---
title: "Monitoring doxy-PEP impact: when to reassess guidance on STI prophylaxis"
id: "plos-medicine-0-how-do-we-monitor-doxy-pep-impact-and-when-should-we-consider-revisiting"
canonical_url: "https://medichelpline.com/clinical-feed/plos-medicine-0-how-do-we-monitor-doxy-pep-impact-and-when-should-we-consider-revisiting"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "PLOS Medicine"
source_url: "https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276"
published_at: "2026-10-21T14:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Monitoring doxy-PEP impact: when to reassess guidance on STI prophylaxis
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/plos-medicine-0-how-do-we-monitor-doxy-pep-impact-and-when-should-we-consider-revisiting
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** PLOS Medicine
- **Source URL:** [Original Journal Publication](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276)
- **Published At:** 2026-10-21T14:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The 2026 **WHO** conditional recommendations endorse **doxy-PEP** for men who have sex with men (MSM) and transgender women (TGW), and call for antimicrobial resistance (AMR) monitoring. Trials in MSM/TGW showed 70%–85% reductions for chlamydia and syphilis and variable reductions for gonorrhea. - **Doxy-PEP** uses a single 200 mg dose within 72 hours after condomless sex. Trial efficacy varied by local tetracycline resistance in **Neisseria gonorrhoeae**, which can already exceed 80% in some areas. - Evidence indicates selection for tetracycline resistance genes (eg, tetM) in **N. gonorrhoeae**, rising phenotypic resistance among users, and expansion of tetracycline resistance genes in gut microbiomes during use. - Bystander effects include reduced colonization but increased tetracycline-resistant colonization of **Staphylococcus aureus**, and persistent shifts in the skin microbiome after doxycycline exposure; clinical consequences remain unclear. - As STI prevalence declines, infections averted per dose fall and number needed to treat (NNT) rises; concurrently AMR externality per dose may grow, changing the cost–benefit balance across settings and populations. - Attributing trends to **doxy-PEP** is challenging: surveillance gaps, heterogeneous uptake, pre-existing trends, and variable study designs complicate causal inference and governance decisions. - Broader benefit/harm accounting should include patient-centered outcomes (reduced anxiety, fewer clinic visits, complications averted) and harms (adverse effects, pregnancy concerns, AMR), not only STI incidence and AMR prevalence. - The authors recommend treating **doxy-PEP** as an adaptive intervention requiring predefined decision rules, periodic transparent review, expanded surveillance capacity, and context-specific thresholds for revisiting guidelines.
## Clinical Analysis & Structured Key Points
[ Skip to main content ](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#main-content) Advertisement * [plos.org](https://plos.org/) * [Create account](https://community.plos.org/registration/new) * [Sign in](https://journals.plos.org/user/secure/login?page=%2Fplosmedicine%2Farticle%3Fid%3D10.1371%2Fjournal.pmed.1005276) * * About * Browse * Publish * [](https://journals.plos.org/plosmedicine/ "PLOS Medicine") * Search [advanced search](https://journals.plos.org/plosmedicine/search) * 0 [Save](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1005276#savedHeader) [Total Mendeley and Citeulike bookmarks.](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1005276#savedHeader) * 0 [Citation](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1005276#citedHeader) [Paper's citation count computed by Dimensions.](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1005276#citedHeader) * 14 [View](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1005276#viewedHeader) [PLOS views and downloads.](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1005276#viewedHeader) * 0 [Share](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1005276#discussedHeader) [Sum of Facebook, Twitter, Reddit and Wikipedia activity.](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1005276#discussedHeader) Open Access Policy Forum Policy Forum articles provide a platform for health policy makers from around the world to discuss the challenges and opportunities in improving health care to their constituencies. [See all article types » ](https://journals.plos.org/plosmedicine/s/other-article-types) # How do we monitor doxy-PEP impact and when should we consider revisiting guidelines? * Yonatan H. Grad , * E-mail: ygrad@hsph.harvard.edu Affiliation Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0001-5646-1314 ](https://orcid.org/0000-0001-5646-1314 "ORCID Registry") ⨯ * Rachel Mittelstaedt, Affiliations Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America, Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, United States of America [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0009-0005-7199-3382 ](https://orcid.org/0009-0005-7199-3382 "ORCID Registry") ⨯ * Remco P. H. Peters Affiliation Department for HIV, Tuberculosis, Hepatitis and Sexually Transmitted