Prevention of Recurrent Urinary Tract Infections by Intravesical Administration of Hyaluronic Acid and Chondroitin Sulphate: A Placebo-Controlled Randomised Trial

doi:10.1016/j.eururo.2010.12.039

European Urology

Volume 59, Issue 4, April 2011, Pages 645-651

https://doi.org/10.1016/j.eururo.2010.12.039 Get rights and content

Abstract

Background

Urinary tract infection (UTI) is a prevalent condition in women during their lifetime with a high rate of recurrence within 3–6 mo.

Objectives

Our aim was to investigate the efficacy and tolerability of the intravesical administration of combined hyaluronic acid (HA) and chondroitin sulphate (CS) in female patients with a history of recurrent UTI.

Design, setting, and participants

We conducted a prospective, randomised, double-blind, placebo-controlled study comparing the intravesical instillation of HA-CS with placebo in women with recurrent UTI.

Intervention

Participants were randomised to receive 50 ml of sterile sodium HA 1.6% and CS 2.0% solution (IALURIL^®) weekly for 4 wk and then monthly for 5 mo.

Measurements

The primary end point of the study was defined as the mean number of UTI per patient per year. Participants were evaluated addressing UTI status/urinary symptoms and with a general health-related quality-of-life (QoL) questionnaire at baseline and after 3, 6, 9, and 12 mo.

Results and limitations

In the intention-to-treat analysis, 57 women were randomly allocated to HA-CS (n = 28) or placebo (n = 29). The UTI rate per patient per year at the end of the study (12 mo) (mean ± SD: −86.6% ± 47.6 vs −9.6% ± 24.6; mean difference: 77%; 95% confidence interval, 72.3–80.8; p = 0.0002) and the mean time to UTI recurrence (52.7 ± 33.4 vs 185.2 ± 78.7 d; p < 0.001) were significantly reduced after treatment with HA-CS compared with placebo. Overall urinary symptoms and QoL measured by questionnaires significantly improved compared with placebo (Pelvic Pain and Urgency/Frequency questionnaire symptom score: 14.53 ± 4.32 vs 9.88 ± 6.77; p = 0.004; SF-36 QoL score: 78.6 ± 6.44 vs 53.1 ± 4.72; p < 0.001). No serious adverse event was reported.

Conclusions

Compared with placebo, HA-CS intravesical instillations significantly reduced UTI rate without severe side effects while improving symptoms and QoL over a 12-mo period in patients with recurrent UTI.

Trial registration

ISRCTN 76354426.

Introduction

An estimated half of women will have at least one episode of urinary tract infection (UTI) requiring antibiotic therapy during their lifetime. Moreover, 25–35% of initial UTI episodes are followed by a recurrent infection within 3–6 mo [1], [2], [3].

Individual susceptibility to UTI is complex and depends on genetic, biologic, and behavioural factors. Among the recognised factors, the interaction between the bacteria and the epithelial cells lining the bladder wall is likely to play a major role [4], [5]. The glycosaminoglycan (GAG) layer lining the transitional epithelium of the human bladder is implicated in this process.

A damaged GAG layer may lead to direct exposure of epithelial cells to urine components, which increases the possibility of bacterial adherence and infection [6], [7]. Various approaches have been developed towards a reversal of the damage and a reconstruction of the GAG layer, including the use of heparin [8], oral pentosan polysulphate [9], and hyaluronic acid (HA) [10], [11], [12].

HA is a major mucopolysaccharide widely found in the connective, epithelial, and neural tissues. Chondroitin sulphate (CS) is also an important structural component for bladder mucosal integrity [13].

These substances have been administered orally, intravesically, or both, with the aim of restoring the integrity of the GAG layer in patients with interstitial cystitis [14]. The positive outcomes obtained in the management of interstitial cystitis suggest that a similar therapeutic approach might be beneficial for treating recurrent UTI.

We report the results of a prospective, randomised, double-blind, placebo-controlled trial aiming to investigate the efficacy and tolerability of intravesical administration of combined HA and CS in reducing the rate of UTI and improving the quality of life (QoL) in female patients with a history of recurrent UTI.

