Effectiveness of intravesical glycosaminoglycans in the treatment of recurrent urinary tract infections: Systematic review and meta-analysis

Abstract

Objective:

The objective of the study was to determine the efficacy of glycosaminoglycans in bladder instillation compared with placebo or other forms of prophylaxis in women with recurrent urinary tract infections (UTIs).

Methods:

A search strategy was performed in the Cochrane central register, Embase, and Medline until October 2020, along with manual searches and reference-list checking. Randomised and nonrandomized studies in women with recurrent UTIs who received hyaluronic acid (HA) or HA plus chondroitin sulfate (CS) were included. A random-effects model was applied to the pooled results. The risk of bias was evaluated using the Cochrane RoB 2 bias tool for clinical trials and MINORS for nonrandomized studies. The quality of the evidence was evaluated by the GRADE method.

Results:

One randomised study and eight nonrandomized studies were included. All evaluated HA or HA plus CS. HA or HA plus CS decreased the average UTI patient-years (mean difference (MD) = −2.62; 95% confidence interval (CI) = −4.00 to −1.23), increased the time to recurrence (MD = 145.70; 95% CI = 61.57 to 229.83), and improved symptoms and quality of life as evaluated through the total pelvic pain and urgency/frequency score (MD = −6.08; 95% CI = −7.68 to −4.48) and the visual analog scale (MD = −4.79; 95% CI = −5.55 to −4.03). There was high heterogeneity in the results, a high risk of bias in the one randomised study, and a low quality of evidence according to GRADE. The number of included studies was low.

Conclusion:

The application of HA or HA plus CS in intravesical instillation is associated with fewer UTI recurrences and improved symptoms and quality of life. The quality of the evidence provided by the studies is limited, so more studies of higher quality are needed to yield definitive conclusions.

Level of evidence:

Not applicable

Keywords

Recurrent urinary tract infection hyaluronic acid chondroitin sulfate women

Introduction

Urinary tract infections (UTIs) are a frequent cause of consultation and disability in affected people and are more frequent in women.¹ Approximately 40–50% of women have at least one UTI in their lifetimes, which carries the risk of a second infection of 24% within 6 months and approximately 70% at 12 months.^1,2 The majority of cases are treated with antibiotics, but they do not always yield satisfactory results, giving rise to antibiotic resistance; favoured by prolonged and intermittent use of antibiotics. Considering that approximately 25% of all antibiotic prescriptions are for the treatment of urinary tract infections, thus becoming a threat to the safety of patients with an increase in single-agent resistance rates are rising to unacceptable levels around the world and intractable UTIs are a real concern.^3–5

Therapy based on the restoration of glycosaminoglycans of the epithelial lining of the bladder has been proposed as one way to treat recurrent UTIs. Glycosaminoglycans are proposed to function as an antimicrobial coating of the bladder to prevent bacterial adherence.² The use of glycosaminoglycans as an intravesical instillation in adults has shown promising results in the treatment of chronic inflammatory conditions of the bladder, with rates ranging between 30% and 71%.⁶

De Vita et al. compared the intravesical administration of hyaluronic acid–chondroitin sulfate (HA-CS) with antibiotic prophylaxis. The evaluations included recurrence of cystitis after 2 and 12 months of treatment, symptoms such as pain as measured on a visual analog scale (VAS), sexual function, quality of life, frequency/urgency symptoms evaluated by the pelvic pain and urgency/frequency (PUF) scale, and maximum cystometric capacity. The results were favourable to the HA-CS group, with significantly improved recurrence of cystitis (mean ± standard deviation (SD) = 1 ± 1.2 vs 2.3 ± 1.4, p = 0.02), visual analog scale score (mean ± SD = 1.6 ± 0.8 vs 7.8 ± 1.6, p < 0.001), and PUF symptom score (mean ± SD = 11.2 ± 2.7 vs 19.6 ± 2.2, p < 0.001) at both evaluations, without any adverse effects. Their findings demonstrated the effectiveness of HA-CS for the treatment of recurrent urinary infections.⁷

Goddard et al. performed a systematic review and meta-analysis to evaluate the efficacy of intravesical application of glycosaminoglycans alone or in combination with other agents for recurrent UTIs in adult women. HA-CS decreased the rate of UTIs per patient per year and prolonged the time to first recurrence.¹ A meta-analysis of the efficacy of glycosaminoglycans for the prevention of recurrent urinary infections was published in 2018, updating this information.

