Evidence from real-world studies and a 2024 survey revealed that the use of doxycycline as postexposure prophylaxis (PEP) for sexually transmitted infections (STIs) in Spain is expanding beyond national clinical guidelines.

Trial data support its preventive efficacy, yet this off-label, community-driven practice persists despite a formal position paper limiting its use to high-risk cases. This situation underscores the need for standardised protocols to ensure safety and curb antimicrobial resistance.

The 2024 survey, conducted by the Spanish sexual health organisation Stop SIDA, found that among respondents who had sex with men in Spain and had previously used doxycycline, 54.6% had taken it at least once as PEP. Respondents most often sourced doxycycline through leftover prescriptions by reporting potential STI exposure to clinicians to obtain a new prescription or by purchasing it online.

Speaking with Medscape’s Spanish edition, Sergio Villanueva Baselga, MSc, research coordinator at Stop SIDA and the survey’s lead author, said, “At that time, there was already talk of clinical trials on doxycycline as postexposure prophylaxis to reduce syphilis and chlamydia infections, and part of the community had been informed of these studies and used it even though medical professionals did not prescribe it.”

He added that many respondents reported buying it online, and some obtained prescriptions through doctors who sold them illegally.

Although the sample was small (150 respondents recruited via social media and Telegram) and not representative, the findings align with the trends observed in Germany and Netherlands.

Ángel Rivero, MD, PhD, internal medicine and HIV/STI specialist and medical director of Barcelona Checkpoint, said that discussion on dating apps has normalised doxy PEP. “There are dating apps that include information in the profile, for example, ‘I am HIV positive with an undetectable viral load, I take doxy PEP, and I am vaccinated against meningitis B.’ Then people who are not familiar with it ask, ‘What is doxy PEP?’ and that is how its use becomes more widespread.”

He described the situations he sees daily: “People to whom we prescribe it because they ask us to, people we recruit, and people who are doing it on their own because they have given it to a colleague or because they have bought it on the street or even in pharmacies that are selling it, even though they should not.”

He noted that informal access persists, driven by its reputation among men who have sex with men and by barriers to formal prescriptions.

Doxycycline for PEP is not included in the 2024 Spanish National Consensus Document on the diagnosis and treatment of STIs. However, the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) issued a position paper endorsed by its Study Group on Sexually Transmitted Infections, the AIDS Study Group, and the Study Group on Mechanisms of Action and Resistance to Antimicrobials. The document states that prescriptions should be individualised and reserved for men who have sex with men and transgender women who are sexually active with men and have had recurrent STIs in the past year.

Gema Fernández-Rivas, MD, PhD, microbiologist at Hospital Germans Trias i Pujol in Badalona, Spain, and spokesperson for SEIMC, confirmed to Medscape’s Spanish edition that the position paper remains valid. She reiterated that doxycycline is not approved for STI prevention and is therefore off-label. She emphasised individualised decision-making and expressed concern over informal use. “We do not know the number of people who are doing this,” she said.

She added that unsupervised use can complicate diagnosis and interpretation and said, “Ideally, institutions should also integrate a database of patients who may be taking doxycycline to monitor and track the entire process.”

Doxycycline is preferred for PEP because of its efficacy against Chlamydia trachomatis and Treponema pallidum (syphilis), good tolerability, and low cost. Its activity against Neisseria gonorrhoeae is variable because of existing tetracycline resistance, which differs by region. Recent real-world evidence, including findings from the PRIDOX study in a Spanish PrEP cohort, shows significant reductions in STI incidence. The recommended regimen is 200 mg administered as soon as possible after condomless sex, ideally within 24 hours and not beyond 72 hours.

A recent review in The Lancet noted that its use is not recommended for cisgender women or transgender men.

In a high-risk cohort of men who have sex with men in southern Spain, doxy PEP was well tolerated and reduced incidence rates per 100 person-years from 31.4 to 7.8 for C trachomatis, from 41.5 to 28.9 for N gonorrhoeae, and from 21.5 to 3.2 for T pallidum.

Only one dose should be taken within a 24-hour period. “Most trials have used single doses,” Fernández-Rivas said. The UK guidance allows a maximum of three doses weekly. Real-world use varies. “Some people use it very systematically, requesting it but then not using it, taking it 2 days a week and claiming they have sex every day. If they had sex 3 days in a row over the weekend, they combined them into Monday’s dose,” Rivero said.

Several centres now suggest structured schedules, such as Mondays and Thursdays, to minimise antibiotic exposure.

Resistance Risks

The widespread use of doxy PEP raises concerns because of its potential contribution to antimicrobial resistance. Increases in tetracycline-resistant gonococcal strains have been observed among doxycycline users. C trachomatis and T pallidum currently show low resistance levels, but sustained selective pressure could change this. Selective pressure may also promote resistance in commensal microbiota, creating risks for patients and antibiotic efficacy at the population level. Resistance to unrelated antimicrobials, such as ceftriaxone, may also be selected due to the proximity of resistance genes.

Longitudinal studies are needed to assess medium- and long-term effects on resistance and microbiota. Research on implementation should be prioritised to guide use, determine effectiveness across populations, and establish treatment duration.

Policy Vacuum

Villanueva Baselga said that doxy PEP is another tool that men who have sex with men rapidly adopted through community knowledge sharing. “And perhaps medical decisions have come too late.”

He noted that Stop SIDA did not support its widespread use. Current strategies target small high-incidence subpopulations, leaving many individuals to use antibiotics without prescriptions or supervision.

Rivero highlighted the wide variation in prescribing practices. “There are units that generally do not prescribe it, and others that do.” He said that clinicians must explain the risk-benefit profile, clarify that doxy PEP is not included in the drug’s technical file, and support shared decision-making. “The problem is that by not being in the technical data sheet, doctors do not feel legally protected.”

He added that reliance on individual clinicians leaves people dependent on their assigned hospital and pushes some towards clandestine routes.

Clinicians and public health experts are responsible for understanding the scope of use. Surveillance is required to assess STI trends and antimicrobial resistance patterns. Systematic, evidence-based guidance is urgently needed to support treatment quality and clinician decision-making.

“Despite this, informal use of doxycycline postexposure prophylaxis, including self-sourcing without a prescription or obtaining a prescription for a different indication, is already occurring, and the intention to use it continues to rise independently of formal policy,” wrote the authors in Eurosurveillance, the journal of the European Centre for Disease Prevention and Control (ECDC).

They noted that most European countries have yet to establish a formal position on the practice, potentially awaiting guidance from international bodies such as the World Health Organization and the ECDC.

The authors suggested that precise, culturally relevant messages developed jointly by community and public health professionals could help people make safer and more informed decisions, regardless of whether national guidelines exist.

Villanueva Baselga, Fernández-Rivas, and Rivero reported having no relevant conflicts of interest.

This story was translated from Medscape’s Spanish edition.