Gepotidacin (Blujepa): A New Oral Antibiotic for Uncomplicated UTIs!!

Urinary Tract Infections (UTIs) – Need for a Novel Antibiotic

Uncomplicated urinary tract infections (UTIs) are among the most common bacterial infections. They are defined as bacterial infections of the bladder in generally healthy individuals who do not have any underlying health issues or structural abnormalities in their urinary tract. Uncomplicated UTIs are notably common among women. It is estimated that up to 80% of women suffer from at least one uncomplicated UTI in their lifetime, and around 45% will face recurrent episodes.

Uncomplicated UTIs are frequently cited as one of the leading conditions for which antibiotics are prescribed. A history of antibiotic use is linked to an increased likelihood of developing antimicrobial resistance, thereby presenting a potential public health issue. Notably, there is an increasing trend of antimicrobial resistance in common uropathogens (UTI-causing bacteria), E. coli, against widely prescribed therapies for uncomplicated UTIs, such as fluoroquinolones. As a result, there is a pressing demand for new oral treatment options.

Gepotidacin (Blujepa)- First in a New Class of Oral Antibiotics

Gepotidacin has been a new oral antibiotic for uncomplicated UTIs for almost three decades. It is bactericidal, a first-in-class triazaacenaphthylene antibiotic. On March 25, 2025, the US Food and Drug Administration approved GSK ‘s Gepotidacin under the brand name Blujepa.  The approval was based on the pivotal Phase III EAGLE-2 and EAGLE-3 clinical trials. The distinctive structure and mode of action of Gepotidacin enable it to maintain effectiveness against target pathogens that have developed resistance to other antimicrobial agents, such as fluoroquinolones. Gepotidacin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections. It is active against most strains of Escherichia coli, Staphylococcus saprophyticus, and Neisseria gonorrhoeae, including those resistant to current antibiotics.

Gepotidacin (Blujepa)- Unique Mechanism of Action

Topoisomerases are enzymes that manage the structural configuration of DNA, a function essential for various biological processes. They are categorized into two types: Type I, which breaks a single DNA strand, and Type II, which cuts both strands. Gepotidacin (Blujepa)  inhibits Type II topoisomerases, including bacterial topoisomerase II (DNA gyrase) and topoisomerase IV, thereby hindering DNA replication. The fluoroquinolones also target DNA gyrase and topoisomerase IV, but the investigations into the structural characteristics of Type II topoisomerase and DNA gyrase suggest that Gepotidacin (BLUJEPA) utilizes a unique binding site, distinguishing it from fluoroquinolones.

Gepotidacin (Blujepa)- Pivotal EAGLE-2 and EAGLE-3 Trials

• Study design – Phase 3, randomised, multicentre, double-blind, double-dummy, non-inferiority trials. Both the trials compared the efficacy and safety of Gepotidacin (1500mg twice daily for five days) to Nitrofurantoin (100 mg twice daily for five days).
• Number of subjects (N) randomized
  • EAGLE-2: N = 1531 (767 participants in the Gepotidacin group and 764 participants in the Nitrofurantoin group).
  • EAGLE-3: N = 1605 (805 in the Gepotidacin group and 800 in the Nitrofurantoin group).
• Main inclusion criteria: Non-pregnant female patients aged 12 years or older, weighing at least 40 kg, who exhibit two or more symptoms, including dysuria, frequency, urgency, or lower abdominal pain, and who show evidence of urinary nitrite, pyuria, or both.
• Results
  • EAGLE-2 – Gepotidacin demonstrated non-inferiority to Nitrofurantoin (Blujepa), achieving a therapeutic success rate of 50.6%, while nitrofurantoin had a success rate of 47.0% [adjusted difference 4.3%, 95% confidence interval (CI) –3.6 to 12.1].
  • EAGLE-3 – Gepotidacin exhibited a statistically significant superiority over Nitrofurantoin (P-value=0.0003). The therapeutic success rate was 58.5% for participants receiving Gepotidacin, compared to 43.6% for those on Nitrofurantoin (adjusted difference 14·6%, 95% CI 6·4 to 22·8).
• Safety profile
  • The most common adverse event associated with Gepotidacin was diarrhoea, which was observed in 14% of patients in EAGLE-2 and 18% of patients in EAGLE-3.
  • The majority of cases were classified as mild or moderate, with no occurrences of life-threatening or fatal events.

Gepotidacin (Blujepa)- Other Pivotal Trial EAGLE -1

• A phase 3, randomized, multicenter, noninferiority study that compared the efficacy of Gepotidacin (2 × 3000 mg 10-12 h apart) with Ceftriaxone (500 mg, intramuscular) plus Azithromycin (1 g, oral) in 400 patients with uncomplicated urogenital gonorrhea
• With a microbiological success rate of 92.6%, Gepotidacin was found to be non-inferior to the leading combination treatment.
• The predominant adverse events reported among Gepotidacin subjects were gastrointestinal in nature.

Gepotidacin (Blujepa)- Indication, Dosage and Administration

• The approved indications are for the treatment of uncomplicated UTIs in adult females (≥40 kg) and paediatric patients (≥12 years, ≥40 kg) caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii complex, Staphylococcus saprophyticus and Enterococcus faecalis.
• Gepotidacin (Blujepa) is available as 750 mg tablets. The recommended dosage is 1,500 mg (two 750 mg tablets) taken orally, twice daily (~12 hours apart), for 5 days.
• Gepotidacin (Blujepa) tablets should be administered after a meal to reduce the possibility of gastrointestinal intolerance.

Gepotidacin (Blujepa)- Common Side Effects

• The most prevalent side effects experienced by 1% or more patients are diarrhea, nausea, abdominal pain, gas, headaches, loose feces, dizziness, vomiting, and vulvovaginal candidiasis.

Gepotidacin (Blujepa)- Warning and Precautions

• Avoid use in individuals with a history of QTc prolongation, those with significant pre-existing cardiac conditions, and patients taking medications that extend the QTc interval.
• Avoid concomitant administration with strong CYP3A4 inhibitors drugs (e.g., itraconazole, ketoconazole).
• Avoid use in patients with severe renal impairment (estimated glomerular filtration rate <30 mL/min) and hepatic impairment (Child-Pugh Class C).

Further Reading

• https://www.mdpi.com/2076-0817/12/4/623
• https://www.ncbi.nlm.nih.gov/books/NBK470195
• https://www.sciencedirect.com/science/article/pii/S2213716521002599#sec0001
• https://journals.asm.org/doi/10.1128/aac.01263-21
• https://academic.oup.com/jac/article/78/5/1137/7072215
• https://www.sciencedirect.com/science/article/pii/S2213716521002599#sec0001
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/218230s000lbl.pdf
• https://pmc.ncbi.nlm.nih.gov/articles/PMC5487655/#sec3
• https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)02196-7/abstract
• https://pubmed.ncbi.nlm.nih.gov/37751016
• https://www.gsk.com/en-gb/media/press-releases/eagle-1-phase-iii-data-show-potential-for-gepotidacin-as-a-new-oral-treatment-option-for-uncomplicated-gc