Abstract
Introduction
Urinary tract infections (UTIs) are incredibly common. The lifetime prevalence of at least one symptomatic UTI in women is estimated to exceed 50%, with 20%–40% experiencing recurrent UTIs (rUTIs). 1 The European Association of Urology (EAU) classifies UTIs to be either localised or systemic; and complicated (patients with risk factors or urinary tract abnormalities) or uncomplicated. 2 As per EAU, rUTIs are defined as at-least two episodes of cystitis in a period of 6 months, or at-least three episodes over twelve months 2 (Appendix 1). Recurrent infections markedly impair quality of life and impact social and intimate relationships, self-esteem, social functioning and work productivity. 3
Empirical antibiotics remains the first-line treatment for cystitis, with Escherichia coli identified as the most common causative organism. 4 Whilst most UTIs respond effectively to antibiotics, the widespread consumption of broad-spectrum antibiotics has contributed to antimicrobial resistance among uropathogens. 5 This highlights an urgent need for alternative therapeutic approaches. Suggested preventative strategies for rUTIs include patient education and lifestyle modification, non-antimicrobial therapies and antimicrobial prophylaxis.
The EAU 2025 guidelines present updated recommendations on non-antibiotic prophylactic approaches in the management of rUTIs. 2 The objective of these guidelines is to not only offer evidence-based recommendations for diagnosis, treatment and prevention but also to address public health priorities, specifically regarding infection control and antimicrobial stewardship. The following article aims to summarise non-antibiotic management of rUTIs and recommend a practical treatment algorithm (Table 1 and Figure 1).
Demonstrates different non-antibiotic management for rUTIs and their relative recommendation in different major guidelines.
Strong – High-quality evidence and/or expert consensus supports use as a first-line preventive approach. Recommended – Supported in specific populations or contexts where benefits outweigh risks. Optional – May be considered; evidence is limited, mixed or conditional, and patient preference or judgment is needed. Emerging/Insufficient/Uncommon – Evidence remains preliminary or not broadly accepted; further research required. Not routine/N/A – Not addressed or not endorsed by the guideline.
AUA, American Urological Association; CS, chondroitin sulphate; EAU, European Association of Urology; HA, hyaluronic acid; NICE, National Institute for Health and Care Excellence.
A suggested treatment algorithm for use in both primary and secondary care in patients with rUTIs.
Non-antibiotic management
Behavioural modifications
Modification of behavioural and environmental risk factors are an important first-line measure, shown to reduce symptomatic episodes of cystitis, thereby improving quality of life and decreasing antibiotic usage. 4 Specifically, despite limited supporting evidence, EAU guidelines recommend that all patients receive counselling regarding risk factor modification. 2 Modifiable risk factors include delayed post-coital voiding, inadequate fluid intake, frequent sexual intercourse 6 of more than four times per week, usage of spermicides, wiping front to back following defecation, vaginal douching and wearing occlusive non-breathable underwear.
Hormonal replacement
Vulvovaginal atrophy in post-menopausal women is a well-recognised risk factor in the development of rUTIs. 7 The decline in oestrogen disrupts the integrity of vaginal epithelium resulting in gradual atrophy. Furthermore, glycogen deficiency decreases lactic acid producing bacteria, interfering with the protective vaginal microbiota. Consequently, the postmenopausal vaginal microbiota facilitates uropathogenic organisms, particularly Escherichia coli, which has the potential to ascend into the urinary tract. 8
Application of topical oestrogen (but not oral oestrogen), in post-menopausal women only, is recommended by both European Association of Urology (EAU) and National Institute for Health and Care Excellence (NICE)2,9 and has demonstrated significant efficacy in reducing UTI recurrence in this cohort. 10 It enhances blood flow, improves epithelial integrity, alleviates dryness and helps restore normal acidic pH levels. 11 Topical oestrogen is generally well tolerated and with minimal systemic absorption. Only minor local adverse effects are reported including irritation, itching, vaginal discomfort and burning. 10 Conversely, systemic use of oestrogen is associated with potentially serious side-effects, including endometrial hyperplasia, venous thromboembolism 12 and increased breast cancer risk. 13
A recent literature review (258 patients total) concluded that administration of average weekly doses of topical oestrogen ⩾850 µg was associated with higher efficacy. 14 Whilst providing patients with a measuring syringe for cream applications can allow patients to accurately administer doses, vaginal suppositories may facilitate increased adherence. 14 Interestingly, there is one study currently in the literature, which has shown that topical oestrogen, as a treatment in pre-menopausal women, may also help prevent rUTIs. 15
Immunomodulation
