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Urinary tract infections (UTIs) are among the most common bacterial infections globally, affecting up to half of all women during their lifetime []. A substantial proportion develop recurrent UTIs (rUTIs), defined by the European Association of Urology as two or more episodes within 6 months or three or more within 1 year []. Beyond the acute burden, rUTIs profoundly impair quality of life, limiting independence, productivity, sexual health, and psychological wellbeing. The societal and economic impact is also significant; in the United States alone, annual direct healthcare costs exceed $2 billion (American dollars), with indirect costs adding further strain [].

The pathophysiology of rUTIs is multifactorial. Recurrence may result from bacterial persistence within the bladder, re‐inoculation from periurethral or intestinal reservoirs, or biofilm formation on the urothelium or indwelling devices [, ]. Defects in urothelial defences, particularly disruption of the glycosaminoglycan (GAG) layer, appear to facilitate bacterial adherence and persistence []. Host immune factors and alterations in vaginal or gut microbiota also contribute to recurrence. Certain populations face especially high risk, such as patients with neurogenic bladder due to spinal cord injury or spina bifida, those requiring intermittent or indwelling catheterisation, and individuals with urinary diversions [, ]. Among non‐neurogenic groups, postmenopausal women are predisposed through hormonal changes, atrophic mucosa, and altered vaginal flora.

Traditional management begins with behavioural and lifestyle modification including adequate hydration, sexual hygiene, and clean toileting habits. Over‐the‐counter options such as cranberry juice or D‐mannose for Escherichia coli ( E. coli ) UTIs may reduce recurrence in select patients [, ]. Alternative antibacterials such as methenamine hippurate have also shown promise in clinical practice to prevent recurrent UTIs in women []. Long‐term prophylactic antibiotics are effective in the short term, but this strategy carries well‐recognised drawbacks including gastrointestinal intolerance, disruption of commensal flora, and the accelerating emergence of antimicrobial resistance [, ]. Multidrug‐resistant (MDR) pathogens, including extended‐spectrum beta lactamase (ESBL)‐producing E. coli , Klebsiella pneumoniae , and Pseudomonas aeruginosa are increasingly prevalent, particularly in patients with neurogenic bladder. These trends are most evident among catheter‐dependent patients, where chronic colonisation and antibiotic exposure amplify antibiotic resistance [, ]. These challenges associated with traditional treatment methods highlight the urgent need for alternative bladder‐targeted therapies.

Intravesical instillation therapy offers a promising alternative. Delivering agents directly into the bladder achieves high local concentrations while minimising systemic absorption and toxicity [, ]. In terms of the mechanism of action, instillations may eradicate pathogens, restore the urothelial barrier, suppress colonisation, or modulate host immunity. Aminoglycosides such as gentamicin, tobramycin, amikacin, and neomycin‐polymyxin have been most widely studied, achieving bactericidal concentrations far exceeding systemic levels, yet with undetectable serum absorption and thereby minimising systemic toxicity [, , , ]. GAG substitutes, including hyaluronic acid (HA) and chondroitin sulphate (CS), aim to restore the protective mucosal layer and reduce bacterial adherence; heparin offers similar GAG‐mimetic and anti‐inflammatory properties [, , , , , , ]. Antiseptic agents such as povidone‐iodine exert broad antimicrobial activity without driving systemic resistance, with promise in neurogenic populations. Other novel approaches, including intravesical fosfomycin and immunomodulators, remain in early‐phase evaluation [, , ].

Despite optimistic findings, widespread adoption of intravesical therapy is limited. Most available studies are small, single‐centred, and observational, with heterogeneous populations, variable dosing regimens, and inconsistent outcome definitions [, ]. Randomised controlled trials (RCTs) are scarce, direct comparisons between agents are lacking, and safety reporting is uneven. Many studies report categorical outcomes such as ‘UTI‐free status’ rather than standardised incidence rates, complicating meta‐analysis and clinical interpretation. Several systematic reviews have evaluated intravesical instillations for rUTI, primarily focusing on uncomplicated female populations. These reviews consistently report reductions in recurrence but involve small sample sizes, heterogeneous protocols, and limited data in patients with neurogenic bladder, catheter dependence or complex urological pathology. Consequently, the generalisability of existing evidence to real‐world urological practice remains uncertain. The present systematic review and meta‐analysis therefore aimed to address this gap by evaluating the efficacy and safety of intravesical instillations across all adult populations with rUTIs, including those with underlying urological pathology, to provide a more clinically representative synthesis.