Infections, World Health Organization, Geneva, Switzerland [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0009-0007-5955-0815 ](https://orcid.org/0009-0007-5955-0815 "ORCID Registry") ⨯ # How do we monitor doxy-PEP impact and when should we consider revisiting guidelines? * Yonatan H. Grad, * Rachel Mittelstaedt, * Remco P. H. Peters ![PLOS](https://journals.plos.org/resource/img/logo-plos-full-color.svg) x * Published: October 21, 2026 * * [Article](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276) * [Authors](https://journals.plos.org/plosmedicine/article/authors?id=10.1371/journal.pmed.1005276) * [Metrics](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1005276) * [Comments](https://journals.plos.org/plosmedicine/article/comments?id=10.1371/journal.pmed.1005276) * [Media Coverage](http://plos.altmetric.com/details/doi/10.1371/journal.pmed.1005276) * [Summary points](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#abstract0) * [Introduction](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#sec002) * [Doxy-PEP may shape pathogen-specific dynamics](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#sec003) * [The shifting balance of benefits and harms](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#sec004) * [The challenge of attributing changes to doxy-PEP](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#sec005) * [Clarifying the indirect effects of doxy-PEP](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#sec006) * [Monitoring and decision-making](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#sec007) * [Considerations for next steps](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#sec008) * [Conclusions](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#sec009) * [References](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#references) * [Reader Comments](https://journals.plos.org/plosmedicine/article/comments?id=10.1371/journal.pmed.1005276) [?](https://journals.plos.org/plosmedicine/s/accepted-manuscripts#loc-early-version) ## This is an uncorrected proof. ## Summary points * The 2026 WHO guidelines recommending doxycycline post-exposure prophylaxis (doxy-PEP) represent the first global antibiotic prophylaxis recommendation for bacterial sexually transmitted infections (STIs), with provisions for antimicrobial resistance (AMR) monitoring. * Doxy-PEP should be governed as an adaptive intervention subject to periodic, transparent review, but establishing decision rules faces challenges. * Doxy-PEP is expected to select for resistance, including in _Neisseria gonorrhoeae_ , _Staphylococcus aureus,_ and the gut and skin microbiomes; the scope of clinical consequences is incompletely understood. * As STI prevalence falls, the benefit per dose declines while the AMR externality per dose is expected to grow, shifting the cost-benefit balance in ways that vary across populations and settings. * Attributing changes in disease prevalence or resistance patterns to doxy-PEP is methodologically difficult, given incompletely understood and complex drivers of pre-existing trends, surveillance limitations, and heterogeneous uptake, raising questions about study designs, data sources, eligibility criteria, and governance mechanisms. * A full accounting of benefits and harms is broader than reduced bacterial STI incidence and AMR. Benefits include consideration of patient-centered outcomes such as reduced anxiety regarding STI acquisition, avoidance of repeated treatment visits, and fewer STI-related complications. Harms include drug side effects, such as gastrointestinal adverse effects and concerns about use in pregnancy. **Citation:** Grad YH, Mittelstaedt R, Peters RPH (2026) How do we monitor doxy-PEP impact and when should we consider revisiting guidelines? PLoS Med 23(10): e1005276. https://doi.org/10.1371/journal.pmed.1005276 **Published:** October 21, 2026 **Copyright:** © 2026 Grad et al. This is an open access article distributed under the terms of the [Creative Commons Attribution License](http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. **Funding:** The project described was supported in part by Grant Number T32 AI007433 (to RM) from the National Institute of Allergy and Infectious Diseases, NIH. The manuscript contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. **Competing interests:** I have read the journal’s policy and the authors of this manuscript have the following competing interests: YHG has received grant funding from the Global Antibiotic Research and Development Partnership, serves on the scientific advisory board of Kanso Diagnostics and Claryx, and has consulted for Analysis Group and GSK. RM was supported by Grant Number T32 AI007433 (to RM) from the National Institute of Allergy and Infectious Diseases, NIH. **Abbreviations:** AMR, antimicrobial resistance; CDC, Center for Disease Control; doxy-PEP, Doxycycline post-exposure prophylaxis; HIV PrEP, HIV pre-exposure prophylaxis; MSM, men who have sex with men; NNT, number needed to treat; STIs, sexually transmitted infections; TGW, transgender women; WHO, World Health Organization. ## Introduction The incidence of bacterial sexually transmitted infections (STIs) has been rising