A prevention strategy that public health agencies have promoted since 2023 has stopped working against gonorrhea in Southern California, according to a new observational study of more than 26,000 patients. Effectiveness fell from 42.3 percent in early 2023 to negative 15 percent by the end of the study period.
The strategy, known as doxyPEP, involves taking a dose of the antibiotic doxycycline within 72 hours of unprotected sex. It remains effective against two other common sexually transmitted infections. Across the full study period, protection measured 66.5 percent against chlamydia and 60.7 percent against syphilis, but 1.8 percent against gonorrhea.
For people currently taking doxyPEP, particularly in Los Angeles, Orange, and San Diego counties, the finding changes what the pill can be expected to do. It does not mean stopping. It means that anyone relying on it as gonorrhea protection now needs to plan around routine testing instead.
Effectiveness Fell From 42 Percent to Below Zero
The study, published in The Lancet Infectious Diseases and reported by CIDRAP, was led by researchers at Kaiser Permanente Southern California and the University of California, Berkeley.
Investigators assessed sexually transmitted infection incidence among 26,582 Kaiser Permanente Southern California members of any gender identity who were assigned male sex at birth, and who were either living with HIV or receiving doxyPEP or HIV pre-exposure prophylaxis. All had at least one STI test between January 2023 and June 30, 2025. The primary outcomes were laboratory-confirmed chlamydia, syphilis, and gonorrhea within 90 days of filling a doxyPEP prescription.
Protection against gonorrhea was moderate early on, said co-lead author Sara Tartof, an infectious disease epidemiologist at Kaiser Permanente Southern California, but "it just diminished rapidly and was no longer evident within a year after implementation."
The window matters. California issued statewide doxyPEP recommendations in early 2023, making it one of the earliest adopters in the country. The 42.3 percent effectiveness figure covers January through April of that year, when the guidance was announced. By the end of the study period, the measured effect had crossed below zero.
Gonorrhea Was Always the Weakest Target
The decline is specific to one pathogen, and it extends a pattern visible from the beginning. In the original doxyPEP clinical trial, conducted in Seattle and San Francisco, chlamydia and syphilis incidence fell by 88 percent and 87 percent, while gonorrhea fell by a more modest 55 percent. A San Francisco observational study published in 2025, after citywide implementation, found chlamydia and syphilis cases cut in half but no decline in gonorrhea. A French trial produced weaker gonorrhea results still.
Two years after statewide implementation in California, doxyPEP was still preventing chlamydia and syphilis at rates in the 60s. That distinction carries weight given the direction of syphilis in the United States, where case counts have continued to rise, including maternal and congenital syphilis.
Paul Adamson, an infectious disease physician and assistant professor at the David Geffen School of Medicine at the University of California, Los Angeles, who was not involved in the study, said the gonorrhea result did not surprise him. He described the lifespan of the strategy against gonorrhea as always likely to be short, and probably a little shorter than expected. But he emphasized what remains: "It's a big benefit to be able to prevent syphilis."
Resistance Genes Rose Fastest in Three Counties
The decline in effectiveness tracked with a rapid rise in tetM, a gene that confers high-level resistance to tetracyclines, the antibiotic class that includes doxycycline. Researchers measured its prevalence in gonorrhea samples collected at sexual health clinics in Los Angeles, Orange, and San Diego counties.
Tartof said doxyPEP still provided some protection when tetM prevalence sat around 20 to 30 percent, but effectiveness disappeared once prevalence climbed to roughly 50 percent or higher.
This is an observational study, and it does not establish that doxyPEP use caused resistance to spread. The researchers note that tetM prevalence accelerated shortly after statewide implementation despite modest uptake of the strategy, a sequence Tartof called worth thinking about.
Adamson offered an alternative reading, suggesting resistant strains in Southern California may have been increasing before the state guidance took effect, partly because patients were seeking doxyPEP on their own well ahead of formal recommendations. He also pointed to rising use of doxycycline as a first-line chlamydia treatment as a possible contributor.
Data from elsewhere line up with the California trend. A 2025 University of Washington study of isolates from a Seattle sexual health clinic found tetracycline resistance genes rose from 27 percent in 2017 to 70 percent by the middle of 2024. A letter to the New England Journal of Medicine reported tetM in US gonorrhea samples climbing from under 10 percent in 2020 to 30 percent in the first quarter of 2024, with the highest prevalence in the Pacific Northwest.
Clinics Reconsider Testing Rather Than Abandoning the Pill
No official guidance has changed. The Centers for Disease Control and Prevention recommended in June 2024 that clinicians discuss doxyPEP with high-risk patients and consider prescribing it, and the agency has suggested it may have contributed to recent small declines in the three most commonly reported STIs.
What the new data change is the expectation attached to the pill in one region. Someone taking doxyPEP in Southern California and skipping routine gonorrhea screening on the assumption of protection is making a decision the evidence no longer supports.
Gonorrhea often produces no symptoms, particularly in the throat and rectum, which is why screening at all exposure sites is standard for people at higher risk. When symptoms do appear, they can include painful urination, unusual discharge, testicular pain, or sore throat. Untreated gonorrhea can cause pelvic inflammatory disease, infertility, and, rarely, disseminated infection.
Anyone taking doxyPEP should talk with the clinician who prescribed it rather than stopping on their own. The relevant conversation is about screening frequency and which sites to test, not about whether to abandon a strategy that still works against two infections.
Key Questions Answered
What is doxyPEP? A prevention strategy in which a dose of the antibiotic doxycycline is taken within 72 hours after unprotected sex to reduce the risk of bacterial sexually transmitted infections.
What did the study find? Among 26,582 patients in Southern California, doxyPEP effectiveness against gonorrhea fell from 42.3 percent in early 2023 to negative 15 percent by the end of the study period. Overall effectiveness against gonorrhea was negative 1.8 percent.
Does it still work against other infections? Yes. Effectiveness was 66.5 percent against chlamydia and 60.7 percent against syphilis across the study period.
Why did it stop working against gonorrhea? The decline tracked with a rise in the tetM gene, which confers high-level resistance to tetracycline antibiotics including doxycycline.
Did doxyPEP cause the resistance? The study cannot establish that. It is observational, and one independent expert suggested resistant strains may have been rising in Southern California before statewide guidance took effect.
Has official guidance changed? No. CDC recommendations on doxyPEP remain in place. The findings affect what patients in the affected region should expect from it.
What should someone taking doxyPEP do now? Speak with the prescribing clinician about screening frequency and which anatomic sites to test, rather than stopping the medication independently.
