Reviewing Recently Approved Antibiotics for Uncomplicated Urogenital Gonorrhea

In December 2025, the FDA approved two antibiotics for the treatment of uncomplicated urogenital gonorrhea, a sexually transmitted infection (STI) caused by the gram-negative bacteria Neisseria gonorrhoeae (N gonorrhoeae).¹ Zoliflodacin (Nuzolvence) received approval as a first-in-class, single oral dose antibiotic for the treatment of uncomplicated urogenital gonorrhea in adults and adolescents.^1,2

Gepotidacin (Blujepa) was first approved by the FDA in March 2025 for the treatment of uncomplicated urinary tract infections in females, caused by the susceptible strains of Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii complex, Staphylococcus saprophyticus, and Enterococcus faecalis.^1,3

In December 2025, FDA approval was expanded to include treatment of uncomplicated urogenital gonorrhea caused by susceptible strains of N gonorrhoeae.¹ Currently, a single dose of intramuscular ceftriaxone is the recommended treatment of choice for uncomplicated gonococcal infections in adults and adolescents (if concomitant chlamydial infection has been excluded).⁴ N gonorrhoeae resistance to other antibiotic classes, such as fluoroquinolones, has increased since the early 1990s, and the Centers for Disease Control and Prevention (CDC) has identified multi-drug resistant gonorrhea as an urgent public health treat.⁴ The rising rates of antibiotic resistance highlights the urgent need for the research, development, and approval of new antibiotics. Understanding the prescribing information of these two new antibiotics will help minimize the potential for adverse reactions and contraindications, reduce the risk of antibiotic resistance, and ensure safe and effective use.

Zoliflodacin

Zoliflodacin is a spiropyrimidinetrione inhibitor that targets type II topoisomerases, which are required for DNA synthesis.⁵ In a pivotal phase 3, multinational, randomized, controlled, open-label, non-inferiority trial, zoliflodacin demonstrated non-inferiority compared to the dual therapy of ceftriaxone plus azithromycin for the treatment of uncomplicated urogenital gonorrhea, with both treatment groups showing comparable safety profiles.

The study enrolled 930 adolescent and adult participants to evaluate the efficacy and safety of a single 3g oral dose of zoliflodacin versus a single dose of 500mg intramuscular injection of ceftriaxone plus 1g oral azithromycin for the treatment of uncomplicated gonorrhea. This trial was the largest clinical trial ever conducted for a new treatment against Neisseria gonorrhoeae infection, with 16 trial sites in regions with a high prevalence of gonorrhea across five countries, including Belgium, the Netherlands, South Africa, Thailand, and the US.⁶

Study results showed that zoliflodacin was noninferior to the combination therapy (5.31%, 95% confidence interval: 1.38-8.65) with urogenital microbiological cure rates of 90.9% (88.1-93.3) and 96.2% (92.9-98.3), respectively, for the microbiological intent-to-treat population.⁷

The most frequently (≥2%) documented side effects after taking zoliflodacin include neutropenia, leukopenia, headache, dizziness, nausea, and diarrhea.⁵ Zoliflodacin is contraindicated in patients with a known hypersensitivity to the agent. It is also contraindicated in patients taking concurrent moderate or strong CYP3A4 inducers, as data suggests the efficacy of zoliflodacin may be reduced.⁵

Zoliflodacin may also cause fetal harm, and a pregnancy test in females of reproductive age is recommended before administering. The prescribing information suggests avoiding use during pregnancy.⁵ Based on animal data, the risk of pregnancy loss may be increased in female partners (of reproductive potential) of males taking zoliflodacin.⁵ Administration may also cause testicular toxicity and may negatively impact male fertility.⁵ Patients should be monitored for hypersensitivity reactions and Clostridioides difficile infection if diarrhea occurs. Specific dosing and administration of zoliflodacin is outlined in Table 1.⁵

