Diagnosis and Management of Recurrent Urinary Tract Infections in Women: A Comparison and Interpretation Based on Existing Guidelines and Evidence

WANG Yibo¹, HE Kaiyu¹, LIANG Guofen¹, YANG Zhenhua¹, ZHAO Tingxian¹, LIAO Biyi¹, ZHANG La¹, LIU Shiwei², GONG Xuezhong³, LIU Xusheng¹, GU Yueyu¹, QIN Xindong¹*, SU Guobin¹,⁴,⁵

¹Department of Nephrology, the Second Clinical Medical College/The Second Affiliated Hospital of Guangzhou University of Chinese Medicine/State Key Laboratory of Traditional Chinese Medicine Syndrome/Guangdong Provincial Key Laboratory of Chinese Medicine/Guangdong Provincial Hospital of Chinese Medicine, Traditional Chinese Medicine Big Data Research Team, Liu Xusheng's Guangdong Famous TCM Doctor Inheritance Studio, Guangzhou 510120, China
²Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, China
³Department of Nephrology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China
⁴Department of Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 11228, Sweden
⁵Nuffield Department of Population Health, University of Oxford, OX1 2JD, United Kingdom

Corresponding authors: GU Yueyu, Associate Professor; E-mail: guyy@guzcm.edu.cn
QIN Xindong, Associate Chief Physician; E-mail: nealtcm@guzcm.edu.cn
SU Guobin, Associate Professor/Associate Chief Physician; E-mail: guobin.su@gzucm.edu.cn

Abstract

Background: Recurrent urinary tract infections (rUTI) represent a common condition among female patients that significantly impacts quality of life, increases healthcare burden, and contributes to global antibiotic resistance. While European and American countries have established independent clinical guidelines for managing female rUTI, China currently lacks a dedicated consensus on this topic.

Objective: To summarize existing evidence and guideline recommendations regarding diagnostic evaluation, treatment strategies, and preventive protocols for rUTI, and to explore applicable management strategies for domestic clinical practice.

Methods: We conducted systematic searches of Chinese and English databases including CNKI, VIP, Wanfang Data Knowledge Service Platform, PubMed, and Web of Science, as well as official websites of urology, nephrology, and obstetrics and gynecology societies. Guidelines related to female rUTI published between 2014 and 2024 were included, along with major randomized controlled trials and observational studies referenced in these guidelines.

Results: A total of 274 articles were included in the review, comprising 98 systematic reviews and meta-analyses, 129 randomized controlled trials, 15 observational studies, and 32 expert opinions/guidelines. For symptom management, guidelines universally recommend routine midstream urine culture during acute episodes. For acute-phase antibiotic therapy, guidelines recommend nitrofurantoin, fosfomycin, and trimethoprim-sulfamethoxazole (TMP-SMX). Evidence-based preventive measures include adequate hydration, estrogen replacement, continuous low-dose antibiotic therapy, immunoactive prophylaxis, and methenamine hippurate.

Conclusion: Most current guidelines primarily target non-complicated cystitis in female populations. While antibiotic protocols for acute infection show consistency across countries, recommendations for preventive measures vary. Future guideline versions should consider broader populations, particularly rUTI patients with complicating factors such as diabetes and kidney disease, to optimize assessment and management of rUTI.

Keywords: Recurrent urinary tract infections; Urinary tract infections; Female; Guidelines; Interventional measures

Introduction

Urinary tract infection (UTI) represents one of the most common bacterial infections, affecting approximately 150 million people globally each year. Due to unique perineal microbiota and physiological structures, women are significantly more susceptible to UTIs than men, with over 60% experiencing at least one UTI during their lifetime [1-2]. Recurrent urinary tract infection (rUTI) is defined as the occurrence of bladder irritation-related symptoms at least twice within six months or three times within one year [2]. The recurrent nature of rUTI not only severely impacts patients' quality of life but also imposes substantial socioeconomic burden [3]. In the United States alone, rUTI accounts for over 7 million medical consultations annually, with associated healthcare expenditures reaching $2 billion per year [4]. Repeated infections and inappropriate antibiotic use have exacerbated the public health challenge of antibiotic resistance [5-6].

