European Association of Urology Guidelines on Urological Infections: Summary of the 2024 Guidelines.

BACKGROUND AND OBJECTIVE: Urological infections significantly impact the wellbeing and quality of life of individuals owing to their widespread occurrence and diverse clinical manifestations. The objective of the guidelines panel was to provide evidence-based guidance on the diagnosis, treatment, and prevention of urinary tract infections (UTIs) and male accessory-gland infections, while addressing crucial public health aspects related to infection control and antimicrobial stewardship. METHODS: For the 2024 guidelines on urological infections, new and relevant evidence was identified, collated, and appraised via a structured assessment of the literature. Databases searched included Medline, EMBASE, and the Cochrane Libraries. Recommendations within the guidelines were developed by the panel to prioritise clinically important care decisions. The strength of each recommendation was determined according to a balance between desirable and undesirable consequences of alternative management strategies, the quality of the evidence (including the certainty of estimates), and the nature and variability of patient values and preferences. KEY FINDINGS AND LIMITATIONS: Key recommendations emphasise the importance of a thorough medical history and physical examination for patients with urological infections. The guidelines stress the role of antimicrobial stewardship to combat the rising threat of antimicrobial resistance, providing recommendations for antibiotic selection, dosing, and duration on the basis of the latest evidence. CONCLUSIONS AND CLINICAL IMPLICATIONS: This overview of the 2024 EAU guidelines offers valuable insights into managing urological infections and are designed for effective integration into clinical practice. PATIENT SUMMARY: The European Association of Urology has issued an updated guideline on urological infections. The guidelines provide recommendations for diagnosis, treatment, and prevention, with a particular focus on minimising antibiotic use because of the increasing global threat of antimicrobial resistance.

Keep it Simple: A Proposal for a New Definition of Uncomplicated and Complicated Urinary Tract Infections from the EAU Urological Infections Guidelines Panel.

The European Association of Urology Urological Infections Guidelines Panel is proposing a new classification scheme for categorizing urinary tract infections (UTIs) into uncomplicated and complicated types. This classification would provide clarity and facilitate effective clinical management of UTIs, and acknowledges the importance of addressing clinical and sex-specific nuances in the care of individual patients.

Patient outcomes by baseline pathogen resistance phenotype and genotype in CERTAIN-1, a Phase 3 study of cefepime-taniborbactam versus meropenem in adults with complicated urinary tract infection.

CERTAIN-1 was a Phase 3, double-blind, randomized, parallel group study of the efficacy and safety of cefepime-taniborbactam versus meropenem in the treatment of adults with complicated urinary tract infection (cUTI), including acute pyelonephritis. We determined susceptibility of Enterobacterales and Pseudomonas aeruginosa baseline pathogens to cefepime-taniborbactam and comparators and characterized ß-lactam resistance mechanisms. Microbiologic response and clinical response were assessed in patient subsets defined by baseline pathogens that were of cefepime-, multidrug-, or carbapenem-resistant phenotype or that carried ß-lactamase genes. Among Enterobacterales baseline pathogens, 26.8%, 4.1%, and 3.0% carried genes for extended-spectrum ß-lactamases (ESBLs), AmpC, and carbapenemases, respectively. Within each treatment group, while composite success rates at Test of Cure in resistant subsets by pathogen species were similar to those by pathogen overall, composite success rates in meropenem patients were numerically lower for cefepime-resistant Escherichia coli (9/19; 47.4%) and ESBL E. coli (13/25; 52.0%) compared with E. coli overall (62/100; 62.0%). Cefepime-taniborbactam achieved composite success in 7/8 (87.5%) patients with carbapenem-resistant Enterobacterales and 8/9 (88.9%) patients with Enterobacterales with a carbapenemase gene (5 OXA-48-group; 2 KPC-3; 2 NDM-1). Cefepime-taniborbactam also achieved composite success in 8/16 (50.0%) patients and clinical success in 13/16 (81.3%) patients with P. aeruginosa; corresponding rates were 4/7 (57.1%) and 6/7 (85.7%) for meropenem. Cefepime-taniborbactam demonstrated efficacy in adult cUTI patients with cefepime-, multidrug-, and carbapenem-resistant pathogens including pathogens with ESBL, AmpC, and carbapenemase genes. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT03840148.