Section snippets

Synopsis

This single-centre randomised controlled trial was conducted in one tertiary reference centre (Policlinico Mater Domini, UMG, Catanzaro, Italy) and began in September 2009. The study was conducted in accordance with good clinical practice guidelines and the Declaration of Helsinki, and our local institutional review board approved the protocol. All subjects gave written informed consent before enrolment in the study. Efficacy and safety data were collected during the treatment period and

Population

A total of 57 women were randomised to sodium HA 1.6%/CS 2.0% solution (n = 28) or placebo (n = 29). Three patients were lost to follow-up during the study. Fifty-four women (mean age: 34.8 ± 11.1 yr) completed the study and were included in the analysis. Fig. 1 shows the study flowchart.

Table 1 lists baseline data gathered at the time of randomisation, which indicated no significant differences between the treatment groups in terms of age, number of UTIs per year recorded, symptoms, and QoL scores.

Urinary tract infections

Discussion

Recurrent UTIs in women are common, result in considerable morbidity and expense, and can be a management problem for physicians. On average, each episode of acute UTI in premenopausal women was shown to be associated with 6.1 d of symptoms, 2.4 d of restricted activity, 1.2 d in which they were not able to attend classes or work, and 0.4 d in bed [2]. Nonantimicrobial prevention strategies are desirable given the adverse effects associated with antimicrobials and the increasing problem with

Conclusions

Effective and safe strategies to prevent recurrent UTI that avoid the use of antimicrobials are highly desirable. Our findings show the efficacy of bladder instillation of combined HA-CS in preventing UTI in this study population. Larger open-label studies or a multicentre registry would be required to corroborate these encouraging results and to demonstrate the generalisability of this treatment option in patients with recurrent UTI.