European and American countries have developed specific guidelines and consensus statements for female rUTI, though recommendations vary. Currently, China lacks independent guidelines or consensus specifically addressing female rUTI [7-8]. This article aims to synthesize existing evidence, compare relevant clinical guidelines from Europe and America, and provide a reference for clinical practice. Given that rUTI guidelines and evidence continue to evolve, clinical decision-making should incorporate patient preferences and local practice environments.

Methods

1.1 Inclusion and Exclusion Criteria

We included guidelines and consensus statements on female rUTI patients, along with major randomized controlled trials (RCTs) and observational studies referenced within these guidelines. After initial retrieval, titles and abstracts were screened, followed by full-text review for final inclusion. The inclusion criteria were: (1) Original clinical studies (RCTs, crossover trials, prospective cohort studies, and retrospective cohort studies) on female rUTI patients (defined as at least two UTIs within six months or three UTIs within 12 months); (2) Participants aged ≥18 years; and (3) Studies referenced in the included guidelines.

Exclusion criteria comprised: (1) Basic research; (2) Non-Chinese or non-English publications; (3) Duplicate publications; (4) Prospective study protocols; (5) Case reports and conference abstracts; (6) Pregnant or lactating patients; (7) History of urological surgery; (8) Urogenital malformations; (9) Urinary incontinence; (10) Catheter use; and (11) Severe renal impairment.

1.2 Search Strategy

Chinese databases (CNKI, VIP, Wanfang Data Knowledge Service Platform) were searched using "recurrent urinary tract infection" as subject or free-text terms. English databases (PubMed, Web of Science) were searched using terms including "Recurrent Urinary Tract Infections," "prevention," and "prophylaxis." Official websites of professional societies were also reviewed, including the Chinese Medical Association, European Association of Urology (EAU), Wiki Guidelines Group (WGG), American Urological Association/Canadian Urological Association/Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction (AUA/CUA/SUFU), Swiss Society of Gynaecology and Obstetrics (SSGO), National Institute for Health and Care Excellence (NICE), Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), Association of Scientific Medical Societies in Germany (AWMF), and American Academy of Family Physicians (AAFP). To reflect recent advances, the search was limited to November 2014–November 2024.

1.3 Literature Screening and Data Extraction

Two authors independently screened literature, reviewed full texts, and extracted data according to the inclusion and exclusion criteria. Disagreements were resolved through collaborative re-review or consultation with corresponding authors. Data extraction focused on diagnosis, treatment, and prevention aspects from various clinical guidelines. For RCTs and observational studies, extracted information included first author, publication year, study type, sample size, diagnostic criteria, and main findings.

The initial search identified 1,764 relevant articles, with 274 ultimately included: 98 systematic reviews and meta-analyses, 129 RCTs, 15 observational studies, and 32 expert opinions/guidelines. The literature screening process is illustrated in Figure 1 [FIGURE:1].

Results

2.1 Diagnosis of rUTI

2.1.1 Diagnostic Evaluation of rUTI

International guidelines [9-14] define rUTI diagnosis through two components: (A) Typical UTI clinical manifestations and signs, including urinary frequency, urgency, dysuria, difficulty urinating, with or without hematuria, with or without urge incontinence, generally without significant systemic symptoms or with mild manifestations. The primary physical sign is mild suprapubic tenderness over the bladder region. (B) Multiple episodes within a short period: at least three UTIs within one year or two within six months, with at least two weeks of asymptomatic interval between episodes [15]. Initial diagnosis requires confirmation through midstream urine bacterial culture, while subsequent infections can be diagnosed with assistance from typical symptoms.

2.1.2 Role of Midstream Urine Culture in rUTI Diagnosis

Guidelines differ regarding whether clean-catch midstream urine culture is required for each rUTI episode. In China, urine culture represents the gold standard for diagnosing rUTI, with >10⁵ CFU considered positive for clean-catch midstream urine, sterile catheterization, or suprapubic aspiration [7]. Most guidelines emphasize midstream urine culture for definitive diagnosis. However, EAU [9] and AAFP guidelines [14] note that urine culture is typically unnecessary when typical rUTI symptoms recur, considering that repeated cultures increase unnecessary healthcare costs and patient waiting time. Nevertheless, urine culture should be performed when UTI symptoms persist after 48 hours of antibiotic therapy.