globally for much of the last decade [[1](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#pmed.1005276.ref001)]. These infections can potentiate the transmission of HIV, be transmitted from mother to child, and cause other serious sequelae like pelvic inflammatory disease and infertility [[2](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#pmed.1005276.ref002)]. Doxycycline post-exposure prophylaxis (doxy-PEP)—a single 200 mg dose of doxycycline taken within 72 hours of condomless sex—is a new intervention to prevent bacterial STIs. Doxycycline has activity against the most prevalent bacterial STI pathogens: _Treponema pallidum_ (syphilis), _Chlamydia trachomatis_ (chlamydia), and _N. gonorrhoeae_ (gonorrhoea). Trials conducted in the US and Europe in men who have sex with men (MSM) and transgender women (TGW), either living with HIV or on HIV pre-exposure prophylaxis (HIV PrEP), established efficacy. Here, doxy-PEP reduced the incidence of chlamydia and syphilis by 70%–85%, and it decreased gonorrhoea incidence by 0%–55%, with variability largely explained by local patterns of gonococcal tetracycline resistance [[3](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#pmed.1005276.ref003)–[5](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#pmed.1005276.ref005)]. While doxy-PEP is highly effective, there is ongoing uncertainty about the extent to which it will select for antimicrobial resistance (AMR) among both bacterial STIs and other pathogens. In 2024, the United States Center for Disease Control (CDC) issued guidelines recommending doxy-PEP for MSM/TGW with a recent bacterial STI, with individual patient reassessment recommended every 3–6 months. Guidelines and uptake differ across global settings, with a general approach of adopting doxy-PEP to some extent [[6](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#pmed.1005276.ref006)–[9](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#pmed.1005276.ref009)], and many countries are working on policy frameworks currently. Even where doxy-PEP is not recommended, as in the Netherlands, broad informal use has been reported [[10](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#pmed.1005276.ref010)]. In 2026, the World Health Organization (WHO) published conditional recommendations for doxy-PEP use among MSM/TGW, representing a landmark in public health: the first global recommendation for antibiotic prophylaxis against STIs, together with a provision to monitor AMR [[11](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#pmed.1005276.ref011)]. The guidelines mark an advance in STI prevention for MSM/TGW. The acknowledgment in these guidelines and others of the need to monitor AMR reflects the tension inherent in doxy-PEP [[12](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#pmed.1005276.ref012)]: it relies on an antibiotic that exerts ecological pressure across commensal and pathogenic organisms beyond its intended targets. Comparisons are often drawn between HIV PrEP and doxy-PEP, in part because emergence of antiviral resistance was a major concern in the early days of HIV PrEP [[13](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#pmed.1005276.ref013)]. Doxy-PEP is unique from HIV PrEP in the broadness of its activity against bacterial bystander pathogens. As doxy-PEP is taken up, we expect—and in some settings are already seeing—declining incidence of syphilis and chlamydia as well as signals suggesting increasing resistance in _N. gonorrhoeae_ and bystander organisms [[14](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#pmed.1005276.ref014)–[18](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#pmed.1005276.ref018)]. But many important questions remain around monitoring and what to do with what we learn. In the case of HIV PrEP, monitoring for resistance in patients who became HIV–positive after taking PrEP was critical to establishing that the benefits of HIV PrEP outweighed the harms at the individual and population scales [[13](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#pmed.1005276.ref013)]. Monitoring the impact of doxy-PEP is not straightforward. Surveillance capacity is uneven, attribution of shifts in disease prevalence and resistance to doxy-PEP is difficult, the clinical consequences of changes in resistance prevalence will vary by location, and revising recommendations seen as preventing disease will be hard to enact. These anticipatable difficulties argue for engaging with these challenges now. We suggest that doxy-PEP should be understood as an adaptive intervention that requires continued evaluation and for which modification, when warranted, should be informed by pre-defined criteria. ## Doxy-PEP may shape pathogen-specific dynamics Syphilis, chlamydia, and gonorrhea are often addressed as a single indication for doxy-PEP, but their resistance dynamics differ. _T. pallidum_ has no known acquired resistance to doxycycline, and efforts to develop resistance in vitro have suggested that it faces evolutionary roadblocks [[19](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#pmed.1005276.ref019)]. The appearance of doxycycline resistance in _T. pallidum_ would be a major concern for doxy-PEP, as