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Adherence to European Association of Urology Guidelines and State of the Art of Glycosaminoglycan Therapy for the Management of Urinary Tract Infections: A Narrative Review and Expert Meeting Report
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Citation Excerpt :
Exogenous GAGs, especially in the combination of HA + CS and CaCl2 (Ialuril; IBSA, Lugano, Switzerland), were originally investigated for efficacy in patients with painful bladder syndrome and interstitial cystitis who had not benefited from other therapies [44]. More recent studies showed its efficacy in preventing rUTIs in patients with at least three episodes of bacterial cystitis in the previous year [45]. Early observational studies suggested that exogenous intravesical HA could reduce the frequency of episodes of rUTIs [46,47].
Urinary tract infections (UTIs) have a significant impact on patient’s quality of life and society. Antibiotic therapy is the primary approach for the management of UTIs; however, it has major limits in the prevention of recurrent UTIs (rUTIs), also increasing the risk of development of multidrug-resistant micro-organisms.
The aim of this paper is to discuss the European Association of Urology guidelines for the management of UTIs/rUTIs, the level of adherence to these recommendations, and the available evidence on the use of glycosaminoglycans (GAGs) as a possible alternative treatment to prevent rUTIs.
This narrative review and expert meeting report is based on a literature search concerning the currently available UTI guidelines, the results of a survey administered to 227 urologists, and the opinion of an expert panel in the field of UTIs.
Results obtained from the literature search showed that adherence to guidelines is not optimal. The survey demonstrated that antibiotics remain one of the treatments of UTIs. However, most of the urologists are aware of the problem caused by the resistance to antibiotics and prefer alternative methods for the prophylaxis of UTIs. Considering the alternative methods, the authors concluded that GAG therapy is highly effective in preventing rUTIs.
Adherence to the international guidelines is important to align the clinical practice and avoid the spreading of antibiotic resistance. The survey outlines that the misuse and overuse of antibiotics are major problems; an analysis of clinical evidence confirms that GAG therapy is a valuable therapeutic approach to prevent the recurrence of episodes of UTIs and to limit the onset of antibiotic resistance.
Although antibiotic therapy is primarily used for the management of urinary tract infections (UTIs), misuse and overuse of antibiotics are of concern. Adherence to the international guidelines is important to prevent the spreading of antibiotic resistance. Clinical evidence confirms that the use of glycosaminoglycans is a valuable therapeutic approach to prevent UTI recurrence and limit the onset of antibiotic resistance.
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Our results suggest that intravesical HA/CS in combination with an oral formulation may reduce urinary symptoms and improve QoL at short-term (1 yr) follow-up.
We investigated whether hyaluronic acid (HA) and chondroitin sulfate (CS) have a protective effect against the bladder toxicity of radiotherapy for prostate cancer. HA/CS used for weekly bladder irrigation for 6 wk and given orally with curcumin and quercetin for 12 wk reduced urinary incontinence symptoms and bother measured at 1-year follow-up. This may hold promise as a preventive treatment if the results are confirmed in further trials.
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This chapter presents an important and recent progress of biological macromolecules as antimicrobial agents. Microbial infections continue to threaten human health and posture a pronounced economic worry to society. To resolve this emergency, huge works are required to improve and develop antimicrobial macromolecules. Natural antimicrobial macromolecules such as polysaccharides, proteins, fatty acids, etc. contain a large number of molecules, which perform effective antimicrobial action due to their excellent biochemical characteristics. The use of these biological macromolecules and their composites is a probable way to reduce the development of pathogen resistance materials. The first part of the chapter describes biological macromolecules (chitosan, cellulose, alginate, gelatin, collagen, keratin) and their antimicrobial activity. The second part discusses the potential antimicrobial activity of macromolecule composites as effective antimicrobial platforms. Based on their antimicrobial mechanisms, the third part comprehensively elucidates their applications in addressing challenges associated with drug delivery, wound dressing, food packaging, etc.
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Las infecciones urinarias son muy prevalentes entre las mujeres y cuando son recurrentes conllevan malestar a las pacientes, un elevado coste sanitario y representan una de las causas más frecuentes de uso de antibióticos. Para prevenirlas existen varias opciones que incluyen tanto tratamientos antibióticos (profilaxis antibiótica continua o poscoital) como medidas no antibióticas (medidas higiénicas, vitamina D, arándanos, D-manosa, probióticos, estrógenos, vacunas, instilaciones intravesicales), pero con diferente nivel de evidencia y, a veces, de mala calidad, por lo que se necesitan nuevos estudios aleatorizados y comparativos que permitan diseñar la mejor estrategia de prevención.
Urinary tract infections are highly prevalent among women and when they are recurrent they can lead to patient discomfort and high healthcare costs, and they represent one of the most frequent causes of antibiotic consumption. There are several options to prevent RUTI which include both antibiotic treatment (continuous or postcoital antibiotic prophylaxis) and non-antibiotic measures (hygienic measures, vitamin D, blueberries, D-mannose, probiotics, oestrogens, vaccines, intravesical instillations), but with different levels of evidence, sometimes of poor quality, and therefore new randomized and comparative studies are needed to choose the best strategy.
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InfectionsPrevention of Recurrent Urinary Tract Infections by Intravesical Administration of Hyaluronic Acid and Chondroitin Sulphate: A Placebo-Controlled Randomised Trial

Abstract

Background

Objectives

Design, setting, and participants

Intervention

Measurements

Results and limitations

Conclusions

Trial registration

Introduction

Section snippets

Synopsis

Population

Urinary tract infections

Discussion

Conclusions

Epidemiology of urinary tract infections: incidence, morbidity and economic costs

Am J Med

The etiology of urinary tract infection: traditional and emerging pathogens

Am J Med

Risk factors for second urinary tract infection among college women

Am J Epidemiol

Dynamic interactions between host and pathogen during acute urinary tract infections

Urology

Pathogenesis and management of recurrent urinary tract infections in women

World J Urol

The bladder mucus (glycosaminoglycan) layer in interstitial cystitis

J Urol

Epithelial coating techniques in the treatment of interstitial cystitis

Urology

Treatment of interstitial cystitis with intravesical heparin

Br J Urol

Analysis of long-term Elmiron therapy for interstitial cystitis

Urology

Infections
Prevention of Recurrent Urinary Tract Infections by Intravesical Administration of Hyaluronic Acid and Chondroitin Sulphate: A Placebo-Controlled Randomised Trial