Systematic Review and Meta-Analysis Provide no Guidance on Management of Asymptomatic Bacteriuria within the First Year after Kidney Transplantation.

(1) Background: Urinary tract infections (UTIs) are among the most frequent complications in kidney transplant (KT) recipients. Asymptomatic bacteriuria (ASB) may be a risk factor for UTIs and graft rejection. We aimed to evaluate available evidence regarding the benefit of screening and treatment of ASB within the first year after KT. (2) Evidence acquisition: A systematic literature search was conducted in MEDLINE, the Cochrane Library CENTRAL and Embase. Inclusion criteria were manuscripts in English addressing the management of ASB after KT. The PICO questions concerned Patients (adults receiving a KT), Intervention (screening, diagnosis and treatment of ASB), Control (screening and no antibiotic treatment) and Outcome (UTIs, sepsis, kidney failure and death). (3) Evidence synthesis: The systematic review identified 151 studies, and 16 full-text articles were evaluated. Seven were excluded because they did not evaluate the effect of treatment of ASB. There was no evidence for a higher incidence of lower UTIs, acute pyelonephritis, graft loss, or mortality in patients not treated with antibiotics for ASB. Analysis of comparative non-randomized and observational studies did not provide supplementary evidence to guide clinical recommendations. We believe this lack of evidence is due to confounding risk factors that are not being considered in the stratification of study patients.

Urosepsis 30-day mortality, morbidity, and their risk factors: SERPENS study, a prospective, observational multi-center study.

PURPOSE: To provide a descriptive report of mortality and morbidity in the first 30 days of diagnosis of urosepsis. Secondary aim is to identify risk factors of unfavourable outcomes. METHODS: Prospective observational multicentre cohort study conducted from September 2014 to November 2018 in European hospitals. Adult patients (≥ 18 years) diagnosed with acute urosepsis according to Sepsis-2 criteria with confirmed microbiological infection were included. Outcomes were classified in one of four health states: death, multiple organ failure, single organ failure, and recovery at day 30 from onset of urosepsis. Descriptive statistics and ordinal logistic regression analysis was performed. RESULTS: Three hundred and fifty four patients were recruited, and 30-day mortality rate was 2.8%, rising to 4.6% for severe sepsis. All patients who died had a SOFA score of ≥ 2 at diagnosis. Upon initial diagnosis, 79% (n = 281) of patients presented with OF. Within 30 days, an additional 5% developed OF, resulting in a total of 84% affected. Charlson score (OR 1.14 CI 1.01-1.28), patients with respiratory failure at baseline (OR 2.35, CI 1.32-4.21), ICU admission within the past 12 months (OR 2.05, CI 1.00-4.19), obstruction causative of urosepsis (OR 1.76, CI 1.02-3.05), urosepsis with multi-drug-resistant(MDR) pathogens (OR 2.01, CI 1.15-3.53), and SOFA baseline score ≥ 2 (OR 2.74, CI 1.49-5.07) are significantly associated with day 30 outcomes (OF and death). CONCLUSIONS: Impact of comorbidities and MDR pathogens on outcomes highlights the existence of a distinct group of patients who are prone to mortality and morbidity. These findings underscore the need for the development of pragmatic classifications to better assess the severity of UTIs and guide management strategies. STUDY REGISTRATION: Clinicaltrials.gov registration number NCT02380170.

Impaired Semen Quality in Patients with Chronic Prostatitis.