Gepotidacin

Gepotidacin is a triazaacenaphthylene bacterial type II topoisomerase inhibitor.³ This approval was based from data of the EAGLE-1 phase 3 trial results, which were published in The Lancet, showing that gepotidacin (oral, 2 doses of 3000 mg) was noninferior, with a 92.6% (187 of 202; 95% CI, 88.0%-95.8%) success rate at urogenital site when compared with a 91.2% (186 of 204; 95% CI, 86.4%-94.7%) success rate for intramuscular ceftriaxone (500 mg) plus oral azithromycin (1000 mg) combined therapy.⁸

The EAGLE-1 study was an open-label noninferiority trial examining oral gepotidacin compared with ceftriaxone plus azithromycin. Participants had to have a body weight over 45 kg, and had suspected uncomplicated urogenital gonorrhea (including mucopurulent discharge), a positive laboratory test result for Neisseria gonorrhoeae, or both. Patients were randomly allocated in a 1:1 ratio to each treatment group, stratified by sex and sexual orientation.⁸

The primary efficacy end point was defined as eradication of gonorrhea at test of cure (days 4-8). The noninferiority margin was prespecified at –10%. The primary outcome was assessed in the microbiological intention-to-treat population, with all participants randomly allocated to a study treatment who received at least 1 dose of their treatment and had confirmed ceftriaxone-susceptible N gonorrhoeae isolated from the baseline culture of their urogenital specimen, The Lancet authors explained.⁸

The dosing, side effects, drug interactions, and warnings and precautions vary depending on whether the antibiotic is given for uncomplicated urogenital gonorrhea or uncomplicated urinary tract infections.³ When given at doses indicated for the treatment of uncomplicated urogenital gonorrhea, the most prevalent (≥2%) side effects include diarrhea, nausea, abdominal pain, vomiting, flatulence, dizziness, soft feces, headache, fatigue, and hyperhidrosis.³ Gepotidacin is contraindicated in patients with a known hypersensitivity to the antibiotic. It should be avoided in patients with a history of QTc prolongation or relevant cardiac disease.³ Patients who take medications that prolong the QTc interval or strong CYP3A4 inhibitors should avoid gepotidacin.³

Gepotidacin concentrations may be increased in patients with severe renal impairment (eGFR < 30 mL/min) or severe hepatic impairment (Child-Pugh Class C), and use should be avoided.³ When using this medication for uncomplicated urogenital gonorrhea, patients should avoid administration with moderate CYP3A4 inhibitors, or two or more of the following risk factors which may increase drug exposure: weighing 45 kilograms to 60 kilograms, moderate renal impairment (eGFR 30 to 59 mL/min) or moderate hepatic impairment (Child-Pugh Class B).³

Gepotidacin has several documented drug interactions, which may impact serum concentrations. An increase in gepotidacin exposure has been documented when given with CYP3A4 inhibitors, however CYP3A4 inducers may decrease gepotidacin concentrations in the body.³ Gepotidacin may also increase digoxin concentrations. It should be avoided with all medications that are significantly metabolized by CYP3A4.³ Clinical trials have also indicated gepotidacin is a reversible acetylcholinesterase inhibitor and may enhance the effect of other acetylcholinesterase inhibitors. Patients with medical conditions that can worsen by inhibiting acetylcholinesterase should be monitored.³ Like zoliflodacin, patients on gepotidacin should be monitored for hypersensitivity reactions and Clostridioides difficile infection if diarrhea occurs. Specific dosing and administration of gepotidacin is outlined in Table 1.

Why is This Important?