We synthesised the available evidence on intravesical therapies for preventing rUTIs in adults and children, with quantitative pooling of aminoglycosides, HA monotherapy, and HA with CS (HA + CS) combined therapy where feasible, and narrative synthesis of other agents. Outcomes assessed included recurrence rates, microbiological resistance, and safety. By critically appraising and integrating the evidence, we aimed to clarify the therapeutic role of intravesical instillations and identify priorities for future clinical research.

A systematic search was performed in PubMed/MEDLINE, Embase, Cochrane CENTRAL, Scopus and Web of Science for studies published between January 2000 and April 2025. The search was last updated on 15 April 2025. Search terms combined Boolean operators, Medical Subject Headings (MeSH) and keywords, including ‘recurrent urinary tract infection’, ‘intravesical’, ‘instillation’, ‘gentamicin’, ‘HA’, ‘CS’, and ‘heparin’. Reference lists of all included studies were manually screened for additional eligible articles. We included RCTs and observational cohorts that investigated intravesical instillation of any agent for the prevention of rUTIs in adults or children, with either neurogenic or non‐neurogenic lower urinary tract dysfunction. A rUTI was defined as two or more symptomatic, culture‐confirmed infections within 6 months or at least three within 12 months, although studies using slightly modified but clinically comparable definitions were also accepted. Exclusion criteria were animal studies, case reports, conference abstracts without full text, and non‐English publications. Two reviewers (M.K., A.A.) independently screened titles, abstracts and full texts. Discrepancies were resolved by consensus or, where necessary, by consultation with a third reviewer (A.B.).

Data extraction was performed independently in duplicate using a piloted form (Microsoft Excel; Microsoft, Redmond, WA, USA). Extracted information included study design, setting, sample size, population characteristics, intervention details (agent, dose, instillation schedule, and duration), comparator, follow‐up, and outcomes. Where available, data on antimicrobial resistance and serum drug concentrations were also collected. The risk of bias for randomised trials was assessed using the Cochrane Risk of Bias 2 (ROB2) tool. Non‐randomised studies were evaluated using the Risk Of Bias In Non‐randomised Studies of Interventions (ROBINS‐I), with Newcastle‐Ottawa Scale domains applied to assess comparability. All assessments were performed in duplicate, with disagreements resolved through discussion.

The primary outcome was UTI recurrence, reported as either events per patient‐year or the proportion of patients experiencing at least one recurrence during follow‐up. Secondary outcomes included time to recurrence, antimicrobial resistance, and safety/tolerability. Study‐defined outcomes of symptomatic rUTIs were accepted, with definitions recorded as reported. Given the heterogeneity of interventions, we pre‐specified three therapeutic families for quantitative synthesis: (i) aminoglycosides (e.g., gentamicin, amikacin), (ii) HA monotherapy, and (iii) HA + CS combined therapy. Studies reporting comparable outcomes were pooled using random‐effects meta‐analysis. Between‐study heterogeneity was quantified with τ 2 (tau 2 ) and I 2 statistics. Planned subgroup analyses examined effects by population type (neurogenic vs non‐neurogenic bladder) and, for aminoglycosides, by specific antibiotic. These analyses were pre‐specified in the PROSPERO protocol. Sensitivity analyses included leave‐one‐out re‐estimation, alternative estimators for between‐study variance, and exclusion of high‐risk‐of‐bias studies. All analyses were conducted in R (version 4.5.1, ‘meta package’; R Foundation for Statistical Computing, Vienna, Austria), with figures generated via ‘ggplot2’.

From 2642 identified citations, 25 studies met the eligibility criteria and were included in the final analysis (Fig. ). This comprised one RCT and 24 observational cohorts, spanning both adult and paediatric populations with either neurogenic or non‐neurogenic bladder dysfunction. Across these 25 studies, >1000 participants were enrolled. Cohorts included patients performing intermittent self‐catheterisation, those with indwelling catheters, and individuals with urinary diversion. In all, 12 studies focused on neurogenic bladder populations, most commonly spinal cord injury or spina bifida, while the remainder examined non‐neurogenic groups such as postmenopausal women and individuals with idiopathic rURI. Most studies were single‐centre observational cohorts, with sample sizes ranging from <20 to >100 participants. Follow‐up durations varied considerably, from as little as 3 months to as long as 3 years, although most outcomes were reported within a 6–12‐month window. Geographically, the evidence base drew primarily from Europe, North America, and Asia, providing moderate global representation.

