Written by Lavanya Chavhan (B.Pharm) and Aishwarya Shinde (B.Pharm)
Reviewed and Fact Checked by Vikas Londhe M.Pharm (Pharmacology)
In a significant development in the fight against urinary tract infections (UTIs), the U.S. Food and Drug Administration (FDA) has approved Blujepa (gepotidacin), a groundbreaking oral antibiotic designed to treat uncomplicated UTIs in female patients aged 12 and older. This marks the first new class of oral antibiotics for UTIs in nearly three decades, offering hope to millions of women who suffer from recurrent infections that are increasingly resistant to traditional treatments.
Background and Need for New Treatments
UTIs are primarily caused by bacteria, most commonly Escherichia coli (E. coli) (75-95% of cases). Other pathogens include Klebsiella pneumoniae, Proteus mirabilis Staphylococcus saprophyticus (common in young women) and Enterococcus faecalis potentially affecting the bladder (cystitis), urethra (urethritis), or kidneys (pyelonephritis).
Conventional treatment for Uncomplicated UTIs includes first-line antibiotics Nitrofurantoin, Trimethoprim-sulfamethoxazole (TMP-SMX), Fosfomycin. Alternatives treatment includes Cephalexin and Amoxicillin-clavulanate if resistance is low.
In Complicated UTIs like UTI in pregnancies, diabetes, or kidney involvement (pyelonephritis) broad-spectrum antibiotics are implemented like Ciprofloxacin, Levofloxacin, and intravenous Ceftriaxone. More severe infections may need piperacillin/tazobactam, meropenem, ertapenem, or doripenem.
UTI is one of the most commonly affecting bacterial infection affecting 150 million people per year globally. Women are at higher risk (50-60% experience ≥1 UTI in their lifetime) due to shorter urethras. Elderly & catheterized patients also have increased susceptibility.
Antibiotic resistance is the rising concern in UTI treatment, resistance to TMP-SMX, fluoroquinolones (e.g., Ciprofloxacin), and beta-lactams complicated the treatment process. ESBL-producing E. coli which is resistant to penicillin/Cephalosporins is a growing concern and which can leads to longer infections, higher recurrence rates, and increased use of IV antibiotics.
These increased concerns of antibiotic resistance necessitating the development of new antibiotics with novel mechanisms of action.
Blujepa (Gepotidacin): A Novel Approach
Blujepa is developed by GlaxoSmithKline (GSK) is a novel first-in-class triazaacenaphthylene antibiotic that belongs to a new category called bacterial topoisomerase inhibitors. It exhibits a unique mechanism of action distinct from other antibiotics, targeting bacterial type II topoisomerases.
Gepotidacin selectively inhibits bacterial DNA gyrase (topoisomerase II) and topoisomerase IV, both critical enzymes for DNA replication and transcription. Unlike fluoroquinolones (which stabilize topoisomerase-DNA cleavage complexes), gepotidacin blocks the ATP-independent strand-passage reaction, preventing DNA relaxation and decatenation.
It binds to a novel site on the GyrB (gyrase) and ParE (topoisomerase IV) subunits, distinct from fluoroquinolone binding sites.
This reduces the likelihood of cross-resistance with existing antibiotics. By interfering with DNA replication and repair, gepotidacin causes lethal double-stranded DNA breaks, leading to bacterial cell death.
This unique mechanism reduces the likelihood of antimicrobial resistance, making it a promising solution for recurrent or treatment-resistant UTIs
Clinical Trials and Approval
The FDA’s approval of Blujepa was based on results from two pivotal Phase III clinical trials, EAGLE-2 and EAGLE-3.
The EAGLE-2 trial was a Phase III, randomized, double-blind study evaluating the efficacy and safety of gepotidacin. Trial was conducted across multiple centres worldwide, the trial enrolled non-pregnant females weighing at least 40 kg who exhibited symptoms such as dysuria, frequency, urgency, or lower abdominal pain, along with evidence of urinary nitrite or pyuria. Participants were randomly assigned to receive either oral gepotidacin (1500 mg twice daily for 5 days) or oral nitrofurantoin (100 mg twice daily for 5 days). The primary endpoint was therapeutic success, defined as complete symptom resolution and microbiological eradication of the uropathogen without the need for additional antimicrobial treatment. In the EAGLE-2 trial, therapeutic success was achieved in 50.6% of patients treated with gepotidacin compared to 47.0% of those receiving nitrofurantoin demonstrating non-inferiority of gepotidacin to nitrofurantoin.
EAGLE-3 trial was randomized, double-blind, double-dummy, non-inferiority trial compared gepotidacin (1500 mg twice daily for 5 days) to nitrofurantoin (100 mg twice daily for 5 days), a standard uUTI treatment. The results demonstrated that gepotidacin was statistically superior to nitrofurantoin in achieving therapeutic success at the test-of-cure visit (days 10–13). Specifically, therapeutic success was observed in 58.5% of patients receiving gepotidacin compared to 43.6% in the nitrofurantoin group.
Safety Profile
Blujepa carries the warning signs of QTc prolongation and hypersensitivity reactions. The safety profile of gepotidacin was consistent with previous studies. Common adverse events were gastrointestinal-related, such as diarrhea (16%) and nausea (4%). Most of these adverse events were mild or moderate, with severe events occurring in less than 1% of participants.
Impact and Future Directions
The approval of Blujepa is a crucial milestone in addressing the growing challenge of antibiotic resistance in UTIs. It provides a new treatment option for patients experiencing recurrent infections and offers hope for reducing the strain on healthcare systems.
As noted by GSK’s Chief Scientific Officer, Tony Wood, this approval is significant for women who face recurrent infections and rising resistance rates.
In conclusion, the FDA’s approval of Blujepa marks a significant advancement in the treatment of uncomplicated UTIs, offering a new and effective option for managing these common infections. As the first new oral antibiotic for UTIs in nearly 30 years, Blujepa represents a promising step forward in combating antimicrobial resistance and improving patient outcomes.
References
1. Blujepa (gepotidacin) approved by US FDA for treatment of uncomplicated urinary tract infections (uUTIs) in female adults and paediatric patients 12 years of age and older, GSK, 25 March 2025, available from https://www.gsk.com/en-gb/media/press-releases/blujepa-gepotidacin-approved-by-us-fda-for-treatment-of-uncomplicated-urinary-tract-infections/
2. Flores-Mireles AL, Walker JN, Caparon M, Hultgren SJ. Urinary tract infections: epidemiology, mechanisms of infection, and treatment options. Nat Rev Microbiol. 2015 May; 13(5):269-84. DOI: 10.1038/nrmicro3432. Epub 2015 Apr 8. PMID: 25853778; PMCID: PMC4457377
3. Bono MJ, Leslie SW. Uncomplicated Urinary Tract Infections. [Updated 2025 Feb 21]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470195/
4. Sabih A, Leslie SW. Complicated Urinary Tract Infections. [Updated 2024 Dec 7]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK436013/
5. Mareș C, Petca RC, Popescu RI, et al, Update on Urinary Tract Infection Antibiotic Resistance-A Retrospective Study in Females in Conjunction with Clinical Data. Life (Basel). 2024 Jan 9;14(1):106. Doi: 10.3390/life14010106. PMID: 38255721; PMCID: PMC10820678
6. Emina K. Sher, Amina Džidić-Krivić, et al, Current state and novel outlook on prevention and treatment of rising antibiotic resistance in urinary tract infections, Pharmacology & Therapeutics, Volume 261, 2024, 108688, https://doi.org/10.1016/j.pharmthera.2024.108688
7. Blujepa (gepotidacin), Highlights Of Prescribing Information, available from https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/218230s000lbl.pdf
8. Wagenlehner, Florian 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, The Lancet, Volume 403, Issue 10428, 741 – 755
9. Clinical Implications, Study Takeaways of Gepotidacin for Uncomplicated UTIs, 28 March 2025, Contagion Live, available from https://www.contagionlive.com/view/clinical-implications-study-takeaways-of-gepotidacin-for-uncomplicated-utis
Add a Comment