Background/Objectives: Chronic prostatitis/chronic pelvic pain syndrome CP/CPPS is a rather common condition and in recent years many studies have shown contradictory results regarding its impact on semen quality. This prospective cohort study set out to investigate how CP/CPPS affected the parameters of semen in a prospective cohort of patients compared with the WHO 2021 reference group. Methods: From 2013 to 2022, a total of 1071 patients with suspicion of CP/CPPS received a comprehensive andrological examination. Complete semen analysis was carried out in compliance with WHO 2010 guidelines, comparing every study population semen variable to the WHO 2021 reference group (n~3500). Results: All evaluated semen parameters had median values that fell within a normal range. Nonetheless, approximately 25% of patients had values for each semen variable that were lower than the WHO reference group's fifth percentile. In particular, bacteriospermia was associated with a negative impact on semen volume. Conclusions: This is the largest study that compares all standard semen parameters in patients suffering from CP/CPPS to WHO 2021 reference values. It provides evidence of an impairment of conventional semen parameters.

Descending perineal syndrome cure by deep transversus perinei ligament repair: surgical options.

Descending perineal syndrome (DPS) was described by Parks et al. as descent of the anus on straining, typically 3-4 cm below a line drawn from the coccyx to the lower end of the. DPS is associated with obstructed defecation, with increased bulging of the perineum with straining, although perineal descent can also be seen at rest. In their review, Chaudhry and Tarnay stated: "It is controversial whether surgical management is even an option for patients with DPS". The deep transversus perinei (DTP) ligaments are the suspensory ligaments of the perineal body (PB). DTP are approximately 4 cm long. They attach behind the upper 2/3 and lower 1/3 of the descending ramus. If, at childbirth, the PB is overstretched and displaced laterally and inferiorly, the DTP lengthens. DPS is described as descent of the anus on straining, typically 3-4 cm below a line drawn from the coccyx to the lower end of the symphysis. DPS is associated with obstructed and often, assisted defecation, with increased bulging of the perineum with straining descent of the anus on straining. The surgical methodology begins as a standard PB repair which dissects the rectum from the vagina and PB and approximates the displaced components of the PB. We added an additional step: identifying the DTPs, shortening and reinforcing them with the Tissue Fixation System (TFS) minisling or No. 2 polyester sutures. High cure rates for obstructed defecation were achieved with the TFS minisling, and initial results using No. 2 polyester sutures are favourable. The key messages from both operations is DPS is caused by stretching and elongation of DPS ligaments, and these are surgically repairable.

Chronic pelvic pain of "unknown origin" in the female.

The remit of this review is confined to the experimental scientific works and surgeries based on the Integral Theory Paradigm (ITP). Chronic pelvic pain (CPP) is a major societal problem which is said to occur in up to 20% of women. The pathogenesis of CPP of "unknown origin" is said to be unknown and CPP is said to be incurable. According to the ITP, however, CPP is said to be mainly caused by the inability of loose or weak uterosacral ligaments (USLs) to mechanically support visceral nerve plexuses (VPs), T11-L2 and S2-4. These fire off de novo impulses, interpreted by the cortex as pain coming from the end organs. CPP, when it occurs simultaneously in multiple pelvic sites, is associated with uterine/apical prolapse (often minimal) and bladder symptoms such as overactive bladder (OAB), nocturia, retention. This combination of symptoms was described in 1993 as the "posterior fornix syndrome" (PFS). As such, CPP when associated with the PFS, is potentially curable by surgical repair of USLs. However, patients with CPP generally complain only of one symptom, CPP. This is known as the "Pescatori iceberg" effect. Other PFS symptoms are "under the surface" and must be sought out by direct questioning. The diagnostic algorithm is helpful in locating other associated symptoms. Definitive diagnosis of CPP, caused by USL laxity, is immediate alleviation of pain by mechanical support of USLs by using the speculum test or by tampons in the posterior fornix. Treatment of CPP can be non-surgical, by strengthening USLs by squatting exercises, supporting USLs mechanically with tampons or USL surgery. Coexisting bladder symptoms are (variously) improved or cured. URL for CPP https://www.pelviperineology.org/volume/36/issue/3.

Therapeutic strategies for uncomplicated cystitis in women.