doxycycline is one of the only alternatives to penicillin treatment. Doxy-PEP is highly effective against _C. trachomatis_ , and like _T. pallidum_ , no resistance has been observed. In contrast, _N. gonorrhoeae_ develops resistance to tetracyclines, and some areas of the world already have rates of resistance exceeding 80% [[20](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#pmed.1005276.ref020),[21](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#pmed.1005276.ref021)]. High-level resistance (Minimum Inhibitory Concentrations ≥ 16 µg/mL) is conferred by the plasmid-borne _tetM_. Evidence of selection for _tetM_ in the DOXYVAC study [[22](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#pmed.1005276.ref022)], alongside increasing phenotypic resistance among doxy-PEP users in Seattle [[17](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#pmed.1005276.ref017)], increasing _tetM_ prevalence in the US [[14](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#pmed.1005276.ref014)], and an association between decreasing doxy-PEP efficacy against gonorrhea with increasing _tetM_ prevalence [[16](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#pmed.1005276.ref016)], is consistent with the expectation that widespread antibiotic use will reduce _N. gonorrhoeae_ prevalence initially in settings with relatively low starting prevalence of tetracycline resistance, but that it will also select for resistance. As resistant strains spread, effectiveness is reduced. In the absence of changes in behavior or transmission networks, prevalence returns toward prior levels, driven by the resistant strains [[15](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#pmed.1005276.ref015)]. The restructuring of the _N. gonorrhoeae_ population, in which doxy-PEP could select for strains with reduced susceptibility to cephalosporins, may prove a consequential long-term cost of the intervention [[14](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#pmed.1005276.ref014),[23](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#pmed.1005276.ref023)]. The broader ecological costs of doxy-PEP can be seen in the impact on bystander organisms. Among doxy-PEP users, _Staphylococcus aureus_ colonization was reduced, but those colonized had higher rates of tetracycline-resistant _S. aureus_ [[17](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#pmed.1005276.ref017)], with potential consequences of selecting for multidrug-resistant strains [[24](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#pmed.1005276.ref024)]. An analysis of the gut microbiome from the DoxyPEP trial found minimal shifts in microbial composition but significant expansion and increased expression of tetracycline resistance genes over six months, with a dose-response pattern [[25](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#pmed.1005276.ref025)]. Moreover, a study of 100 mg daily doxycycline for 56 days showed persistent changes to the skin microbiome, even more than 200 days after finishing the antibiotic course [[26](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005276#pmed.1005276.ref026)]. The clinical consequences of these observations are not yet clear. ## The shifting balance of benefits and harms Changes to the cost-benefit logic of doxy-PEP are anticipatable. As disease prevalence falls, the risk of acquiring an STI per sexual encounter declines. The benefit per dose, measured in infections averted, shrinks accordingly, and the number needed to treat (NNT) to prevent a single infection rises. This is true for any prophylaxis used in a declining epidemic and is an argument for progressively concentrating the intervention on those with the highest residual risk. Simultaneously, if the increases in AMR result in clinical consequences such as treatment failures and harder-to-treat infections, the AMR externality per dose will grow. This could drive costs that will be borne by future patients facing treatment failures and healthcare systems managing harder-to-treat infections. While those using doxy-PEP gain its benefits now, the costs of resistance would be expected to fall at some point in the future, potentially years later, potentially on others, and where the extent of selection for resistance is only a forecast. The calculations of benefits and harms will differ across global settings. Where baseline gonorrhea resistance is already very high, where syphilis epidemiology is driven by heterosexual networks, or where the burden of _S. aureus_ infections is elevated, the balance of benefits and harms may differ from what was observed in the trial populations. Moreover, in locations without sufficient infrastructure for monitoring disease incidence and antimicrobial resistance, building or expanding this infrastructure adds additional complexity to the cost-benefit calculation. Benefits and harms will also differ across sexual orientations and gender identities. Doxy-PEP has been highly effective in MSM/TGW, but efficacy in _cis-_ gender women has not yet been established. A study of doxy-PEP use in _cis-_ gender women in Kenya did not significantly reduce bacterial STIs, although this m
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