Considering evolving antibiotic resistance trends, we recommend mandatory urine culture with susceptibility testing for initial diagnosis. For recurrent cases, midstream urine culture should be performed whenever possible, particularly when resistance is suspected or treatment efficacy is suboptimal, to guide antibiotic adjustment.

2.1.3 Routine Cystoscopy, Urinary Imaging, and Gynecological Examination in rUTI

Most society guidelines consider routine cystoscopy to have low diagnostic yield in practice [9-10,14]. A systematic review evaluating cystoscopy in women with rUTI found that <1.5% of patients had life-threatening lesions [16-17]. Therefore, cystoscopy is generally not recommended for rUTI patients without risk factors during initial diagnosis. However, cystoscopy and imaging should be performed for recurrent UTIs unresponsive to antibiotics, or when painless gross or microscopic hematuria is present, to exclude bladder lesions or urinary tract structural abnormalities.

When urinary obstruction, stones, foreign bodies, or suspected space-occupying lesions are suspected, cystoscopy can identify obstruction location and severity and determine stone position, size, and quantity, providing important diagnostic value [7,10]. Ultrasound serves as a non-invasive, convenient imaging method for measuring post-void residual urine and assessing bladder emptying function, particularly suitable for initial screening and repeated measurements [7]. For patients with suspected urinary obstruction, intravenous urography (IVU) is simple to perform with minimal risk [10,18]. Computed tomography urography (CTU) has become more commonly used due to its high resolution and comprehensive information, clearly displaying urinary tract structures and lesions, especially for diagnosing obstructive conditions like ureteral stones [9].

Gynecological examination can help exclude anatomical or functional factors contributing to rUTI, such as uterine prolapse [19]. For postmenopausal rUTI patients, gynecological examination also helps identify and manage menopause-related vaginal or urinary issues. It serves as a primary basis for diagnosing genitourinary syndrome of menopause (GSM), including observation of vulvovaginal atrophy symptoms and assessment of urinary tract atrophy [20].

We recommend that rUTI patients consider urinary system color Doppler ultrasound. For patients with non-Escherichia coli cultures, suspected urinary stones, cystitis glandularis, or urinary tumors, cystoscopy or CT urography with contrast may be performed according to SSGO 2020 [11] and AWMF 2017 [21] recommendations. When evaluating patients with prior pelvic surgery history, cystoscopy serves as an important diagnostic tool to identify anatomical variations from surgery, including urethral strictures or obstruction, urinary fistulas, and urethral or bladder diverticula. However, as cystoscopy is an invasive procedure, performing it during the acute phase of bladder and urethral infection may increase infection dissemination risk. Additionally, anesthesia complications such as allergic reactions and cardiopulmonary depression may occur. For postmenopausal rUTI patients, we recommend collaborative gynecological examination.

Guideline recommendations regarding rUTI diagnosis are compared in Table 1 [TABLE:1] [9-14,21-22].

2.2 Acute Management of rUTI

Most societies indicate that antibiotics for acute rUTI episodes should align with those for acute uncomplicated cystitis. Recent EAU, AUA, and Chinese urology guidelines recommend nitrofurantoin, fosfomycin, TMP-SMX, and levofloxacin for acute rUTI episodes (Table 2 [TABLE:2]) [7,9-10,22]. Domestic recommendations still include fluoroquinolones, though these may cause cardiac QTc interval prolongation, tendon rupture, and aortic dissection. In recent years, the U.S. Food and Drug Administration (FDA) has issued the highest-level black box warning for this class [23]. Consequently, some guidelines have excluded levofloxacin from recommendations.

A 2024 meta-analysis by HADIDI et al. [24] included 13 RCTs (n=3,856) comparing fosfomycin with nitrofurantoin, TMP-SMX, and ciprofloxacin for UTI treatment. Results showed fosfomycin was superior in both clinical and microbiological cure compared to other antibiotics, while ciprofloxacin was inferior in adverse event rates and recurrence rates. These findings support fosfomycin as the most effective antibiotic for uncomplicated UTI in terms of clinical cure, microbiological cure, and adverse events.