Recurrent urinary tract infections are a debilitating entity in which interventions are sought to reduce the burden of disease; treatment options that have shown effectiveness and have been previously summarised in reviews are of great value for decision-making. Given the appearance of new evidence regarding the use of intravesical glycosaminoglycans, we believe it would be useful to summarise the new evidence available. The present systematic review and meta-analysis evaluated the effectiveness against recurrent UTI of glycosaminoglycans in bladder instillation compared with antibiotics or other forms of prophylaxis in adult women.

Methods

To prepare this systematic review, the recommendations of the Cochrane Collaboration for systematic reviews and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) were followed. This study was registered at PROSPERO with the number CRD42021244174.

Eligibility criteria

Controlled clinical trials, quasi-experimental studies, and prospective and retrospective cohort studies were enrolled if they evaluated intravesical instillation with glycosaminoglycans (hyaluronic acid and/or chondroitin sulfate). The patients had to be women older than 18 years with a diagnosis of recurrent uncomplicated UTIs. The studies had to compare the glycosaminoglycans with standard prophylaxis by antibiotics or hygienic dietary measures such as cranberry juice or probiotics. Studies in patients with a neurogenic bladder, a history of immunosuppression, and/or a history of urinary tract neoplasia were excluded. Descriptive studies such as case series or case reports were excluded, as were observational studies that did not measure associations between interventions and outcomes. There was no language restriction, nor was there any restriction by type of publication or status.

Outcomes

The primary outcomes were the number of episodes of bacteriologically confirmed recurrent UTIs per year after initiating treatment and the time to first recurrence of a UTI. The secondary outcomes were a change in symptoms evaluated through different scales (pelvic pain, urgency/urinary frequency) and quality of life.

Search strategy

A search was conducted through MEDLINE via Ovid, EMBASE, LILACS, and the Cochrane Central Register of Controlled Trials (CENTRAL) from January 1980 to December 2022 (Appendix 1). We also searched in other electronic sources to find additional studies: ClinicalTrials.gov, International Clinical Trials Registry Platform, DARE, and PROSPERO. The grey literature (unpublished) was consulted, such as conference abstracts, OpenGray databases, Google, and Google Scholar. Additional studies were sought in the reference lists of the selected articles.

Selection of studies and data collection

Two researchers independently identified and selected the titles and abstracts that were obtained from the search strategy. When there were doubts regarding their eligibility, a full-text review was necessary. The authors considered whether to include each article according to the inclusion and exclusion criteria and by considering the research question within the patient, intervention, comparison, outcome (PICO) paradigm. Disagreements were resolved by discussion between the two reviewers.

To extract information from the articles of interest, a data extraction sheet was designed in which characteristics such as the study design, researchers, participants, interventions, comparators, results, and sample size were entered. The evaluators confirmed all data entries and checked them at least twice to verify the integrity and accuracy of the information.

Assessment of risk of bias

The evaluation was performed with version 2 of the risk-of-bias tool of the Cochrane collaboration for randomised clinical trials, structured in five fixed domains.⁸ The nonrandomized studies were evaluated with the methodological index for nonrandomized studies (MINORS) tool, which has the appropriate domains for the evaluation of nonrandomized intervention studies.⁹

Evaluation of quality of evidence

The quality of the evidence for all our results was judged using the GRADE (grading of recommendations assessment, development and evaluation) working group method.¹⁰

Statistical analysis

The statistical analysis was performed in Review Manager version 5.4. The final outcome variables are shown in terms of standardised mean difference (MD), taking into account that the results in the primary studies were given as continuous variables. A random-effects model was used given the heterogeneity found, which was greater than 75%. To estimate the degree of heterogeneity between the results of the studies, statistical tests such as the I² statistic were applied, which describes the variability due to heterogeneity and not to sampling error. Its interpretation can be guided by the following ranges: 0–40%: may not be important; 30–60%: may represent moderate heterogeneity; 50–90%: may represent significant heterogeneity; 75–100%: considerable heterogeneity. The results are reported in forest plots to estimate the effect of each included study through its 95% confidence interval (CI).⁸

Sensitivity analysis

This was performed based on the risk of bias: those with a high risk of bias were excluded. It was statistically evaluated according to the Mantel–Haenszel test.

Other analysis

We could not perform publication bias nor subgroup analysis due to a low number of studies.

Results

We caught 684 studies by the designed search strategy. Of these, nine studies were included for qualitative and quantitative analysis^{3,6,7,11–16} (Figure 1).