The 2025 EAU guidelines included revised guidance on immunomodulatory therapy in rUTI prophylaxis. 2 These updates were primarily informed by a recent systematic review and meta-analysis evaluating the efficacy and safety of five agents: StroVac, OM-89, ExPEC4V, MV140, and Solco-Urovac (2882 patients total). 16 This review concluded that of the studied agents, uro-vaxom (OM-89) demonstrated the highest reduction with a relative risk (RR) of 0.78 at 6 months (1537 patients, 10 studies). 16 Urovac (Strovac) given as intramuscular injection was associated with RR of 0.75. ExPRC4V, which specifically targets E. coli was not found to significantly reduce UTI recurrence (RR 0.82). 16 Uromune (MV140) is a sublingual administration with papers from multiple countries. It is also the vaccine with the longest-observational study, completed in the United Kingdom, which concluded that 54% of the 89 included patients were UTI-free 5–9 years after first receiving the vaccine. 17
Although the review overall concluded a modest short-term benefit in reducing rUTI incidence, certainty of the evidence was poor, which is reflected in the EAU guidelines with a ‘weak’ recommendation. 2 Immunomodulatory agents are well tolerated, with few serious adverse events and no reported deaths. Reported side effects included gastrointestinal discomfort, vaginitis and headache, varying by agent and route of administration. 16 Further, focused literature on individual agents, as opposed to pooled analysis, is required to establish conclusive evidence on the long-term efficacy of vaccinations as a prophylactic treatment option in rUTIs.
Prophylaxis with probiotics (Lactobacillus spp.)
The efficacy of probiotic use, particularly lactobacillus spp., as prophylactic treatment in rUTIs remains inconclusive. Current evidence is insufficient to support definite recommendations regarding duration of probiotic prophylaxis, optimal dosage or the route of administration (oral or vaginal). Further high-quality studies are necessary to determine if their use results in a clinically significant benefits in reducing rUTIs, which is reflected in the 2025 EAU guidelines. 2 No further specification is mentioned in the guidelines.
Prophylaxis with cranberry
Despite cranberry products historically been considered an effective non-antimicrobial treatment for the prevention of rUTIs, current evidence does not fully support their clinical efficacy. 18 No statistically significant reduction in the incidence of symptomatic cystitis amongst women with rUTI was observed through a Cochrane systematic review and meta-analysis, when compared to placebo. 18 Nonetheless, the EAU guidelines advocate consideration of cranberry prophylaxis, given its favourable risk–benefit profile. Whilst it is not specifically associated with any side effects, caution is required in diabetic patients given the propensity of cranberry products to increase blood glucose levels. In our treatment algorithm, we have reflected cranberry products within ‘conservative measures’. There has been no research yet into informing clinicians on optimal dosing regimens or treatment duration for cranberry products.
Prophylaxis with D-mannose
D-mannose works by inhibiting bacterial adhesion of E. coli to epithelial cells, thereby preventing bacterial colonisation and invasion. 19 A Cochrane systematic review evaluating 719 patients demonstrated no statistically significant benefit in the prevention of rUTIs when compared against placebo, other non-antibiotic supplements or antibiotic prophylaxis. 19 Due to the limited number of high-quality studies, further research is required to further establish clinical efficacy to inform future management strategies involving D-mannose. While the EUA endorses its use for rUTIs, patients must be counselled regarding the limited strength of supporting evidence.
Despite limited evidence supporting their efficacy, D-mannose, and cranberry products remain reasonable nonantibiotic choices for prevention of recurrent UTIs owing to their favourable safety profiles. In clinical practice, they may be considered as adjunctive measures, particularly in patients seeking to minimise antibiotic exposure. Their use should be accompanied by counselling that current data do not establish definitive benefit, and expectations should be set accordingly. However, given their low risk of adverse effects, a therapeutic trial may be justified in motivated individuals.
Intravesical installations
Current EAU guidelines support the administration of intravesical hyaluronic acid (HA) and chondroitin sulphate (CS) as a prophylactic treatment for rUTIs. The recommendation is based, in part, on findings from a meta-analysis involving 800 patients involving two randomised controlled trials and six non-randomised studies, which demonstrated that HA, with or without CS was associated with a significantly reduced mean episodes of symptomatic cystitis per year and a prolonged duration to reoccurrence. 20 Due to limited research on the use of HA and CS monotherapy, current EAU guidance favours the combined use of both agents in rUTI prophylaxis. 20 In terms of side-effect profile, it seems that moderate-pain after administration of the instillation, which is self-limiting, is the most common side-effect with one multicentre study reporting no serious adverse events. 21 At present, there remains no completed studies comparing intravesical instillations to intravesical antibiotics.