Based on this evidence, we believe that although guidelines recommend nitrofurantoin, fosfomycin, and TMP-SMX as first-line treatments for acute rUTI episodes, clinicians should comprehensively consider local antibiotic susceptibility patterns and potential adverse effects when selecting appropriate antibiotics [25-26]. Long-term antibiotic use may also promote super-resistant bacteria and even refractory urosepsis [2]; therefore, antibiotic treatment duration should follow guideline recommendations whenever possible.

2.2.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in Acute rUTI

NSAIDs treat acute UTI primarily by inhibiting inflammatory responses and reducing urinary symptoms [27-28]. Most guidelines suggest that for patients with mild-to-moderate cystitis symptoms, NSAIDs may be used as an alternative or adjunct to antimicrobial therapy after patient consultation [29-31]. An RCT (n=494) comparing ibuprofen versus fosfomycin in women with acute uncomplicated UTI found that at day 28, women receiving ibuprofen had significantly reduced antibiotic needs (35% vs. 100%; P<0.0001), with 67% recovering without antibiotics. However, compared to antibiotic-treated women, ibuprofen-treated women had higher symptom burden at day 7 and increased risk of developing pyelonephritis. The SSGO guideline notes that although diclofenac can reduce antibiotic use in uncomplicated cystitis, it increases pyelonephritis risk [31]. Therefore, NSAID efficacy in UTI treatment requires careful evaluation.

We recommend NSAIDs as adjunctive therapy before midstream urine culture and susceptibility results become available when significant urinary irritation symptoms are present. However, NSAIDs should be used cautiously in patients with prior pyelonephritis history to avoid masking symptoms and delaying treatment.

2.2.2 Self-Diagnosis and Treatment in Acute rUTI Episodes

Most guidelines [9-10,12,14] recommend that if patients are well-informed, have high adherence, can communicate effectively, and self-assess symptoms, they may self-diagnose and initiate empirical treatment before obtaining midstream urine culture results (Table 3 [TABLE:3]). An RCT by SCHAEFFER et al. [32] evaluating self-initiated antibiotic therapy in rUTI patients (n=34, with 28 patients followed for 355 months and 84 symptom episodes) showed that intermittent self-initiated therapy allows patients to start short-course antibiotics when symptoms appear, reducing long-term antibiotic exposure and consequently lowering resistance risk and adverse effects. The SEIMC guideline [12] notes that for patients with fewer than three UTIs annually, prophylactic self-initiated antibiotic therapy can reduce long-term antibiotic use.

We recommend that community and outpatient physicians strengthen patient education for rUTI, helping patients accurately assess their condition, identify acute episodes promptly, and initiate intermittent antibiotic therapy rationally based on previous urine culture results. Patients should contact physicians promptly if symptoms persist or worsen. Clinicians should document urine culture data while recording patients' self-diagnosis and treatment frequency and symptom resolution to assist in developing personalized treatment plans.

2.3 Preventive Measures During rUTI Remission

During rUTI remission, preventive measures should be considered to prevent recurrence, including behavioral modifications, oral non-antibiotic agents, topical therapies, UTI vaccines, intravesical agents, and oral antibiotics (Table 4 [TABLE:4]) [9-14,21-22,33].

2.3.1 Increased Fluid Intake

All guidelines recommend increased fluid intake as the first-line preventive measure [9-12,14,21]. In dehydration states, concentrated urine and reduced voiding frequency create favorable conditions for bacterial proliferation in the urinary system. A 12-month RCT in premenopausal women with rUTI found that daily fluid intake >1.5 L reduced cystitis episodes and antibiotic use compared to intake <1.5 L/d [34].

2.3.2 Oral Non-Antibiotic Agents

2.3.2.1 Cranberry Products: Cranberry contains proanthocyanidins that interfere with bacterial adhesion (e.g., E. coli) to urothelial cells by preventing bacterial fimbriae from binding to urothelial receptors, reducing bacterial colonization. Cranberry components may also alter bacterial morphology (e.g., from rod-shaped to spherical), increasing bacterial expulsion [35-36].