Figure 1.

PRISMA flowchart of study selection.

Characteristics of included studies

The main characteristics of the included studies are summarised in Table 1. One study was randomised, and the other eight were nonrandomized. The duration of treatment was on average 4 months, with a maximum of 12 months.

Table 1.

Included studies.

Author(s)	Study design	Patients	Intervention	Comparator	Primary outcome	Follow-up
Constantinides et al.¹¹	Not randomised	Women 18–45 years, history of UTIs	HA, 40 mg once a week for 4 weeks, then once a month for 4 months. Follow-up for another 7 months	Retrospective review of patient records. Starting before HA	Average UTI patient-years, time to recurrence	15.8 months
Lipovac et al.¹²	Not randomised	Women 17–34 years, history of UTIs	HA, 40 mg once a week for 4 weeks, then once weekly for 5 months. Follow-up for 6 months	Retrospective review of patient records. Starting before HA	Average UTI patient-years, time to recurrence	14 months
De Vitta et al.⁷	Randomised, controlled	Women with an average age of 60 years	HA 800 mg + CS 1 g once a week for 4 weeks, then once every 2 weeks for 4 weeks	TMP/SMX (200/40) once weekly for 6 months	Average UTI patient-years	12 months
Raymond et al.¹³	Not randomised	Women 35–70 years	HA, 40 mg once a week for 4 weeks, then once a month. Average nine instillations	Retrospective review of patient records. Starting before HA	Changes in VAS and PUF scores.	21 months
Cicione et al.¹⁴	Not randomised	Women with an average age of 53 years	HA 800 mg + CS 1 g once a week for 4 weeks, then once monthly for 5 months	Retrospective review of patient records. Starting before treatment	Average UTI patient-years, time to recurrence	24 months
Gugliotta et al.¹⁵	Retrospective cohort	Women with an average age of 38 years	HA 800 mg + CS 1 g once a week for 4 weeks, then once monthly for 4 months	TMP/SMX (200/40) once weekly for 6 months	Average number of UTIs per year, percentage of patients UTI-free at 12 months	12 months
Ciani et al.⁶	Cases and controls	Women 18–75 years	HA 800 mg + CS 1 g once a week for 4 weeks, then once every 2 weeks for 4 weeks, then monthly. Different schemes	Standard prophylaxis (antibiotic, cranberry, probiotics, or combination)	UTI recurrence at 12 months of treatment	12 months
Sacco¹⁶	Quasi-experimental	Women with an average age of 52.2 years	HA 800 mg + CS 1 g once every 2 weeks for four doses. Then once monthly for 4 months	Retrospective review of patient records. Starting before treatment	Average UTI patient-years, time to recurrence	12 months
Scarneciu et al.³	Quasi-experimental	Women from 19 to 69 years	HA, 40 mg once a week for 4 weeks, then once a month. Average nine instillations	Retrospective review of patient records. Starting before treatment	Changes in VAS score, PUF score, and voiding volume	20 months

UTI: urinary tract infection; HA: hyaluronic acid; CS: chondroitin sulfate; TMP/SMX: trimethoprim/sulfamethoxazole; VAS: visual analog scale; PUF: pain and urgency/frequency.

The nine studies included a total of 754 patients. In all of them, the main inclusion criterion was the history of recurrent UTI. In seven, the primary objective was the evaluation of the average UTIs per patient-year, as well as the average time to first recurrence, measured in days. Secondary outcomes included changes in voiding volume, overall PUF score, and VAS and 36-Item Short Form Health Survey (SF-36) scores.

Risk of bias assessment

We evaluated the risk of bias of the randomised study through RoB2 for the synthesis of the evidence. Domain 1 was rated with some precautions. Domains 2, 3, and 5 were considered to have a low risk of bias, and Domain 4, which evaluates the measurement of the results, presented a high risk of bias. As a result, the studies overall had a high risk of bias. This was reflected in the outcomes of the number of UTIs and PUF total score.

The eight nonrandomized studies were evaluated following the items of MINORS for nonrandomized intervention studies, such that two studies (Constantinides et al. and Cicione et al.) were evaluated with a high risk of bias with this tool, while the rest had a low risk of bias. The assessments of risk of bias for the clinical trial and for nonrandomized studies as well as their scales are shown in Supplementary Figure 1a, Supplementary Figure 1b, and Supplementary Figure 1c, respectively.