Due to the rise of antibiotic resistance, the development of new, first-in-class antibiotics is critical. Ciprofloxacin was used as a recommended treatment for gonorrhea in the past, until resistance was documented throughout the United States.⁴ In 2007, the CDC no longer recommended ciprofloxacin and other fluoroquinolones as empiric therapy for gonorrhea.⁴ Intramuscular ceftriaxone is presently the recommended treatment of choice for uncomplicated urogenital gonorrhea.⁴ The CDC has identified drug-resistant gonorrhea as a public health threat,⁴ with over with over 543,000 provisional infections currently reported in the United States in 2024.⁹

These newly approved treatments will offer oral administration options to providers and patients. However, based on limited clinical safety data, these novel antibiotics should be reserved for those with no other treatment options to decrease the development of drug-resistant organisms.^1,3,5 It is presently unknown how these antibiotics will fit into current treatment recommendations for gonorrhea. However, the newly approved treatment options may be reasonable alternatives where currently recommended antibiotic regimens have failed, reinfection has been ruled out, and resistance to N gonorrhoeae has been documented by antimicrobial susceptibility testing.^1,3,5,10

References

1.FDA Approves Two Oral Therapies to Treat Gonorrhea. FDA. December 12, 2025. Accessed January 6, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-two-oral-therapies-treat-gonorrhea

2.Innoviva Specialty Therapeutics. U.S. FDA Approves NUZOLVENCE® (zoliflodacin), a First-in-Class, Single-dose, Oral Antibiotic for the Treatment of Uncomplicated Urogenital Gonorrhea in Adults and Adolescents. Accessed January 7, 2026. https://innovivaspecialtytherapeutics.com/u-s-fda-approves-nuzolvence-zoliflodacin-a-first-in-class-single-dose-oral-antibiotic-for-the-treatment-of-uncomplicated-urogenital-gonorrhea-in-adults-and-adolescents/

3.Blujepa [package insert]. Durham, NC: GlaxoSmithKline; 2025. https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Blujepa/pdf/BLUJEPA-PI-MG.PDF

4.Centers for Disease Control and Prevention (CDC). Drug-Resistant Gonorrhea. August 18, 2025. Accessed January 7, 2026. https://www.cdc.gov/gonorrhea/hcp/drug-resistant/index.html

5.Nuzolvence [package insert]. Entasis Therapeutics; 2025. https://innovivaspecialtytherapeutics.com/wp-content/uploads/2025/12/NUZOLVENCE-zoliflodacin-Full-Prescribing-Information-December-2025.pdf

6. Innoviva Specialty Therapeutics Announces Publication in The Lancet of Positive Zoliflodacin Phase 3 Data for the Treatment of Uncomplicated Urogenital Gonorrhea. Innoviva press release. December 12, 2025. Accessed December 12, 2025.
https://innovivaspecialtytherapeutics.com/innoviva-specialty-therapeutics-announces-publication-in-the-lancet-of-positive-zoliflodacin-phase-3-data-for-the-treatment-of-uncomplicated-urogenital-gonorrhea/

7. Innoviva Specialty Therapeutics Presents Findings from Subgroup Analyses of zoliflodacin in uncomplicated gonorrhea at the 2024 Sexually Transmitted Infections Conference. Innoviva press release. September 19, 2024. December 12, 2025.
https://innovivaspecialtytherapeutics.com/innoviva-specialty-therapeutics-presents-findings-from-subgroup-analyses-of-zoliflodacin-in-uncomplicated-gonorrhea-at-the-2024-sexually-transmitted-infections-conference/

8.Ross JDC, Wilson J, Workowski KA, et al. Oral gepotidacin for the treatment of uncomplicated urogenital gonorrhea (EAGLE-1): a phase 3 randomised, open-label, non-inferiority, multicentre study. Lancet. 2025;405(10489):1608-1620. doi:10.1016/S0140-6736(25)00628-2

9.Centers for Disease Control and Prevention (CDC). Sexually Transmitted Infections Surveillance, 2024 (Provisional). STI Statistics. September 23, 2025. Accessed January 7, 2026. https://www.cdc.gov/sti-statistics/annual/index.html

10.Contagion Editorial Team. Zoliflodacin Emerges as a First-in-Class Oral Option Against Drug-Resistant Gonorrhea. Contagion Live. December 24, 2025. Accessed January 6, 2026. https://www.contagionlive.com/view/zoliflodacin-emerges-as-a-first-in-class-oral-option-against-drug-resistant-gonorrhea