Large clinical trial finds zoliflodacin promising for uncomplicated urogenital gonorrhea
February 24, 2026
CATIE news story
- Researchers recruited more than 900 people to explore different regimens for gonorrhea
- A clinical trial of the new antibiotic zoliflodacin found it was as effective as standard therapy
- Side effects associated with zoliflodacin were generally mild to moderate
The germs that cause gonorrhea (N. gonorrhoeae) are most commonly spread during condomless anal, oral and vaginal intercourse. These germs can also be passed from mother to child during the birthing process.
People with gonorrhea do not always experience symptoms. However, in people who were assigned male at birth (AMAB), gonorrhea can cause discharge from the urethra as well as a burning sensation while urinating. If left untreated, the germs that cause gonorrhea can affect the testicles and prostate.
People assigned female at birth (AFAB) who have gonorrhea can develop a burning sensation while urinating, discharge from the vagina, pain in the lower abdomen, and vaginal bleeding between periods or after sex. What’s more, gonorrhea can contribute to pelvic inflammatory disease, infertility and other complications.
Gonorrhea causes inflammation in delicate wet tissues, which can act as a portal, or gateway, for other sexually transmitted infections (STIs), including HIV.
These symptoms, complications and risks for other infections underpin the need for sexually active people to get regular checkups and screening for gonorrhea and other STIs.
Gonorrhea treatment
Since the mid-1940s, there has been a range of treatment options—antibiotics—for gonorrhea. However, the germs that cause this infection have gradually developed the ability to resist many antibiotic treatments.
A scientific advisory panel to the Public Health Agency of Canada (PHAC) has released interim guidance for the treatment of gonorrhea.
In adults (and in young people 10 years of age and older), the advisory panel recommends the following treatment “for all uncomplicated infections (urethral, endocervical, vaginal, rectal and pharyngeal)”:
- the antibiotic ceftriaxone 500 mg given as an intramuscular injection in a single dose
In many countries, ceftriaxone has become the leading treatment for gonorrhea.
Other recommendations from the scientific advisory panel related to the management of gonorrhea can be found here. PHAC also has a Gonorrhea Guide.
Reports from around the world, including East Asia and Europe, suggest that the germs that cause gonorrhea are becoming less susceptible to ceftriaxone, with some cases of treatment failure. There is an urgent need to develop new antibiotics for the treatment of gonorrhea.
Enter zoliflodacin
Researchers have been developing the antibiotic zoliflodacin for the past decade. Recently, data from a phase III randomized controlled clinical trial of zoliflodacin in cases of uncomplicated gonorrhea affecting the urogenital tract have become available. The data show that zoliflodacin is a promising treatment regardless of sex or HIV status.
Study details
Researchers enrolled participants aged 12 and older who had uncomplicated gonorrhea affecting the urogenital tract (urogenital gonorrhea). Participants were randomly assigned in a 2:1 ratio to one of the following regimens, each taken once:
- zoliflodacin 3 g (taken as an oral suspension) – 621 people
- ceftriaxone 500 mg (given as an intramuscular injection) + azithromycin 1 g (taken as oral pills) – 309 people
Participants were recruited from clinics in the following countries:
- Belgium
- the Netherlands
- South Africa
- Thailand
- United States
The average profile of participants at study entry was as follows:
- age – 30 years
- assigned male at birth – 88%; assigned female at birth – 12%
- major ethno-racial groups: Black or of African descent – 55%; Asian – 12%; White – 12%
- 21% of participants had HIV
The clinical trial took place between November 2019 and March 2023.
Focus on symptoms
The main symptoms of gonorrhea among participants were distributed as follows:
Assigned male at birth:
- discharge from the urethra – 98%
- pain or discomfort when urinating – 86%
Assigned female at birth:
- discharge from the vagina – more than 60%
- pain or discomfort when urinating – 34%
- vulvovaginal irritation – 32%
- vaginal bleeding between periods – 18%
Results
The study was primarily designed to assess the proportion of people who were cured of gonorrhea in the urogenital tract with the study drugs. This was done by taking swabs from the urinary tract six days after treatment. Swabs were wiped on culture media to transfer any bacteria that were collected to see if they would grow in the lab in the days and weeks ahead. If no bacteria grew, then participants were considered cured of gonorrhea.
Overall, researchers found that the following proportions of participants were cured at urogenital sites:
- zoliflodacin – 97%
- ceftriaxone + azithromycin – 100%
Statistical analysis found that zoliflodacin was no worse in its effectiveness than the combination of ceftriaxone + azithromycin. The technical-statistical term for this finding is “non-inferior.”