Interventions were diverse, encompassing intravesical aminoglycosides (10 studies), GAG replenishment therapies (12 studies), heparin (two studies), and antiseptics such as povidone‐iodine (one study). Study characteristics are summarised in Table [, , , , , , , , , , , , , , , , , , , , , , , , ] with instillation protocols detailed in Table .

In all, 10 studies evaluated intravesical aminoglycoside instillations, most commonly gentamicin, with smaller cohorts investigating amikacin or neomycin‐polymyxin. Across these studies, therapy was consistently associated with substantial reductions in UTI recurrence. Six studies reported extractable incidence rate ratios (IRRs) and were included in a random‐effects meta‐analysis [, , , , , ]. Individual study estimates ranged from an IRR of 0.13 (95% CI 0.09–0.18; Abrams et al. []) to 0.50 (95% CI 0.25–0.99; Mouhssine et al. []), with all demonstrating fewer infections compared with baseline or control groups. The pooled IRR was 0.23 (95% CI 0.15–0.37, P < 0.001), corresponding to a 77% reduction in rUTI risk (Fig. ). Substantial heterogeneity was observed ( I 2 = 70.2%, τ 2 = 0.12, P = 0.005), reflecting variability in effect size, although the direction of benefit was uniform across studies [, ].

Subgroup analyses explored treatment effects by patient population and antibiotic agent. In neurogenic bladder cohorts (four studies), the pooled IRR was 0.21 (95% CI 0.12–0.37; I 2 = 72.4%), while two non‐neurogenic studies reported a pooled IRR of 0.30 (95% CI 0.00–268.43; I 2 = 72.4%). The test for subgroup differences was not significant ( Q = 0.38, degrees of freedom [df] = 1, P = 0.54). Analysis by agent showed results as follows: five gentamicin studies reported a pooled IRR of 0.21 (95% CI 0.14–0.32; I 2 = 64.0%), while the single amikacin study yielded an IRR of 0.50 (95% CI 0.25–0.99). The test for subgroup differences was statistically significant ( Q = 5.26, df = 1, P = 0.02). Leave‐one‐out re‐estimation demonstrated consistent pooled IRRs ranging from 0.21 to 0.26, with all CIs excluding unity. Between‐study heterogeneity ( I 2 ) fluctuated between 16.5% and 75.6% depending on the study omitted, but the overall effect remained stable. Importantly, several included cohorts specifically recruited patients colonised with MDR organisms, and even within these high‐risk groups, recurrence rates were significantly reduced.

Six studies evaluated HA monotherapy for the prevention of rUTIs. Four trials provided extractable data suitable for pooling, while two reported categorical outcomes only and were synthesised narratively [, , , , , ]. The pooled random‐effects meta‐analysis of the four quantitative studies demonstrated a risk ratio (RR) of 0.15 (95% CI 0.05–0.43, P = 0.011), corresponding to an ~85% relative risk reduction compared with baseline or control (Fig. ). Heterogeneity was considerable ( Q = 21.3, df = 3, P < 0.001; I 2 = 85.9%, τ 2 = 0.38), reflecting variability in dosing schedules, treatment durations and population characteristics. Leave‐one‐out sensitivity analysis showed pooled RRs ranging from 0.12 to 0.19. In neurogenic populations, the pooled RR was 0.26 (95% CI 0.10–0.68; I 2 = 0%), while in non‐neurogenic groups the estimate was similar (RR 0.25, 95% CI 0.001–71.9) but with wide CIs and significant heterogeneity ( I 2 = 78%). The test for subgroup differences was not significant ( P = 0.90).

Four studies evaluated the combined use of HA and CS [, , , ]. The pooled estimate was imprecise and not statistically significant (RR 0.41, 95% CI 0.04–4.77; P = 0.465) []. The CIs were wide and heterogeneity substantial, reflecting differences in formulations, instillation schedules, and enrolled populations (Fig. ). Three comparative studies were included in the quantitative synthesis. The Damiano et al. [] RCT demonstrated a marked reduction in culture‐confirmed UTIs with HA + CS compared with placebo (RR 0.14, 95% CI 0.08–0.23) []. The Gugliotta et al. [] retrospective cohorts showed similar results (RR 0.49, 95% CI 0.36–0.66). In contrast, the large multicentre observational study by Ciani et al. [] yielded an effect estimate close to null (IRR 0.99, 95% CI 0.69–1.43). Pooled analysis of these trials suggested an overall reduction in recurrence risk, but heterogeneity was high ( I 2 >80%). Incorporating the Cicione et al. [] pre–post cohort (RR ~0.11) in a pre‐specified sensitivity analysis reinforced the apparent direction of benefit, although heterogeneity persisted.