Uncomplicated cystitis is affecting many women of all ages and has a great impact on the quality of life, especially in women suffering from recurrent, uncomplicated cystitis. By far the most frequent uropathogen, E. coli, may have acquired increasing resistance against a variety of oral antibiotics, which may differ between countries and regions. Therefore, local resistance data are important to be considered. On the other hand, non-antibiotic therapy has also become an option which should be discussed and offered to the patient. In patients suffering from recurrent uncomplicated cystitis, individual risk factors and possible behavioral changes should first be taken into account. Non-antimicrobial prophylactic strategies shown to be successful in well-designed clinical studies are the next options. Long term antibiotic prophylaxis, however, should only be considered as a last option. For some of those patients self-diagnosis and self-treatment may be suitable, e.g. by using a recognized questionnaire.

T cells in testicular germ cell tumors: new evidence of fundamental contributions by rare subsets.

BACKGROUND: Immune cell infiltration is heterogeneous but common in testicular germ cell tumors (TGCT) and pre-invasive germ cell neoplasia in situ (GCNIS). Tumor-infiltrating T cells including regulatory T (Treg) and follicular helper T (Tfh) cells are found in other cancer entities, but their contributions to TGCT are unknown. METHODS: Human testis specimens from independent patient cohorts were analyzed using immunohistochemistry, flow cytometry and single-cell RNA sequencing (scRNA-seq) with special emphasis on delineating T cell subtypes. RESULTS: Profound changes in immune cell composition within TGCT, shifting from macrophages in normal testes to T cells plus B and dendritic cells in TGCT, were documented. In most samples (96%), the CD4+ T cell frequency exceeded that of CD8+ cells, with decreasing numbers from central to peripheral tumor areas, and to tumor-free, contralateral testes. T cells including Treg and Tfh were most abundant in seminoma compared to mixed tumors and embryonal carcinoma. CONCLUSION: Despite considerable heterogeneity between patients, T cell subtypes form a key part of the TGCT microenvironment. The novel finding of rare Treg and Tfh cells in human testis suggests their involvement in TGCT pathobiology, with implications for understanding tumor progression, to assess patients' prognosis, and as putative targets for personalized immunotherapy.

The Diagnosis, Treatment, and Prevention of Recurrent Urinary Tract Infection.

BACKGROUND: Urinary tract infection has a one-year prevalence of 11% in women and ranges among the most common reasons for consulting a primary care physician and for receiving a prescription for antibiotics. In the case of recurrent urinary tract infection (rUTI), there are questions about the further work-up, treatment, and preventive measures. METHODS: The systematic literature search performed for the update of the German clinical practice guideline on uncomplicated urinary tract infection (043-044) (up to February 2022) was supplemented with a selective search for clinical trials (up to August 2023). RESULTS: Urine culture and ultrasonography are reasonable steps in the diagnostic evaluation of rUTI. Further invasive testing is suggested for men but is not routinely indicated for women. Antibiotics are among the most effective preventive measures (risk ratio [RR] 0.15, 95% confidence interval [0.1; 0.3]) but carry a high risk of side effects. Non-antibiotic preparations such as cranberry juice (RR 0.74 [0.5; 0.99]), mannose (RR 0.23 [0.14; 0.37]), and vaginal estrogen (RR, 0.42 [0.30; 0.59]) can also reduce the infection rate, with a low risk of side effects. Increased daily fluid intake has been shown to lower infection rates in the short term (odds ratio [OR] 0.13 [0.07; 0.25]); the use of hygienically advisable wiping techniques after passing stool or urine has been little studied but can be implemented with no risk. CONCLUSION: rUTI poses a challenge for the treating physician. The measures to be taken must be considered on an individual basis. Vulnerable groups, such as older patients, need special attention.

The oxytocin antagonist cligosiban reduces human prostate contractility: Implications for the treatment of benign prostatic hyperplasia.