Evaluation of the quality of the evidence

Using the GRADE method, we defined the quality of the evidence of the retrieved publications and the degree of confidence we had in their estimates to make a recommendation. For the main outcome or primary objective, there was a low quality of evidence from these results. The improvement in quality of life and improvement of symptoms, evaluated through the VAS and the PUF scale, were evaluated as having very-low- and low-quality evidence, respectively (Supplementary Table 1).

Primary outcome

In general, the studies showed a positive effect of treatment on the primary and secondary outcomes. When comparing the use of HA or HA plus CS versus the control, the former was associated with a significant decrease in the average UTI patient-years (MD = −2.62; 95% CI = −4.00 to −1.23, p < 0.0002; Figure 2(a)). Thus, the time to recurrence was longer (MD = 145.70; 95% CI = 61.57 to 229.83, p = 0.0007; Figure 2(b)).

Figure 2.

(a) Average UTI patient-years. (b) Time to recurrence (days).

Secondary outcome

In the evaluation of the improvement of symptoms and quality of life, HA plus CS or HA was associated with a significant reduction in PUF score (MD = −6.08; 95% CI = −7.68 to −4.48, p < 0.00001; Figure 3(a)). The same was true of the evaluation through VAS (MD = −4.79; 95% CI = −5.55 to −4.03, p < 0.00001; Figure 3(b)). Although there was a slight tendency of an improved perception of well-being as evaluated through the SF-36 scale in those who were treated with glycosaminoglycans, this difference was not significant (MD = 5.67; 95% CI = −0.03 to 11.37, p = 0.05; Figure 3(c)).

Figure 3.

(a) Change in pelvic pain urgency/frequency (PUF) total score. (b) Change in VAS pain score. (c) Change in SF-36 score. (d) Change in voiding volume.

An alternative to evaluate the quality of life and symptoms was through the change in voiding volume, which was higher in those patients treated with HA plus CS or HA (MD = 107.24; 95% CI = 29.78 to 184.70, p = 0.007; Figure 3(d)).

Evaluating the heterogeneity for each of the aforementioned results, I² was greater than 75%. Given this significant variability, a random-effects model was used for each of the analyses.

Sensitivity analysis

In the sensitivity analysis according to the risk of bias (excluding high-risk patients), we found that for the average UTI per patient-years, the MD remained statistically significant (MD = −2.32; 95% CI = −4.33 to −0.31, p = 0.02). The results of time to recurrence were less robust; if we excluded those with a high risk of bias, the MD was not statistically significant (MD = 84.01; 95% CI = −65.54 to 233.57, p = 0.27).

Regarding the change in VAS and the total PUF score, the sensitivity analysis of both outcomes still showed differences in favour of the glycosaminoglycan intervention (VAS: MD = −4.32; 95% CI = −4.57 to −4.08, p < 0.00001; total PUF score: MD = −5.92; 95% CI = −7.60 to −4.23, p < 0.00001).

Discussion

This systematic review and meta-analysis included 754 patients from nine randomised and nonrandomized studies. No studies that investigated the use of CS as a single agent were found by our search strategy.

Seven studies showed that the intravesical instillation of HA or HA plus CS compared with standard care achieved an average reduction of −2.62 episodes per patient-year and an increase in the time to the first recurrence of 145.7 days in adult women. Although this last outcome in the sensitivity analysis showed a positive tendency to increase the time to recurrence, it was not statistically significant if studies with a high risk of bias were excluded.

Intravesical instillation was also associated with a reduction in the total PUF score of −6.08 and a decrease of −4.79 in the perceived pain evaluated through the VAS. These scales allow us to evaluate a symptomatic improvement and, with it, quality of life. These differences persisted when the studies with a high risk of bias and the randomised study were excluded, respectively (total PUF score = −5.95; VAS change = −4.32).^3,6,7,11,12

On the contrary, this systematic review and meta-analysis estimated that glycosaminoglycans can reduce chronic pelvic inflammation by different pathways, thus explaining the increase in voiding volume or cystometric capacity at 12 months of follow-up.

In addition to effectiveness, safety must be considered when interpreting the results of the review, as glycosaminoglycan instillation is an invasive procedure (intravesical application that includes performing bladder catheterization) that can be painful. Among the studies that reported adverse effects, only mild to moderate pelvic pain, dysuria, or urethral pain was reported after instillation. This type of adverse event was reported by 129 patients in those studies that reported events.