Leave‐one‐out sensitivity analyses confirmed that no single study unduly influenced the pooled result. Excluding individual trials yielded pooled RRs ranging from 0.27 (95% CI 0.00–761.12) when omitting Ciani et al. [], to 0.69 (95% CI 0.01–60.21) when omitting Damiano et al. []. Across all iterations, the direction of effect consistently favoured HA + CS, although wide CIs reflected the small evidence base and underlying heterogeneity.

Several intravesical agents were evaluated in single studies or small series, limiting opportunities for quantitative pooling. Two small cohorts assessed intravesical heparin. Ablove et al. [] reported a case series of patients with refractory rUTIs, most of whom experienced reductions in infection frequency, with some remaining infection‐free during follow‐up. However, outcomes were descriptive only and lacked extractable recurrence rates. In a prospective cohort, Dutta and Lane [] studied 39 older women treated with a 6‐week course of intravesical heparin, with or without maintenance therapy. During active treatment, 30.8% experienced a UTI, and in the subsequent 6 months 46.2% had at least one recurrence, although only 17.9% met criteria for rUTIs. The regimen was well tolerated, and overall infection rates were lower than expected based on baseline history. Nevertheless, heterogeneous reporting precluded formal meta‐analysis.

A single, large prospective trial by Moussa et al. [] investigated daily intravesical povidone‐iodine in 119 patients with neurogenic bladder managed with clean intermittent catheterisation. Prior to treatment, participants experienced four to five symptomatic UTIs annually, often necessitating emergency care and hospitalisation. Following initiation of povidone‐iodine, symptomatic UTIs decreased by 99.2% (IRR 0.008, 95% CI 0.001–0.059), paralleled by reductions in emergency visits (99.2%) and hospitalisations (99.9%). Antimicrobial resistance patterns also improved []. Rahnama’i et al. [] conducted a retrospective cohort study comparing intravesical CS ( n = 50) with low‐dose long‐term oral antibiotics (LDLTAB, n = 51) and with combined therapy (LDLTAB + CS, n = 50). In the CS group, mean infection rates declined from 7.1 to 0.45 episodes/year over 12 months, accompanied by significant improvements in quality of life (EuroQoL five Dimensions [EQ‐5D] questionnaire score increased from 58.2 to 80.4). Both the combined therapy and antibiotic‐only groups demonstrated reductions, but CS was superior to antibiotics alone, which reduced recurrence only to 1.8 episodes/year and did not meaningfully improve quality of life. Although encouraging, the retrospective design and heterogeneous comparators limited eligibility for meta‐analysis [].

In a multicentre trial, Torella et al. [] randomised 69 women to intravesical HA + CS, HA + CS plus fosfomycin, or fosfomycin alone. At 12 months, 72.7% of HA + CS patients and 75% of HA + CS plus fosfomycin patients remained recurrence‐free, compared with only 30.4% in the fosfomycin arm. Symptom burden scores also improved in both HA + CS groups. However, outcomes were expressed as recurrence‐free proportions rather than incidence rates, preventing inclusion in pooled analyses []. Other studies also reported reductions in infection frequency but presented outcomes in formats unsuitable for meta‐analysis. Andretta et al. [], Chernyak and Salamon [] and Chitteti et al. [] each documented reductions in UTI frequency or increases in UTI‐free proportions, but without sufficient detail to calculate event rates. Bilsen et al. [] reported a rate ratio comparing on‐treatment with post‐treatment phases, a methodological approach distinct from the pre‐ vs during‐treatment contrasts used in our pooled analysis and was therefore described narratively.

Of the 25 studies included in this review, three studies were identified as randomised trials and therefore the ROB2 tool was used to assess their risk of bias. The risk of bias of the remaining 22 studies was assessed using the Newcastle‐Ottawa scale parameters. Two studies initially planned as randomised trials were converted to non‐randomised prospective designs prior to enrolment and were therefore not considered methodologically equivalent to RCTs. ROB2 domains were applied to transparently reflect the resulting high risk of bias. The 22 non‐randomised studies were all either of moderate or high quality. Using Agency for Healthcare Research and Quality conversion criteria, most non‐randomised studies were classified as poor quality due to limited comparability, despite adequate cohort selection and outcome ascertainment. Four studies met criteria for fair quality, while three large comparative cohorts with multivariable adjustment were rated as good quality.