Secondary analyses
As mentioned earlier, the study was primarily designed to assess the ability of antibiotics to treat gonorrhea in the urogenital tract. However, these bacteria can infect places other than the urogenital tract—such as the throat and rectum. When the researchers analyzed data (from swabs of these other parts of the body) to find out if participants were cured by the study antibiotics, the results were as follows:
Gonorrhea in the throat
- zolifoldacin – 79% cured (42 of 53 people)
- ceftriaxone + azithromycin – 79% cured (22 of 28 people)
Gonorrhea in the rectum
- zoliflodacin – 87% cured (69 of 79 people)
- ceftriaxone + azithromycin – 89% cured (31 of 35 people)
The present study wasn’t designed to provide definitive results for the treatment of gonorrhea in the throat and rectum, otherwise the numbers of participants with gonorrhea in those body parts would have been much greater. But the findings from the study are nevertheless promising.
There was no statistically significant difference in the effectiveness of zoliflodacin versus ceftriaxone + azithromycin when researchers compared several other factors from participants, such as the following:
- sex
- sexual orientation
- use of HIV pre-exposure prophylaxis (PrEP)
- HIV status
Safety
Both regimens used in this study were considered “generally well tolerated” by the research team. Side effects were mild or moderate, and in most cases, they were similar regardless of regimen used. Notable side effects were as follows:
Zoliflodacin
- headache – 10%
- less-than-normal levels of neutrophils – 7%
- less-than-normal levels of white blood cells – 4%
Ceftriaxone + azithromycin
- injection site pain – 12%
- less-than-normal levels of neutrophils – 8%
- diarrhea – 7%
None of the side effects were serious and no one died because of exposure to the study medicines.
Focus on lab measures
It is normal during an infection (such as gonorrhea) for levels of white blood cells, including neutrophils, to rise—this is part of the immune system’s response to infection. When the infection is treated, levels of these cells fall. However, the decrease in white blood cells (of which neutrophils are a subset) was noticeable in lab tests. This change is explained below.
Statistical analysis found that people of African descent and men were more likely to have detectable decreases in white blood cells and particularly neutrophils after treatment. However, these decreases were not associated with any symptoms or complications. There were no similar decreases found in people of Asian or White ancestry in the study. Also, people with HIV did not have a detectable decrease in their levels of white blood cells.
The researchers noted that other studies have found that some people of African descent can have lower-than-expected levels of neutrophils. However, they argue that in the absence of symptoms or complications associated with this finding, the apparent decrease in neutrophil levels is caused by laboratories using reference ranges derived from tests on White people and applying them to people of African descent. Therefore, the researchers did not attribute any clinical significance to the lab tests that found mildly low levels of neutrophils (or other white blood cells) in participants in the present study.
Bear in mind
The present study was a landmark for at least the following reasons:
- It was a large phase III study.
- It used a novel antibiotic—zoliflodacin—that was found roughly similar in effectiveness as ceftriaxone + azithromycin for uncomplicated urogenital gonorrhea.
This is good news because there are dwindling antibiotic options for gonorrhea. As zoliflodacin is a new antibiotic, researchers checked for the possibility of resistance occurring in participants who used it, but they did not find any. This is reassuring.
What’s more, the results from this study paved the way for zoliflodacin to recently gain approval by the Food and Drug Administration (FDA) for prescription by doctors in the U.S. for people with uncomplicated urogenital gonorrhea.
For the future
Women, adolescents and pregnant people had relatively low enrollment in the study, so hopefully future clinical trials will focus on these populations. Also, the research team noted that more studies are needed to explore the effect of zoliflodacin in people with gonorrhea infection in the throat.
How long will zoliflodacin be useful?
As mentioned earlier, the bacteria that cause gonorrhea have developed the ability over time to become resistant to many antibiotics. It is inevitable that these bacteria will develop resistance to zoliflodacin at some point in the future. Hopefully, this will not happen soon. To decrease the risk of zoliflodacin-resistant bacteria, it may be useful to design laboratory studies (and, if promising, subsequently in people) that test the effects of combination therapy for gonorrhea, such as the following:
- zoliflodacin + doxycycline
- zoliflodacin + azithromycin
Doxycycline is an antibiotic increasingly used to reduce the risk of gonorrhea (doxyPEP) and it is also used for the treatment of chlamydia. Therefore, studies of zoliflodacin + doxycycline in people are important to find out if these drugs interact (raise or lower concentrations of each other in blood and tissues and/or affect the antibacterial activity of each other). Azithromycin is an antibiotic that is widely used for the treatment of STIs, so its interaction with zoliflodacin also requires study.
