term effects of wider doxy-PEP and doxy-PrEP use will be on the emergence of antimicrobial resistance. Experts generally agree that both strategies should ideally be implemented within medically supervised settings so that the individual risks and benefits of PEP or PrEP can be weighed.

The dangers of uncontrolled use are obvious: there is no way to detect infections in time and treat them effectively, test for resistance, or involve partners in care — all these factors further accelerate the development of resistance.

N gonorrhoeae is already known for a rapidly evolving resistance profile, the Robert Koch Institute (RKI) noted in its guide on gonorrhea. In Germany in 2025, for the first time there were local transmissions of highly drug-resistant N gonorrhoeae. The identified strains were resistant to ceftriaxone, cefixime, azithromycin, ciprofloxacin, and tetracycline; the cases involved heterosexual men with contact with sex work, according to the RKI.

Widely resistant strains are increasingly spreading globally, as numerous studies in recent years have shown. The World Health Organization (WHO) has placed N gonorrhoeae on its priority list of bacterial pathogens. Increased use of doxy-PEP and doxy-PrEP heightens selective pressure not only on gonococci but also on other pathogens. A research group led by Olusegun O. Soge at the University of Washington in Seattle demonstrated this in surveillance data from more than 2300 MSM infected with N gonorrhoeae between 2017 and 2024.

Between 2021 and 2024 — after doxy-PEP became widely established — the researchers found a sharp increase in isolates carrying the tetR resistance gene, with most cases now showing high-level resistance. In addition, doxy-PEP users from July 2023 to August 2024 were more often colonized with tetracycline-resistant Staphylococcus aureus and group A streptococci than nonusers.

Further studies confirmed these findings and showed that the spread of largely resistant N gonorrhoeae strains is not confined to identified risk groups. Infectious disease specialists in North Carolina found a marked rise in tetR across all studied groups — including MSM, heterosexual men and women — from 2019 to 2020, after which the incidence stabilized.

The question to weigh is this: Do antibiotic-based STI prophylaxis strategies prevent enough infections that would otherwise require antibiotic treatment? And does this subsequently increase or decrease the need for antibiotics?

Efficacy Against Chlamydia and Syphilis

So far, doxy-PEP has shown very high efficacy against chlamydia and syphilis and reduced the relative risk for N gonorrhoeae infections by about 55%. Doxy-PrEP has shown reductions in STI incidence of roughly 80% in smaller studies. To date, it does not appear to have had major effects on total antibiotic use.

However, that could change quickly as both strategies become more popular. Experts recall the example of azithromycin, which was long used as an effective syphilis therapy until resistance rates skyrocketed within a few years. Today, nearly all circulating Treponema pallidum strains are resistant to this once highly effective antibiotic.

Doxycycline could face a similar fate, sequencing-modeling studies suggest. Likewise, its effects on efficacy against pathogens outside the STI spectrum require further investigation.

Better knowledge of the drivers of resistance might make antibiotic STI prophylaxis safer. The necessary data come mainly from clinical follow-up of people on HIV PrEP and from STI surveillance. This monitoring allows for the identification of individual risk factors and the provision of targeted information about the benefits and risks of both prophylaxis methods.

Crucially, routine follow-up appointments also provide opportunities to detect overuse — for example, by comparing the number of prior symptomatic infections in a patient’s history with the planned use of doxy-PEP — and to ensure early detection and treatment of STIs, especially when they are asymptomatic.

Informal doxy-PrEP use should not lead to stigma for users. Integration into existing monitoring programs would be desirable to promote controlled use and to offer alternatives when appropriate. In the long term, doxy-PEP and doxy-PrEP dispensing should be supported by guidelines, and implementation of those guidelines and their effects on resistance should be monitored through suitable surveillance systems.

WHO Alert: Rising Drug Resistance

Last year the WHO once again warned of antimicrobial resistance: global rates of drug-resistant infections are rising steeply, the agency’s experts said. For clinicians, staying up to date on developments is therefore especially important.

Comprehensive information on antibiotic resistance and surveillance is available on a dedicated page of the RKI, which, in cooperation with other reference centers and consultative laboratories, is responsible for tracking the resistance situation in Germany.

This story was translated from Univadis Germany, part of the Medscape Professional network.