Recurrent UTIs remain a persistent and burdensome condition that substantially impairs quality of life across a spectrum of patient groups, from those with neurogenic bladder reliant on intermittent catheterisation to women with idiopathic recurrence [, , ]. For decades, clinical practice has relied heavily on LDLTAB prophylaxis. While this strategy provides partial relief, it carries significant ecological and clinical burden, including gastrointestinal side effects, disruption of the commensal microbiota, Clostridioides difficile infection, and facilitating the potential emergence of MDR organisms. Against this backdrop, bladder‐directed therapies have developed as a biologically coherent and clinically sound alternative []. This review synthesises the contemporary evidence for intravesical instillations and supports their role as effective, well‐tolerated and antibiotic‐sparing interventions for select patients with refractory rUTIs.

Among the 25 included studies, the most consistent outcomes arose from intravesical aminoglycosides, particularly gentamicin, with smaller datasets available for amikacin and neomycin‐polymyxin [, , ]. When studies reporting comparable outcomes were pooled, the estimated IRR was ~0.23, corresponding to a three‐ to four‐fold reduction in infection rates relative to baseline or comparator groups. This benefit was observed in both neurogenic and non‐neurogenic populations and extended to cohorts with likely MDR organisms, in whom systemic options are increasingly limited [, ]. Sensitivity analyses confirmed that the pooled effect was not driven by any single study, with point estimates remaining stable and CIs consistently excluding the null. Heterogeneity was substantial, reflecting differences in dosing, instillation schedules, comparators and baseline risk, yet the direction of effect was uniformly favourable. The biological plausibility of these findings is compelling: intravesical administration achieves drug concentrations far above systemic minimum inhibitory concentrations while avoiding clinically harmful absorption. Across all studies that measured serum levels, aminoglycosides were undetectable and no nephrotoxicity or ototoxicity was reported []. The ability to generate potent local bactericidal activity without systemic toxicity offers a clear mechanistic basis for the lasting clinical benefit of intravesical aminoglycosides.

Hyaluronic acid monotherapy represents a mechanistically distinct, non‐antibiotic approach aimed at restoring the GAG barrier of the bladder epithelium [, , , ]. Disruption of this barrier facilitates bacterial adherence, biofilm formation, and chronic mucosal inflammation; exogenous HA seeks to reconstitute the anti‐adherence surface while dampening inflammatory signalling. In pooled analyses, HA was associated with a substantial relative reduction in recurrence, ~85% compared with baseline or control groups, although heterogeneity was high [, , ]. Variation in treatment schedules, population type and outcome definitions accounted for much of this inconsistency. Despite these limitations, the direction of effect was consistently favourable, and no serious adverse events were reported, making HA a credible antibiotic‐sparing option for patients who cannot tolerate systemic prophylaxis or who prioritise stewardship‐based approaches [].

The two HA studies excluded from pooling nonetheless provided supportive evidence. Zabkowski and Słowikowska‐Hilczer [] evaluated 23 women with recurrent cystitis, reporting that after induction and maintenance HA therapy, 69.6% remained recurrence‐free at 8 months, 21.7% showed partial improvement, and only 8.7% continued to experience recurrences. The regimen was well tolerated with no significant adverse events. Similarly, Fidan et al. [] studied 15 children with neurogenic bladder, with 80–90% achieving either complete or partial response, reflected in marked reductions in infection frequency. Although event rates were not reported, these findings highlight potential benefit in paediatric neurogenic populations.

Combined therapy with HA + CS has been hypothesised to also augment GAG layer replenishment [, , , , ]. Several individual trials reported large benefits, including a randomised comparison demonstrating substantial reductions in culture‐confirmed infections vs placebo []. However, pooled estimates were imprecise, with wide CIs and significant between‐study heterogeneity, reflecting differences in formulation, schedule, comparators and patient populations. A pre–post cohort reported dramatic within‐patient reductions, but this design is susceptible to regression to the mean and confounding. Collectively, the data suggest possible benefit in selected settings, but they do not permit generalisable recommendations beyond those already established for HA monotherapy. This uncertainty has practical implications: combination products are more costly and logistically demanding, and incremental benefit, if it exists, must be demonstrated in adequately powered comparative trials before broader clinical adoption can be justified.