Current evidence regarding cranberry product efficacy remains inconclusive, with most guidelines [9-10,12,14,33] providing weak-to-moderate recommendations. The AUA guideline offers no recommendation due to limited and contradictory evidence. The NICE guideline, based on reducing antimicrobial resistance and favorable benefit-risk ratio, recommends cranberry products for non-pregnant women and children/adolescents under 16. The EAU guideline, synthesizing seven meta-analyses and considering adverse effects and potential preventive benefits, provides a moderate recommendation. A 2024 systematic review of 20 intervention trials (n=3,091, including 18 RCTs and 2 non-RCTs) showed cranberry intake significantly reduced UTI incidence (RR=0.73, 95%CI=0.59-0.91), representing a 27% reduction compared to placebo and 54% compared to no treatment, while reducing antibiotic use (RR=0.51, 95%CI=0.30-0.87) and alleviating UTI-related symptoms [37].

We believe that despite low evidence quality, cranberry represents a viable option for rUTI-susceptible populations given its minimal adverse effects, potential to reduce antimicrobial resistance, and possible benefits. Future research should focus on evaluating stable formulations and effective dosages.

2.3.2.2 D-Mannose: D-Mannose, an isomer of glucose, participates in protein glycosylation [38]. Enterobacteria such as uropathogenic E. coli (UPEC) utilize FimH adhesin molecules on type 1 fimbriae to bind mannosylated host proteins on urothelial surfaces [39]. D-Mannose can compete for these binding sites, preventing bacterial attachment to urothelial glycoprotein receptors and reducing UTI risk [40-41]. Due to insufficient evidence quality, most guidelines [9,11-13,24,33] provide conditional recommendations for D-mannose in rUTI prevention. However, a recent RCT showed D-mannose did not reduce the proportion of women with rUTI history requiring outpatient treatment for recurrent UTI compared to placebo [42].

We consider D-mannose a promising antibiotic-sparing therapy for preventing female rUTI, though current evidence remains low-quality and requires further validation of clinical utility and specific role in rUTI prevention. The recommended dosage is 2 g D-mannose dissolved in 200 mL water, administered for six months.

2.3.2.3 Methenamine Hippurate: Methenamine hippurate decomposes into ammonia and formaldehyde in acidic environments. Formaldehyde inhibits cell division and blocks synthesis of 1,3-thiazine-4-carboxylic acid, interfering with methionine synthesis—a key metabolite for cytoplasmic synthesis—thereby inhibiting nucleic acid and cytoplasm synthesis to achieve antibacterial effects. When urine pH >6.5, concurrent urine acidification and vitamin C supplementation (100 mg) is recommended for maximal efficacy.

Prior to its 2022 update, EAU and AUA/CUA/SUFU guidelines considered methenamine hippurate evidence limited or contradictory, preventing clear recommendations. The SEIMC guideline, based on potential carcinogenic risk and limited evidence, did not recommend methenamine hippurate. However, a 2022 multicenter non-inferiority RCT (ALTAR trial) comparing methenamine hippurate with low-dose antibiotics for UTI prevention showed methenamine hippurate was non-inferior to daily low-dose prophylactic antibiotics [43]. A 2023 RCT (n=205) comparing methenamine hippurate with low-dose antibiotics for preventing female rUTI demonstrated that methenamine hippurate serves as an effective alternative [17]. Current NICE guidelines recommend a dosage regimen of twice daily, one tablet per dose, possibly combined with high-dose vitamin C (1,000 mg) daily, though this has not become standard treatment.

We believe methenamine hippurate represents an effective alternative to low-dose antibiotics with favorable cost-effectiveness and no antibiotic resistance risk. However, no direct evidence currently supports its use for preventing catheter-associated rUTI. Further clinical exploration in patients with complicating factors is recommended.

2.3.3 Topical Therapies

2.3.3.1 Probiotics: Lactobacillus represents the predominant commensal microorganism in the vagina and periurethral area, playing a crucial role in preventing pathogen attachment and migration to bladder urothelium and maintaining urogenital health. Lactobacillus prevents pathogen colonization by occupying epithelial cell adhesion sites and produces antimicrobial substances including hydrogen peroxide, lactic acid, and bacteriocins that inhibit pathogen growth [44-47]. Significant reduction in Lactobacillus levels correlates with increased vaginal E. coli colonization [48].

Due to limited and contradictory evidence, most guidelines provide no clear recommendation or do not mention probiotics. Only the EAU guideline offers a weak recommendation based on available data, noting that low evidence quality prevents definitive recommendations regarding administration routes, optimal dosage, and treatment duration. A 2024 meta-analysis of five RCTs (n=552) comparing probiotics versus placebo as adjunctive therapy found probiotics superior to placebo in achieving normal Nugent scores (≤3) (RR=1.38, 95%CI=1.01-1.89, P<0.04, I²=72%), but sensitivity analysis excluding the lowest-weight study did not support probiotic use as adjunctive UTI therapy [49]. The EAU guideline specifically notes that only certain strains may effectively prevent UTI, with evidence supporting L. rhamnosus GR-1, L. reuteri RC-14, L. reuteri B-54, L. casei shirota, and L. crispatus CTV-05 [50-53].

We acknowledge that while some studies and meta-analyses support specific Lactobacillus strains for rUTI prevention, evidence quality and consistency remain insufficient for definitive guideline recommendations. Future research should focus on clinical applications of specific effective strains, optimize dosing regimens, and provide more precise evidence to ensure probiotic efficacy and safety in UTI prevention.

2.3.3.2 Local Vaginal Estrogen Replacement Therapy: Local vaginal estrogen replacement therapy (VERT) maintains vaginal epithelial integrity, regulates vaginal pH, and promotes an acidic environment that inhibits harmful bacterial growth [54-55]. Most guidelines recommend local vaginal estrogen for postmenopausal patients with recurrent infections. The AUA guideline recommends that clinicians offer vaginal estrogen therapy to all postmenopausal women with rUTI to reduce infection risk. EAU, SSGO, and SEIMC specifically propose that local vaginal estrogen effectively reduces rUTI incidence in postmenopausal patients with vaginal atrophy. Although current evidence shows vaginal estrogen is less effective than antibiotics, it still provides benefit compared to placebo.

A 2023 systematic review of 10 RCTs (n=2,608) summarized the benefits of vaginal estrogen in reducing rUTI risk and associated urinary symptoms in postmenopausal women, supporting its efficacy in improving urinary symptoms and decreasing rUTI risk [56].

We believe local vaginal estrogen replacement therapy is recommended by most guidelines for preventing rUTI in postmenopausal women. Before initiating treatment, clinicians should note contraindications including history of endometrial or breast cancer, thromboembolic disease (e.g., deep vein thrombosis or ischemic stroke), and acute liver disease due to cholestasis exacerbation risk [57]. Common vaginal estrogen formulations include vaginal creams, vaginal estrogen tablets (e.g., 17β-estradiol vaginal tablets), and vaginal estrogen rings (e.g., estradiol-releasing vaginal ring Estring) [58-59]. Specific usage and regimens are detailed in Table 5 [TABLE:5]. No clear evidence indicates differential efficacy among various vaginal estrogen formulations for rUTI prevention.

2.3.3.3 Immunoactive Prophylaxis for UTI: Immunoactive prophylaxis activates dendritic cells, neutrophils, and helper T cells, triggering B lymphocytes to release IgA. IgA forms a protective layer on mucosal surfaces, providing immune protection [60-61]. AUA, SSGO, SEIMC, and AWMF guidelines recommend OM-89 for immunoactive prophylaxis, though evidence quality remains limited, preventing strong recommendations.

OM-89 (Uro-Vaxom) is an oral capsule containing extracts from 18 heat-killed UPEC strains that stimulates the host immune system through mucosa-associated lymphoid tissue in the gastrointestinal, respiratory, and urogenital tracts, increasing bacterial-specific antibody concentrations [62]. Meta-analysis shows OM-89 effectively reduces rUTI in adult women (RR=1.94, 95%CI=0.65-5.86), though evidence quality is low [63]. The guideline expert panel strongly recommends OM-89 vaccine prophylaxis for rUTI. However, OM-89 is only effective against UPEC strains. The recommended regimen is 6 mg OM-89 capsule daily for 90 days, followed by a 3-month drug holiday, then 10-day booster treatments during months 7, 8, and 9 [64].

MV140 (Uromune) is a novel sublingual immunomodulator containing inactivated uropathogenic strains including E. coli, Klebsiella pneumoniae, Proteus vulgaris, and Enterococc faecalis. Sublingual administration induces T cell-specific adaptive immune responses in urogenital tissues [65-66]. A systematic review of two retrospective and three prospective cohort studies showed MV140 reduced rUTI episodes and/or increased UTI-free probability [67]. LORENZO-GÓMEZ et al. [68] published a 2022 RCT evaluating MV140 in 240 women with UTI, demonstrating that annual UTI frequency decreased from six episodes pre-treatment to zero during the 9-month observation period. MV140 shows minimal adverse effects and promising clinical efficacy in reducing rUTI. The recommended regimen is two daily sprays sublingually for three months.

StroVac is a vaccine for long-term rUTI prevention containing 10⁹ inactivated pathogens from five bacterial species (E. coli 7.5×10⁸, Morganella 3.75×10⁷, Proteus mirabilis 3.75×10⁷, Klebsiella pneumoniae 1.5×10⁸, Enterococcus faecalis 2.5×10⁷). StroVac activates gut-associated lymphoid tissue (MALT), stimulating systemic immunity and enhancing mucosal immune defense in the urinary tract, reducing pathogen adhesion to urothelium. A 2023 RCT randomized 173 participants to StroVac vaccination versus 100 mg nitrofurantoin daily for three months, demonstrating that StroVac provides a potential non-antibiotic option for rUTI prevention with lower adverse event rates than nitrofurantoin [69]. The recommended regimen is three injections of 0.5 mL at 1-2 week intervals, followed by a 12-month drug holiday, then a 0.5 mL booster injection [70].

We believe immunomodulators show potential for rUTI prevention, but heterogeneous and limited evidence necessitates cautious clinical application. Different immunomodulator types may suit different patient needs. OM-89 capsules have gained relatively broad recognition but are limited to short-term prevention with insufficient long-term evidence. Before considering immunomodulators, clinicians should note potential contraindications including allergic reactions, severely compromised immune function (e.g., undergoing immunosuppressive therapy), and acute exacerbations of certain chronic diseases (e.g., asthma, COPD, diabetes, autoimmune disorders). Additionally, use in pregnant or lactating women should be deferred when necessary.

2.3.3.4 Intravesical Therapy: The glycosaminoglycan (GAG) layer comprises negatively charged polysaccharides on the bladder mucosal surface that form a critical protective barrier against bacterial adhesion [71]. GAG deficiency is considered a common initial step in the pathogenesis of many chronic inflammatory bladder diseases, including rUTI, and may increase bacterial internalization into urothelial cells, leading to intracellular bacterial community (IBC) formation [72]. Intravesical instillation of hyaluronic acid (HA) and chondroitin sulfate (CS) forms a physical barrier on the bladder mucosal surface, restoring the GAG protective layer covering bladder urothelium [73], thereby preventing bacterial adhesion and invasion and reducing recurrence risk. SSGO and EAU guidelines recommend HA and CS for rUTI prevention; other guidelines do not mention or recommend this approach. The EAU guideline suggests considering intravesical therapy (IVA) when less invasive treatments are ineffective, noting this approach can reduce UTI frequency and prolong intervals between infections.

A 2022 systematic review by REDDY et al. [74] included 13 studies (n=764, including 2 RCTs and 11 non-RCTs) evaluating IVA therapy (including gentamicin combined with hyaluronic acid and chondroitin sulfate) in patients failing oral antibiotic therapy, demonstrating good efficacy in reducing rUTI. Ialuril is a common GAG therapy for rUTI, with a recommended regimen of weekly instillations for the first month, followed by a 5-month maintenance period with monthly instillations [75-76], providing sustained protection and reducing UTI recurrence.

We believe intravesical GAG therapy prevents rUTI recurrence by restoring the GAG layer and has been recommended in some guidelines with demonstrated clinical efficacy. However, optimal treatment frequency and duration remain undetermined, and additional high-quality studies are needed to validate long-term efficacy and safety.

2.3.3.5 Continuous Low-Dose Antibiotic Prophylaxis: Guidelines consider continuous low-dose antibiotics the most effective method for preventing UTI recurrence [19,21,77-85]. An RCT including 404 rUTI patients using clean intermittent self-catheterization (CISC) compared continuous low-dose antibiotic prophylaxis versus no prophylaxis. During 12 months of observation, antibiotic prophylaxis significantly reduced UTI incidence compared to no prophylaxis (RR=0.52, 95%CI=0.44-0.61, P<0.0001), indicating a 48% reduction [86]. Another systematic review and meta-analysis of 23 RCTs (n=1,572) evaluating antibiotic prophylaxis for rUTI found antibiotic prophylaxis significantly superior to placebo in reducing UTI risk (RR=0.15, 95%CI=0.08-0.29, P<0.0001, I²=57%). Head-to-head comparisons of different antibiotics showed similar efficacy among nitrofurantoin, trimethoprim (± sulfamethoxazole), and norfloxacin, with intermittent prophylaxis (e.g., post-coital) equally effective as continuous strategies [87]. The AWMF guideline recommends 3-6 months of continuous antibiotic prophylaxis for patients with frequent UTI recurrences when behavioral modifications and non-antibiotic measures fail. EAU expert opinion notes no consensus regarding optimal duration of continuous antimicrobial prophylaxis, with most studies employing 3-12 months of prophylaxis until resistance develops. Antimicrobials may be used as continuous low-dose prophylaxis long-term or as post-coital prophylaxis, with no significant difference in effectiveness between methods, and no statistically significant differences among various antibiotic regimens (Table 6 [TABLE:6]).

We believe antibiotics represent the most effective method for preventing UTI recurrence and should be considered when behavioral modifications and non-antibiotic measures fail. Antibiotic prophylaxis efficacy is limited to the treatment period, and the optimal balance between duration and potential toxicity or adverse effects remains unclear. Potential benefits must be weighed against risks including drug toxicity, resistance selection, and impact on patient microbiota. Individualized treatment should consider local uropathogen susceptibility patterns, potential adverse events, resistance development, and patient preferences.

Conclusion

This article summarizes diagnostic, therapeutic, and preventive strategies for rUTI from multiple international guidelines, which demonstrate high consistency in rUTI definitions and evaluation criteria. Most guidelines recommend similar antibiotics for acute episodes, including nitrofurantoin, fosfomycin, and TMP-SMX. Evidence-based preventive measures include estrogen replacement, continuous low-dose antibiotic therapy, immunoactive prophylaxis, and methenamine hippurate. Based on these findings, we have compiled a management flowchart for female rUTI (Figure 2 [FIGURE:2]) for domestic clinical reference.

Current guidelines primarily target healthy, non-pregnant women with uncomplicated cystitis. Future guideline versions should consider broader populations, particularly rUTI patients with complicating factors such as diabetes and kidney disease, to optimize assessment and management.

Author Contributions

WANG Yibo, SU Guobin, QIN Xindong, and GU Yueyu were responsible for study design, analysis and interpretation of results, manuscript writing and revision, and take responsibility for the article. WANG Yibo and LIANG Guofen conducted initial literature screening. HE Kaiyu, YANG Zhenhua, ZHAO Tingxian, and LIAO Biyi coordinated data collection. LIU Xusheng, LIU Shiwei, GONG Xuezhong, and all authors contributed to manuscript interpretation and revision.

Conflict of Interest

The authors declare no conflict of interest.

Funding

This work was supported by the Ministry of Education "Chunhui Plan" Cooperative Scientific Research Project (HZKY20220109); Guangdong Provincial Hospital of Chinese Medicine Top Talent Research Special Fund (BJ2022KY11); Guangdong Provincial Hospital of Chinese Medicine Traditional Chinese Medicine Science and Technology Research Special Fund (YN2024MS012, YN2020QN18, YN2020QN24, YN2018QL08); National Natural Science Foundation of China (82004205); National Administration of Traditional Chinese Medicine Emergency Research Special Project for COVID-19 Prevention and Treatment (2023ZYLCYJ02-18); 2024 Guangdong Provincial Famous TCM Doctor LIU Xusheng Inheritance Studio Construction Project (Guangdong TCM Office Letter [2023] No. 108); Shenzhen "Three Famous Medical Projects" (SZZYSM202206014); and Guangzhou Science and Technology Plan Project (2025A03J2702).

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Received: March 20, 2025; Revised: June 28, 2025
Edited by JIA Mengmeng