Woojong Park, PharmD; CentraCare Paynesville
Background: Urinary tract infections (UTI) are one of the most common infections affecting females. Traditionally, empiric therapy with oral antibiotics has been widely accepted as a standard of care for uncomplicated UTIs. Nitrofurantoin, sulfamethoxazole-trimethoprim, fosfomycin, and pivmecillinam are approved as first-line therapies by the US Food and Drug Administration (FDA). However, the use of these agents is limited by increasing antibiotic resistance, lack of efficacy, or certain comorbidities. There is an increasing demand for a novel first-line oral agent to treat uncomplicated UTIs.
Objective: The purpose of EAGLE-2 and EAGLE-3 (Efficacy and Safety of Gepotidacin in the Treatment of Uncomplicated Urogenital Gonorrhea) was to compare the safety and efficacy of gepotidacin at doses of 1500 mg twice daily for 5 days versus nitrofurantoin 100 mg twice daily for 5 days in female patients with uncomplicated urinary tract infections.
Study Design: The EAGLE-2 and 3 studies were phase 3, double-blind, randomized, multicenter, non-inferiority trials conducted in 219 sites globally. To be eligible for the study, participants must be aged 12 years or older, non-pregnant, and female assigned at birth. Participants must have had two or more uncomplicated UTI symptoms within 96 hours of study entry with urinary nitrite, pyuria, or both. Exclusion criteria included participants with concomitant medications or a medical condition that could be a safety concern, signs or symptoms of complicated urinary tract infection, symptoms known or suspected to be caused by another disease, uncontrolled diabetes, and CrCl of less than 60 mL/min. The primary endpoint was therapeutic success, defined as both absence of symptoms and reduction of qualifying nitrofurantoin-susceptible uropathogens from 105 CFU/mL at baseline to <103 CFU/mL. The secondary endpoint was non-inferiority comparison to nitrofurantoin.
Results: Therapeutic success in EAGLE-2 was 50.6% (162/320) for gepotidacin versus 47.0% (135/287) for nitrofurantoin (adjusted difference 4.3%, 95% CI -3.6 to 12.1; post-hoc α-adjusted 96.2% CI -4.1 to 12.6). In EAGLE-3, therapeutic success was 58·5% (162/277) for gepotidacin versus 43.6% (115/264) for nitrofurantoin (adjusted difference 14.6%, 95% CI 6.4 to 22.8; post-hoc α-adjusted 96.4% CI 5.9 to 23.4). The lower limit of the 95% CI could not be used to determine non-inferiority because the study used a group sequential design with α spending at the interim analysis. Therefore, the study calculated post-hoc α-adjusted CIs to compare the lower limit of the CI to the non-inferiority margin. The study defined clinical outcome of unable to determine as either a missing baseline score, a missing test-of-cure assessment, or when a patient received other systemic antimicrobials not for uncomplicated UTI before the test-of-cure visit. Such an outcome was categorized as a clinical failure. The number of patients who did not achieve therapeutic success due to missing data was calculated post-hoc as 10.0% (32/320) for gepotidacin and 6.6% (19/287) for nitrofurantoin in EAGLE-2, and 10.8% (30/277) for gepotidacin and 8.7% (23/264) for nitrofurantoin in EAGLE-3. Diarrhea was the most common adverse event, with 111 (14%) of 766 patients reporting in EAGLE-2 and 147 (18%) of 804 patients in EAGLE-3. No potentially life-threatening or fatal adverse events were reported in either studies.
Conclusions: The results of this study supports the use of gepotidacin for first-line use in uncomplicated UTI. Gepotidacin showed a statistically significant difference in terms of therapeutic success, with common adverse events being mild-to-moderate diarrhea.
Key Point: Oral gepotidacin 1500 mg twice daily for 5 days was shown to be non-inferior to oral nitrofurantoin 100 mg twice daily for 5 days in terms of therapeutic success in both studies. The EAGLE studies may contribute to the addition of a novel uncomplicated UTI first-line therapy for females. Limitation of these studies should be considered however; the EAGLE studies had an extensive inclusion criteria, implying that the study population may not accurately represent that of clinical practice.
References:
- Czajkowski K, Broś-Konopielko M, Teliga-Czajkowska J. Urinary tract infection in women. Prz Menopauzalny. 2021;20(1):40-47.
- 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.