Note well
In the current study, zoliflodacin was supplied in a sachet containing granules of the drug that were mixed with a small amount of water in a container, shaken vigorously, and then swallowed as a single dose. The drug was taken within two hours of eating a meal. An orally available antibiotic may make a more acceptable regimen for some people with gonorrhea who do not like intramuscular injections (this is how ceftriaxone is administered).
The U.S. FDA recently approved another new oral antibiotic—gepotidacin—for the treatment of uncomplicated gonorrhea. Neither gepotidacin nor zoliflodacin is approved in Canada yet.
Pharmaceutical companies need to submit dossiers on gepotidacin and zoliflodacin to Health Canada for its review for approval. Currently, ceftriaxone and most antibiotics commonly used to treat STIs are generic, so their cost is relatively low. Gepotidacin and zoliflodacin are new antibiotics, and it is likely that if they are approved in Canada, they will be expensive. This may affect who can access these drugs. If they are approved in Canada, it may be useful for public health authorities to develop guidelines to help healthcare practitioners decide when to use these drugs.
—Sean R. Hosein
Resources
Canada raises dose of preferred antibiotic for gonorrhea – CATIE News
Gonorrhea guide: Key information and resources – Public Health Agency of Canada
Sexually transmitted and blood-borne infections: Guides for health professionals – Public Health Agency of Canada
Chlamydia and LGV guide: Treatment and follow-up – Public Health Agency of Canada
Gonorrhea – CATIE
Scientists in France assess antibiotic resistance in people who use doxycycline post-exposure prophylaxis (doxyPEP) – CATIE News
New antibiotic (gepotidacin) looks promising for gonorrhea – CATIE News
TreatmentUpdate 245 – CATIE
Doxycycline for STI prevention shows significantly decreased rates of chlamydia and syphilis in a major clinic – CATIE News
Doxycycline to help prevent bacterial STIs – CATIE
REFERENCES:
- Luckey A, Balasegaram M, Barbee LA, et al. Zoliflodacin versus ceftriaxone plus azithromycin for treatment of uncomplicated urogenital gonorrhoea: an international, randomised, controlled, open-label, phase 3, non-inferiority clinical trial. Lancet. 2026 Jan 10;407(10524):147-160.
- Workowski KA. Zoliflodacin shows benefit as an oral treatment for uncomplicated gonorrhoea. Lancet. 2026 Jan 10;407(10524):106-107.
- Atallah-Yunes SA, Ready A, Newburger PE. Benign ethnic neutropenia. Blood Reviews. 2019 Sep; 37:100586.
- Jacobsson S, Golparian D, Oxelbark J, et al. Pharmacodynamics of zoliflodacin plus doxycycline combination therapy against Neisseria gonorrhoeae in a gonococcal hollow-fiber infection model. Frontiers in Pharmacology. 2023 Dec 7; 14:1291885.
- Luckey A, Alirol E, Delhomme S, et al. Effect of food on the pharmacokinetics of zoliflodacin granules for oral suspension: Phase I open-label randomized cross-over study in healthy subjects. Clinical and Translational Science. 2023 May;16(5):770-780.
- Kline MC, Oliveira Roster K, et al. Comparing strategies to introduce two new antibiotics for gonorrhea: A modeling study. Clinical Infectious Diseases. 2026 Jan 8;81(Supplement 5):S249-S255.
- Kanesaka I, Kong FYS, Vanbaelen T, et al. An overview of potential combination therapies with ceftriaxone as a treatment for gonorrhoea. Expert Reviews in Antiinfective Therapy. 2025 Jul;23(7):459-467.
- Komorowski AS, Eshaghi A, Burbidge J, et al. Detection of non-travel-associated, ceftriaxone non-susceptible Neisseria gonorrhoeae FC428-like harbouring the mosaic penA60 allele in Ontario, Canada. Canada Communicable Disease Reports. 2025 Dec 12;51(10-11/12):420-426.
From Canadian AIDS Treatment Information Exchange (CATIE).
This content was originally published by CATIE, Canada’s source for HIV and hepatitis C information.
Source: CATIE:
https://www.catie.ca/catie-news/large-clinical-trial-finds-zoliflodacin-promising-for-uncomplicated-urogenital-gonorrhea
For more information visit CATIE's Information Network at www.catie.ca
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