BACKGROUND AND PURPOSE: With increasing life expectancy, benign prostatic hyperplasia (BPH) consequently affects more ageing men, illustrating the urgent need for advancements in BPH therapy. One emerging possibility may be the use of oxytocin antagonists to relax smooth muscle cells in the prostate, similar to the currently used (although often associated with side effects) α1-adrenoceptor blockers. EXPERIMENTAL APPROACH: For the first time we used live-imaging, combined with a novel image analysis method, to investigate the multidirectional contractions of the human prostate and determine their changes in response to oxytocin and the oxytocin antagonists atosiban and cligosiban. Human prostate samples were obtained and compared from patients undergoing prostatectomy due to prostate cancer as well as from patients with transurethral resection of prostate tissue due to severe BPH. KEY RESULTS: The two cohorts of tissue samples showed spontaneous multidirectional contractions, which significantly increased after the addition of oxytocin. Different to atosiban, which showed ambiguous effects of short duration, only long-acting cligosiban reliably prevented, as well as counteracted, any contractile oxytocin effect. Furthermore, cligosiban visibly reduced not only oxytocin-induced contractions, but also showed intrinsic activity to relax prostatic tissue. CONCLUSION AND IMPLICATIONS: Thus, the oxytocin antagonist cligosiban could be an interesting candidate in the search for novel BPH treatment options.

[Urosepsis: pathophysiology, diagnosis, and management-an update]. / Urosepsis: Pathophysiologie, Diagnose und Management ­ ein Update.

Urinary tract infections vary widely in their clinical spectrum, ranging from uncomplicated cystitis to septic shock. Urosepsis accounts for 9-31% of all cases of septicemia and is often associated with nosocomial infections. A major risk factor for urosepsis is the presence of obstructive uropathy, caused by conditions such as urolithiasis, tumors, or strictures. The severity and course of urosepsis depend on both the virulence of the pathogen and the patient's specific immune response. Prompt therapy, including antimicrobial treatment and eradication of the infection source, along with supportive measures for circulatory and respiratory stabilization, and adjunctive therapies such as hemodialysis and glucocorticoid therapy, is crucial. Due to demographic changes, an increase in cases of urosepsis is expected-thus, it is of utmost importance for urologists to be familiar with targeted diagnostics and effective treatment.

[Priapism]. / Priapismus.

Priapism is defined as penile erection lasting more than four hours that is unrelated to sexual arousal. Priapism is classified based on the oxygenation of the penile tissue into ischemic and non-ischemic subtypes. As the most common form, ischemic priapism is usually associated with pain and carries a significant risk of permanent loss of erectile function; thus, rapid intervention is necessary. Initial therapy consists of corporal aspiration and injection of sympathomimetic agents. If detumescence is not achieved, a cavernosal shunt is necessary. Non-ischemic priapism is less common than the ischemic type and is usually the result of perineal trauma. In this subtype, there is usually no pain and treatment is initially conservative. Recurrent (stuttering) priapism is a variant of the ischemic subtype, but is self-limiting and usually occurs during sleep with a duration of less than three to four hours. In the case of prolonged erection, therapy is analogous to that of the ischemic subtype.

On the relationship between various anticoagulants and robot-assisted radical prostatectomy: a single-surgeon serial analysis.

Prostate cancer patients often have other health conditions and take anticoagulants. It was believed that surgery under anticoagulants could worsen surgical results. This study aims to explore the safety of robot-assisted prostatectomy in anticoagulated patients, without any exclusion criteria. The study included 500 patients who underwent RARP by a single surgeon between April 2019 and August 2022. Patients were divided into two groups: Group 1, consisting of 376 men (75.2%), did not receive any anticoagulation, while Group 2, with 124 patients (24.8%), received different forms of anticoagulation. Then, the anticoagulation group was divided into 4 subgroups according to their definite anticoagulation: the aspirin 15.6%, new oral anticoagulants (NOAC) 5.4%, Vitamin K antagonist (VKA) 2%, and dual-antiplatelet therapy (DAPT) 1.8% subgroup. Postoperative complications and readmission rates were compared between the two study groups and subgroups. Patients in the combined group 2 were older and they also carried more comorbidities compared to men in group 1 (p = 0.03, p = 0.001).The study groups had similar oncological results, with 40.4% of patients having locally advanced cancers. Catheter days were longer in the anticoagulation group (4.5 vs 4 days, p = 0.001). No significant differences were observed between study groups for overall, minor, and major complications (p = 0.160, 0.100, and 0.915, respectively). In addition, readmissions were low (5.6%) and similar between the study groups (p = 0.635). Under cautious management, RARP under diverse anticoagulation regimes is safe and has comparable results to men with no medications. Further prospective studies must be conducted to confirm our findings.

