What information is available on the new drug gepotidacin for treatment of uncomplicated urinary tract infections?

Introduction
Urinary tract infections (UTIs) are common bladder infections that occur in patients who are otherwise healthy; these infections cause symptoms such as urinary frequency/urgency, dysuria, or suprapubic pain.1 Urinary tract infections occur most commonly in women, with up to 60% of women reporting a history of 1 or more UTIs in their lifetime. Escherichia coli causes up to 90% of UTIs; other gram-negative bacteria that are implicated in causing UTIs include Klebsiella pneumoniae, proteus mirabilis, and Pseudomonas aeruginosa.2 Infections with gram-positive organisms (eg, Staphylococcus saprophyticus, Enterococcus spp., and Group B streptococcus) occur more commonly in older adults and pregnant women. Treatment of UTIs is guided by whether the infection is “complicated” or “uncomplicated”. Complicated UTIs are generally more challenging to treat; a UTI may be considered “complicated” if there are signs of involvement outside the bladder, if the patient has a known anatomical or functional problem with their urinary tract, or if the patient is immunocompromised, pregnant or male.1-3 Infections in otherwise healthy individuals who do not meet these criteria are considered uncomplicated.

Typically, oral agents such as nitrofurantoin, trimethoprim/sulfamethoxazole, and fosfomycin are used first-line to treat uncomplicated UTIs in women.1,3 If these agents cannot be used, oral beta-lactams or fluoroquinolones may be considered.1 However, bacterial resistance to many of these therapies is increasing in the United States, with resistance to beta-lactams, trimethoprim/sulfamethoxazole, and fluoroquinolones reported to be above 55%, 22%, and 21%, respectively, among common uropathogens.2 There are also significant safety concerns associated with use of fluoroquinolones; thus, these agents are typically reserved for treatment of serious infections.3 These concerns highlight the need for novel antibiotic treatment options in patients with uncomplicated UTI. In March 2025, the United States Food and Drug Administration (FDA) approved gepotidacin (Bluejepa®) for the treatment of uncomplicated UTIs in females aged ≥12 years, marking the first approval of a novel class of antibiotic to treat UTIs in over 20 years.4 The purpose of this frequently asked question (FAQ) review is to summarize the role and use of gepotidacin for the treatment of uncomplicated UTI.

Drug overview
Gepotidacin is currently approved to treat uncomplicated UTIs in female adults and pediatric patients who are aged ≥12 years and weigh ≥40 kg.5 The product’s labeling specifies that it should be used for uncomplicated UTIs caused by susceptible E. coli, K. pneumoniae, Citrobacter freundii complex, S. saprophyticus, and Enterococcus faecalis. It is administered orally, in tablet form, at a dose of 1500 mg given twice daily for a total of 5 days. The drug should be given after a meal to minimize gastrointestinal disturbance.

Mechanism of action
Gepotidacin is the first drug approved in the class of triazaacenaphthylene antibiotics.5,6 Drugs in this class work by selectively inhibiting type IIA bacterial topoisomerases: topoisomerase IV and the B subunit of DNA gyrase. Inhibition of these topoisomerases causes single-stranded breaks in bacterial DNA, which is bactericidal. Gepotidacin’s mechanism of binding to topoisomerase IV and DNA gyrase is unique to that of fluoroquinolones, suggesting that it may be useful in treating fluoroquinolone-resistant bacterial infections.6,7

Safety considerations
Similar to other oral antibiotic agents, gepotidacin can cause hypersensitivity reactions, dose- and concentration-dependent QTc interval prolongation, Clostridioides difficile infection, and lead to development of drug-resistant bacteria when used in patients who do not have bacterial infections.5 The drug also has a unique warning for acetylcholinesterase inhibition; it can worsen cholinergic effects when used in combination with other acetylcholinesterase inhibitors or succinylcholine-type neuromuscular blocking agents, potentially leading to severe acetylcholine-mediated adverse reactions. It can also reduce the effectiveness of systemic anticholinergic agents or non-depolarizing neuromuscular blockers. Dosage adjustment is not required in patients with mild or moderate renal or hepatic impairment, but it is not recommended in patients with severe renal or hepatic impairment because of an increased risk of QTc prolongation in such patients.