Although the instillation schemes vary between studies, most of them adopt a schedule of applications that consists of an induction period with four weekly instillations, followed by up to four monthly instillations, the most common duration being 4 months. The total number of instillations is also mentioned. Although we wanted to analyse recurrence prevention, the heterogeneity of the studies and their data did not allow us to draw conclusions on this, so more data are required to establish the best strategy in clinical practice.^13,14

The results of this meta-analysis are consistent with published reports with the same characteristics as ours, which have reported statistically significant responses in reducing episodes of UTI recurrence. De Vita et al. reported a reduction of −2.45 patient-year episodes, and Goddard et al. in a similarly designed study found a reduction of −2.56 UTI patient-year. Therefore, ours represents an update of previous publications, the last one published in 2018 with the inclusion of three nonrandomized studies published between 2012 and 2019.^1,2,7 Our studies are similar in methodological design and intent, and the new studies included were mostly nonrandomized, which could explain the similar results in some of the main outcomes.

The main limitation to keep in mind when interpreting our results is the heterogeneity in the control groups, as some control groups used antibiotics, others retrospective review, and others probiotics or cranberry juice, leading to expected methodological differences. A random-effects model was used for the data analysis and synthesis. The positive outcomes from the use of HA/HA plus CS found in our analysis should be interpreted conservatively if one takes into account the weak quality of the evidence, the introduction of biases, and the high heterogeneity when performing the final analyses. Although our primary objective (outcome) was clearly established, other secondary outcomes, such as the change in the VAS pain score and the PUF score, are highly subjective, introducing relevant observation bias. Similarly, the high heterogeneity between the studies and the small number of included studies are limitations that reduce the validity and robustness of the results, so they should be interpreted with caution, although the population belonging to each of the studies was homogeneous in terms of inclusion and exclusion criteria, making our results generalizable. Among the studies enrolled in this meta-analysis, HA plus CS was the intervention evaluated in the one clinical trial, while HA was the only intervention evaluated in some nonrandomized studies. Therefore, differences in the data, designs of the included studies, and strength of the evidence can bias the comparisons, and the effect estimated by the present review should be interpreted with caution.

Conclusion

This systematic review and meta-analysis shows that HA or HA plus CS as an intravesical instillation compared with antibiotic prophylaxis or other forms of prophylaxis is associated with fewer average recurrences of UTIs, improved symptoms, and better quality of life. It is also safe, as indicated by the low rate of reported adverse effects.

The quality of the evidence provided by the studies is limited, so we believe that high-quality research is required. Well-designed studies are needed to evaluate the efficacy and safety of glycosaminoglycans for the prevention of recurrent UTIs.

Supplemental Material

sj-png-1-uro-10.1177_20514158231198553 – Supplemental material for Effectiveness of intravesical glycosaminoglycans in the treatment of recurrent urinary tract infections: Systematic review and meta-analysis

Supplemental material, sj-png-1-uro-10.1177_20514158231198553 for Effectiveness of intravesical glycosaminoglycans in the treatment of recurrent urinary tract infections: Systematic review and meta-analysis by Ricardo Contreras-García and Herney Andrés García-Perdomo in Journal of Clinical Urology

Supplemental Material

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Supplemental material, sj-png-2-uro-10.1177_20514158231198553 for Effectiveness of intravesical glycosaminoglycans in the treatment of recurrent urinary tract infections: Systematic review and meta-analysis by Ricardo Contreras-García and Herney Andrés García-Perdomo in Journal of Clinical Urology

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Supplemental Material

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Supplemental material, sj-xlsx-4-uro-10.1177_20514158231198553 for Effectiveness of intravesical glycosaminoglycans in the treatment of recurrent urinary tract infections: Systematic review and meta-analysis by Ricardo Contreras-García and Herney Andrés García-Perdomo in Journal of Clinical Urology

Footnotes

Appendix 1 Acknowledgements

We thank our family and university.

Conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship and/or publication of this article.

Ethical approval

Not applicable.

Informed consent

Not applicable.

Guarantor

Not applicable.

Contributorship

All authors contributed equally to the planning and realisation of the article.

ORCID iD

Herney Andrés García-Perdomo

Supplemental material

Supplemental material for this article is available online.

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43° Congresso Nazionale SIUD, 13–15 Giugno

2019, https://www.siud.it/43-congresso-nazionale-siud-17-congresso-siud-fisioterapisti-infermieri-ostetriche/

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