Scientific Advances in Understanding the Pathogenesis, Diagnosis, and Prevention of Urinary Tract Infection in the Past 10 Years.

Urinary tract infection (UTI) is a very common disease that is accompanied by various complications in the affected person. UTI triggers diverse inflammatory reactions locally in the infected urinary bladder and kidney, causing tissue destruction and organ failure. Moreover, systemic responses in the entire body carry the risk of urosepsis with far-reaching consequences. Understanding the cell-, organ-, and systemic mechanisms in UTI are crucial for prevention, early intervention, and current therapeutic approaches. This review summarizes the scientific advances over the last 10 years concerning pathogenesis, prevention, rapid diagnosis, and new treatment approaches. We also highlight the impact of the immune system and potential new therapies to reduce progressive and recurrent UTI.

The diagnostic yield of the Meares & Stamey test can be significantly improved by symptom-based patient selection and the experience of the test performer.

BACKGROUND: Even if Meares-Stamey 4-glass (M&S) test is regarded a decisive tool for diagnosing prostatitis its use is only rarely performed in everyday clinical practice. Here, we analyze if the diagnostic yield of the M&S test could be improved by a pre-test categorization of patients due to undergo a M&S test. METHODS: All clinical and microbiological data of patients who underwent M&S test in two urological centers from January 2004 to December 2021 were analyzed in this retrospective cohort study. One center has a dedicated staff member for the study of prostatitis (Cohort I), while the other center is a general urological unit (Cohort II). All patients were divided into 3 groups on the basis of the assembled data: patients with symptoms related to prostatitis only (Group I), patients with symptoms related to both prostatitis and BPH (Group II), patients with symptoms related to BPH only (Group III). The rates of positive microbiological results in each group were compared. RESULTS: In the whole period, 9347 patients were analyzed and categorized as follows: Group I, 1884; Group II, 5151; Group III, 2312. Three-thousand and eight-hundred twenty-three patients showed positive culture results (40.9%). The most common isolated species was Escherichia coli (49.7%), followed by Enteroccus spp. (31.8%). The rates of positive M&S tests in the different symptom groups were: Group I, 1532 (81.4%); Group II, 1494 (29.0%); Group III, 797 (34.4%). The overall rate of positive M&S tests in each urology center showed that the center with a staff member who is dedicated to prostatitis studies (Cohort I) had a significantly higher rate of positive M&S tests than the general urological department (Cohort II) (64.3% vs 31.4%; p < 0.001). CONCLUSIONS: Symptom-based patient selection and dedicated staff members will increase the diagnostic yield of the M&S test and reduce the number of unnecessary tests.

A reference standard for urinary tract infection research: a multidisciplinary Delphi consensus study.

The absence of a consensus-based reference standard for urinary tract infection (UTI) research adversely affects the internal and external validity of diagnostic and therapeutic studies. This omission hinders the accumulation of evidence for a disease that imposes a substantial burden on patients and society, particularly in an era of increasing antimicrobial resistance. We did a three-round Delphi study involving an international, multidisciplinary panel of UTI experts (n=46) and achieved a high degree of consensus (94%) on the final reference standard. New-onset dysuria, urinary frequency, and urinary urgency were considered major symptoms, and non-specific symptoms in older patients were not deemed indicative of UTI. The reference standard distinguishes between UTI with and without systemic involvement, abandoning the term complicated UTI. Moreover, different levels of pyuria were incorporated in the reference standard, encouraging quantification of pyuria in studies done in all health-care settings. The traditional bacteriuria threshold (105 colony-forming units per mL) was lowered to 104 colony-forming units per mL. This new reference standard can be used for UTI research across many patient populations and has the potential to increase homogeneity between studies.

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.