Gepotidacin has many potential drug interactions.5 It should not be used concomitantly with strong inhibitors or strong inducers of cytochrome P450 (CYP) 3A4, because concomitant use can increase (CYP inhibitors) or decrease (CYP inducers) gepotidacin exposure. Similarly, gepotidacin is not recommended for use in combination with narrow therapeutic index drugs that are extensively metabolized by CYP3A4, such as cyclosporine. In line with its warnings and precautions, gepotidacin should not be used in combination with drugs that prolong the QT interval and should be used with caution in combination with other cholinergic or anticholinergic drugs.

Literature summary
The efficacy of gepotidacin for the treatment of uncomplicated UTIs was evaluated in 2 double-blind, double-dummy, phase 3 randomized controlled noninferiority trials (EAGLE-2 and EAGLE-3).8 Both trials included non-pregnant patients aged ≥12 years who were assigned female sex at birth and weighed ≥40 kg; patients had to have at least 2 symptoms of UTI (ie, dysuria, lower abdominal pain, or urinary frequency/urgency) with onset within 96 hours of study entry and urinary nitrite, pyuria, or both. Patients in both trials were randomized (stratified by age and history of recurrent uncomplicated UTIs) to receive oral gepotidacin 1500 mg twice daily or slow-release nitrofurantoin 100 mg twice daily (EAGLE-2, N=1531; EAGLE-3, N=1605); in both trials, the course of therapy lasted for 5 days. The primary outcome assessed was therapeutic response (success or failure) at the test-of-cure visit, which occurred between days 10 and 13 of the trial. Treatment success was defined as a combination of clinical success (a total clinical symptom score of 0 for uncomplicated UTI) and microbiological success (reduction of bacterial uropathogens from ≥105 colony forming units [CFU]/mL at baseline to <103 CFU/mL) without the need for any additional antibiotic use for uncomplicated UTI before the test-of-cure visit. The noninferiority margin was set at 10%, following recommendations from the FDA and the European Medicines Agency. The efficacy analysis population included patients in the microbiological intention-to-treat population (ie, all patients randomly assigned who received ≥1 dose of the study treatment and had 1-2 qualifying uropathogens at baseline) who had nitrofurantoin-susceptible isolates and reached the test-of-cure visit or had attained therapeutic success prior the test-of-cure visit. The individual components of the primary outcome (ie, clinical success/failure and microbiological success/failure) were assessed as secondary outcomes.

At baseline, the average age of patients in the EAGLE-2 and EAGLE-3 trials ranged from 50.4 to 52.4 years, more than 80% of patients were White, and 50% to 67% resided in the Americas.8 Most patients (73%-76%) had normal renal function; about 20% of patients had mild renal impairment (creatinine clearance [CrCl] of 60-89 mL/min), 5% to 7% had moderate renal impairment (CrCl 30-59 mL/min), and less than 1% had severe impairment (CrCl <30 mL/min). Approximately 40% of enrolled patients had a history of uncomplicated UTI recurrence, and 40% to 47% had moderate UTI symptoms. E. coli was the most predominant uropathogen, present in 90% of sampled patients. At the test-of-cure visit in EAGLE-2, therapeutic success was achieved in 50.6% of patients treated with gepotidacin and 47% of patients treated with nitrofurantoin (treatment difference, 4.3%; 95% CI, -3.6% to 12.1%); similar results were seen at the test-of-cure visit in EAGLE-3, with therapeutic success achieved in 58.5% of patients treated with gepotidacin and 43.5% of patients treated with nitrofurantoin (treatment difference, 14.6%; 95% CI, 6.4% to 22.8%). Both trials met noninferiority for the primary outcome. Gepotidacin was also found to be superior to nitrofurantoin for this outcome in EAGLE-3. Among patients with various drug-resistant strains of E. Coli, gepotidacin was generally associated with higher therapeutic success rates than nitrofurantoin. Results for the individual components of the primary outcome (clinical success/failure and microbiological success/failure) were generally similar between groups; however, microbiological success was achieved in more patients treated with gepotidacin (72.2%) versus nitrofurantoin (57.2%) in EAGLE-3.

Other uses
Gepotidacin was also studied for the treatment of uncomplicated urogenital gonorrhea in a phase 3 randomized, open-label, noninferiority trial (EAGLE-1).9 In the EAGLE-1 trial, 628 patients aged ≥12 years weighing ≥45 kg were randomized to receive oral gepotidacin (3000 mg per dose x2 doses given 10-12 hours apart) or intramuscular ceftriaxone 500 mg plus 1 gram of oral azithromycin. At test-of-cure (days 4-8), gepotidacin was found noninferior to ceftriaxone plus azithromycin for the primary outcome of microbiological success (defined by culture-confirmed bacterial eradication of Neisseria gonorrhoeae from the urogenital body site), with more than 90% of patients eliciting a microbiological response in both groups.

Gepotidacin has also been evaluated as a potential treatment option for skin and skin structure infections in a phase 2, dose-ranging trial.10 This trial consisted of an initial, double-blinded period where patients received intravenous gepotidacin 750 mg or 1000 mg every 12 hours for 2 to 3 days followed by an open-label phase where patients could be switched to 1 of 3 oral dosing regimens for a total treatment duration of 10 days. The trial’s primary outcome was a composite of efficacy (measured by cure within 48 to 72 hours after the first dose) and safety (ie, withdrawal due to drug-related adverse events). At the early efficacy visit (within 48 to 72 hours after the first dose), 2 of the 3 dosing groups in the trial met prespecified success criteria for clinical utility.

Conclusion
Overall, gepotidacin is a new oral antibiotic agent with a novel mechanism of action that has demonstrated similar or improved efficacy compared to nitrofurantoin for treatment of uncomplicated UTIs. Gepotidacin may also be an effective option for uncomplicated UTIs that are resistant to other antibiotics, and for other infectious diseases such as uncomplicated urogenital gonorrhea. Future studies will continue to define gepotidacin’s role in therapy for these and other infections.

References

  1. Al Lawati H, Blair BM, Larnard J. Urinary tract infections: core curriculum 2024. Am J Kidney Dis. 2024;83(1):90-100. doi:10.1053/j.ajkd.2023.08.009
  2. Kurotschka PK, Gágyor I, Ebell MH. Acute Uncomplicated UTIs in adults: rapid evidence review. Am Fam Physician. 2024;109(2):167-174.
  3. Anger J, Lee U, Ackerman AL, et al. Recurrent uncomplicated urinary tract infections in women: AUA/CUA/SUFU guideline. J Urol. 2019;202(2):282-289. doi:10.1097/JU.0000000000000296
  4. Hu S, Yu H, Gao J. Gepotidacin: The first-in-class triazaacenaphthylene antibiotic approved for the treatment of uncomplicated urinary tract infections. Drug Discov Ther. 2025;19(2):129-130. doi:10.5582/ddt.2025.01028
  5. Blujepa. Package insert. GlaxoSmithKline LLC; 2025.
  6. Watkins RR, Thapaliya D, Lemonovich TL, Bonomo RA. Gepotidacin: a novel, oral, ‘first-in-class’ triazaacenaphthylene antibiotic for the treatment of uncomplicated urinary tract infections and urogenital gonorrhoea. J Antimicrob Chemother. 2023;78(5):1137-1142. doi:10.1093/jac/dkad060
  7. Collins JA, Osheroff N. Gyrase and topoisomerase IV: recycling old targets for new antibacterials to combat fluoroquinolone resistance. ACS Infect Dis. 2024;10(4):1097-1115. doi:10.1021/acsinfecdis.4c00128
  8. Wagenlehner F, Perry CR, Hooton TM, et al. Oral gepotidacin versus nitrofurantoin in patients with uncomplicated urinary tract infection (EAGLE-2 and EAGLE-3): two randomised, controlled, double-blind, double-dummy, phase 3, non-inferiority trials. Lancet. 2024;403(10428):741-755. doi:10.1016/S0140-6736(23)02196-7
  9. Ross JDC, Wilson J, Workowski KA, et al. Oral gepotidacin for the treatment of uncomplicated urogenital gonorrhoea (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
  10. O’Riordan W, Tiffany C, Scangarella-Oman N, Perry C, Hossain M, Ashton T, Dumont E. Efficacy, safety, and tolerability of gepotidacin (GSK2140944) in the treatment of patients with suspected or confirmed gram-positive acute bacterial skin and skin structure infections. Antimicrob Agents Chemother. 2017;61(6):e02095-16. doi: 10.1128/AAC.02095-16

Prepared by:
Jessica Elste, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

June 2025

The information presented is current as of May 22, 2025. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.