Methenamine hippurate
In acidic environments, methenamine hippurate is hydrolysed forming formaldehyde. 22 The bactericidal effects of formaldehyde acting in the distal convoluted tubules of the kidney, combined with an acidic urinary pH denature bacterial proteins and nucleic acids, thereby exerting preventative effects against rUTIs.22,23 Methenamine hippurate, taken twice daily, was shown to be equally effective as antibiotic prophylaxis in preventing symptomatic cystitis in a randomised controlled trial involving 240 patients. 22 This has led to its recommendation in clinical practice and is reflected in the EAU guidelines. 2 Side effects of methenamine hippurate include bladder irritation, dysuria, haematuria and crystal formation in the bladder in those patients also taking sulphonamides in combination. 24 Of note, methenamine hippurate is contraindicated in renal insufficiency and particularly hepatic insufficiency. In those with pre-existing hepatic problems, excess production of ammonia and formaldehyde during treatment may precipitate acute hepatic failure. 24
Phytotherapy and herbal agents
Over the last few years phytotherapy and herbal remedies have been used as an alternate strategy or as an adjunct in the prevention and management of UTIs. 25 Green tea and garlic extracts have shown to reduce bacterial adhesion and enhancing host defence mechanisms. These interventions might reduce rates of UTI, but more rigorous and high-quality trials are needed before they can be routinely integrated in clinical practice. 26
Emerging strategies and future direction
Beyond conventional prophylactic strategies discussed earlier, several novel approaches are gaining attention in the prevention and management of rUTIs.27,28 Among vaccine-based strategies, Uromune (MV140) remains the most extensively studied immunomodulatory agent. However, multiple new vaccine candidates are under active investigation. One promising research focus is the FimH antigen, 27 an adhesin that mediates E. coli attachment to the urothelium, representing a key step in pathogenesis. Targeting FimH for vaccine development is an area of ongoing investigation, with early studies showing encouraging results.
In parallel, advances in artificial intelligence (AI) are driving the development of machine learning guided risk prediction tools, which hold potential for personalized rUTI prevention. 28 In one study, a predictive model demonstrated high accuracy in identifying patients at risk of developing E. coli rUTIs following clinical encounters and hospitalisation for UTI. Other approaches employing ensemble methods that integrate urinary, haematological and demographic data have achieved diagnostic accuracies of up to 86% in predicting future UTI events. 29
Limitations
Whilst non-antibiotic treatment is clearly promising, there remains some limitations associated with treatment. First, there is a shortage of data on long-term efficacy of non-antimicrobial therapies, particularly with respect to recurrence rates following treatment cessation. Longer-duration studies are essential to establish sustained clinical benefit.
Cranberry proanthocyanidins and D-mannose, on the other hand, have been widely studied, yet meta-analyses report conflicting results, with modest or uncertain benefits compared to placebo. 30 Immunoactive prophylaxis shows good promise, but uptake is limited by availability, regulatory approval status and a lack of large-scale phase III trials. 31 Moreover, whilst this review has not specifically looked at cost analysis, it should be mentioned that one of the most used bladder instillations iAluRil®, has an approximate cost per annum of £704, which compared to trimethoprim prophylaxis (approximately £12) is a significant difference. 32 Finally, a large amount of research thus far has been aimed towards prophylaxis of E. coli UTI whilst there is room for more research on other uropathogens. Collectively, these highlight that while non-antibiotic measures can be useful, their role is limited to being adjunctive. 33
Areas for further research should include more studies directly evaluating non-antimicrobial therapies against antibiotic prophylaxis, including assessment of associated side effects. 34 Perhaps there will also be a role of AI in the smart diagnostics of UTIs. 35
Conclusion
The latest EAU guidelines recommend non-antimicrobial prophylactic treatment interventions for patients with rUTIs. These include behavioural modification, topical oestrogen in post-menopausal women, intravesical installation of HA and CS and methenamine hippurate. These non-antimicrobial treatment approaches have shown promising results with the potential to reduce antibiotic use and limit further antimicrobial resistance. Our suggested treatment algorithm can be utilised to assist practitioners in promoting correct utilisation of non-antibiotic therapies. Further research is essential to confirm their efficacy and further develop guidance in broader implementation in rUTI management.