BACKGROUND: Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action and a unique binding site, providing well balanced inhibition of two type II topoisomerase enzymes. Oral gepotidacin is under investigation to treat uncomplicated urinary tract infections. We aimed to compare the efficacy and safety of oral gepotidacin with that of nitrofurantoin in adolescent and adult female individuals with uncomplicated urinary tract infections. METHODS: EAGLE-2 and EAGLE-3 were phase 3, randomised, multicentre, double-blind, double-dummy, non-inferiority (10% margin) trials, in which patients were enrolled at 219 centres worldwide. Patients assigned female at birth, non-pregnant, aged 12 years or older, weighing 40 kg or more, with two or more symptoms of dysuria, frequency, urgency, or lower abdominal pain, and with evidence of urinary nitrite, pyuria, or both were eligible for inclusion. Patients were randomly assigned (1:1) centrally by interactive response technology to receive oral gepotidacin (1500 mg twice daily for 5 days) or oral nitrofurantoin (100 mg twice daily for 5 days), with randomisation stratified by age category and history of recurrent uncomplicated urinary tract infections. Patients, investigators, and the sponsor study team were masked to treatment assignment. The primary endpoint, therapeutic response (success or failure) at test-of-cure (ie, day 10-13), was evaluated in randomly assigned patients with nitrofurantoin-susceptible qualifying uropathogens (≥105 colony-forming units [CFU] per mL) and who received at least one dose of study treatment. Conforming to regulatory guidance, therapeutic success was defined as combined clinical success (ie, complete symptom resolution) and microbiological success (ie, reduction of qualifying uropathogens to <103 CFU/mL) without other systemic antimicrobial use. Safety analyses included patients who were randomly assigned and who received at least one dose of study treatment. The trials are registered with ClinicalTrials.gov, NCT04020341 (EAGLE-2) and NCT04187144 (EAGLE-3), and are completed. FINDINGS: Studies were undertaken from Oct 17, 2019, to Nov 30, 2022 (EAGLE-2), and from April 23, 2020, to Dec 1, 2022 (EAGLE-3). 1680 patients in EAGLE-2 and 1731 patients in EAGLE-3 were screened for eligibility, of whom 1531 and 1605 were randomly assigned, respectively (767 in the gepotidacin group and 764 in the nitrofurantoin group in EAGLE-2, and 805 in the gepotidacin group and 800 in the nitrofurantoin group in EAGLE-3). After an interim analysis, which was prospectively agreed as a protocol amendment, both studies were stopped for efficacy. Thus, the primary analysis population included only patients who, at the time of the interim analysis data cutoff, had the opportunity to reach the test-of-cure visit or were known to not have attained therapeutic success before the test-of-cure visit. In EAGLE-2, 162 (50·6%) of 320 patients assigned gepotidacin and 135 (47·0%) of 287 patients assigned nitrofurantoin had therapeutic success (adjusted difference 4·3%, 95% CI -3·6 to 12·1). In EAGLE-3, 162 (58·5%) of 277 patients assigned gepotidacin and 115 (43·6%) of 264 patients assigned nitrofurantoin had therapeutic success (adjusted difference 14·6%, 95% CI 6·4 to 22·8). Gepotidacin was non-inferior to nitrofurantoin in both studies and superior to nitrofurantoin in EAGLE-3. The most common adverse event with gepotidacin was diarrhoea (observed in 111 [14%] of 766 patients in EAGLE-2 and in 147 [18%] of 804 patients in EAGLE-3), whereas the most common adverse event with nitrofurantoin was nausea (in 29 [4%] of 760 patients in EAGLE-2 and in 35 [4%] of 798 patients in EAGLE-3). Cases were mostly mild or moderate. No life-threatening or fatal events occurred. INTERPRETATION: Gepotidacin is an efficacious oral antibiotic with acceptable safety and tolerability profiles. As a first-in-class investigational oral antibiotic with activity against common uropathogens, including clinically important drug-resistant phenotypes, gepotidacin has the potential to offer substantial benefit to patients. FUNDING: GSK and the US Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority.