By William Elliott, MD, FACP, and James Chan, PharmD, PhD
The U.S. Food and Drug Administration (FDA) has approved gepotidacin, a first-in-class antibacterial medication for the treatment of uncomplicated urinary tract infections (uUTIs). Gepotidacin is an oral triazaacenaphthylene antibiotic that inhibits two essential enzymes in bacterial deoxyribonucleic acid (DNA) replication. It will be distributed by GlaxoSmithKline as Blujepa. It is the first new class of oral antibiotics approved in nearly 30 years.
Indications
Gepotidacin is indicated for the treatment of female adults and pediatric patients 12 years of age and older weighing at least 40 kilograms with uUTIs caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Citrobactor freundii complex, Staphylococus saprophyticus, and Enterococcus faecalis.1
Dosage
The recommended dose is 1,500 mg (two 750-mg tablets) taken orally twice daily (approximately 12 hours apart) for five days.1 It should be taken after a meal to reduce the possibility of gastrointestinal intolerance.1 Gepotidacin is available as 750-mg tablets.
Potential Advantages
Gepotidacin is a novel first-in-class oral bactericidal agent that inhibits bacterial DNA replication by blocking two essential topoisomerase enzymes (DNA gyrase and topoisomerase IV).1,2 These are distinct target-binding sites compared to other antimicrobials. Gepotidacin is bactericidal against E. coli, including extended-spectrum beta-lactamase producing isolates.3 It has a low potential for development of resistance, since mutation in both targeted enzymes would be required to result in a significant impact on gepotidacin activity.1,3
Potential Disadvantages
Gepotidacin has been associated with a dose- and concentration-dependent prolongation of the QTc interval.1 It should be avoided in patients with a history of QTc interval prolongation, with preexisting cardiac disease, taking antiarrhythmic agents, or taking drugs that potentially may prolong the QTc interval. Because of the risk of increased gepotidacin exposure, concomitant administration with strong CYP3A4 inhibitors should be avoided. Conversely, concomitant administration with strong CYP3A4 inducers should be avoided. Alternative agents should be considered for patients with severe hepatic impairment (Child-Pugh C), or severe renal impairment (estimated glomerular filtration rate < 30 mL/min).1
Gepotidacin is a reversible acetylcholinesterase inhibitor. As such, it may cause increased cholinergic adverse reactions (e.g., dysarthria, diarrhea, nausea, vomiting, hypersalivation, hyperhidrosis) as well as exaggerated effects of concomitantly administered acetylcholinesterase inhibitors. As with all systemic antibacterials, there is a risk of Clostridioides difficile infections. The most common adverse reaction associated with gepotidacin (vs. nitrofurantoin) is diarrhea (16% vs. 3%).1
Comments
The efficacy and safety of gepotidacin for the treatment of uUTIs were evaluated in two parallel-group, double-blind, double dummy, noninferiority trials compared to nitrofurantoin.1,4 Study participants had at least two symptoms consistent with uUTI (dysuria, frequency, urgency, or lower abdominal pain) along with evidence of urinary nitrite or pyuria. Subjects with complicated UTI or an upper UTI were excluded. Participants were randomized to gepotidacin 1,500 mg twice daily with food for five days (trial 1 [EAGLE-2], n = 336; trial 2 [EAGLE-3], n = 292) or nitrofurantoin 100 mg twice daily for five days (trial 1, n = 298; trial 2, n = 275). The mean age of participants was 51.5 years, 84.5% were white, and 40% had a history of recurrence of uUTI.
Efficacy was based on a composite of clinical cure and microbiological cure at the test-of-cure visit (study day 10-13) in the microbiological intention-to-treat nitrofurantoin-susceptible population participants who received at least one dose of study medication and had at least one baseline qualifying uropathogen (≥ 105 CFU/mL). Microbiological response was defined as all qualifying uropathogens reduced to < 103 CFU/mL without administration of other systemic antimicrobials. Clinical cure was defined as resolution of all signs and symptoms of acute cystitis present at baseline and no new signs and symptoms without the need for other systemic antimicrobials. Gepotidacin was found to be noninferior to nitrofurantoin in EAGLE-2 (51.8% vs. 47.0%) and noninferior and superior to nitrofurantoin in EAGLE-3 (58.9% vs. 44.0%). Rates of clinical recurrence (without additional antibiotic treatment) at follow-up for both groups were low (< 4%).4
Clinical Implications
Gepotidacin is the latest and a first-in-class antibacterial medication approved for uUTIs. It follows sulopenem/probenecid approved last October indicated for the treatment of uUTIs caused by designated microorganisms (E. coli, K. pneumoniae, or Proteus mirabilis) in adult women who have limited or no alternative oral antibacterial treatment options and targeting extended-spectrum beta-lactamases (ESBL-E) producing Enterobacterales. UTI is a very common infection. There are numerous treatment options, including nitrofurantoin, trimethoprim/sulfamethoxazole, oral beta-lactams (e.g., amoxicillin-clavulanate), fluoroquinolones (e.g., ciprofloxacin), fosfomycin, and pivmecillinam. Gepotidacin was compared to nitrofurantoin, a recommended first-line therapy, to gain FDA approval, with one of two studies showing superiority against nitrofurantoin-susceptible uropathogens. Launch is expected in the second half of 2025.
References
1. GlaxoSmithKline. Blujepa prescribing information. Revised March 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/218230s000lbl.pdf
2. 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.
3. Flamm RK, Farrell DJ, Rhomberg PR, et al. Gepotidacin (GSK2140944) in vitro activity against gram-positive and gram-negative bacteria. Antimicrob Agents Chemother. 2017;27;61(7):e00468-17.
4. 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.
