Xyloglucan, Hibiscus and Propolis in the Management of Uncomplicated Lower Urinary Tract Infections: A Systematic Review and Meta-Analysis

Background: In the era of antibiotic resistance, an antibiotic-sparing approach presents an interesting alternative treatment of uncomplicated cystitis in women. Our aim is to perform a systematic review and meta-analysis to compare the effectiveness and safety profile of a medical device containing xyloglucan, hibiscus and propolis (XHP) in women with uncomplicated cystitis. Methods: Relevant databases were searched using methods recommended by the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The primary endpoint was clinical or microbiological success, defined as the complete (cure) and/or non-complete (improvement) resolution of symptoms at the end of treatment, or microbiological resolutions. Results: After screening 21 articles, three studies were included, recruiting a total of 178 patients. All three studies used placebo as comparator. A statistically significant difference was found in terms of clinical or microbiological resolution between the medical device and the comparator (3 RCTs, 178 patients, OR: 0.13; 95% CI: 0.05–0.33; p < 0.0001). No clinically significant adverse effects have been reported. Conclusion: A medical device containing xyloglucan, hibiscus and propolis is superior to comparator regimens in terms of clinical effectiveness in adult women with microbiologically confirmed or clinical suspicion of uncomplicated cystitis and is associated with a high patient compliance.


Introduction
The prevalence of recurrent uncomplicated urinary tract infections (rUTIs) in women accounts for about 27% and the impact of those on patients' quality of life is high [1,2]. In particular, suffering from recurrent urinary tract infection has a detrimental influence on patient quality of life, in terms of the level of stress and anxiety [2]. In addition, its management is still under discussion and there is not a consensus [3,4]. The need for an antibiotics-sparing approach, due to the worldwide emergency of antibiotic resistance, and the recent interest in the role of non-antibiotic oral supplements increased the interest among physicians and researchers in the use of medical devices containing phytotherapy and nutraceuticals compounds. On the basis of this considerations, here we focused our attention on a medical device containing xyloglucan, hibiscus and propolis (XHP) in the management of women affected by rUTIs. Recently Cai et al. demonstrated in a prospective clinical trial the clinical and microbiological efficacy of XHP in improving quality of life in women affected by rUTIs, reducing symptomatic episode and the use of antibiotics [5]. This study has been based on the encouraging results from previous published RCTs [6][7][8].
In this sense, the use of XHP seems an interesting tool for use in everyday clinical practice for improving antimicrobial stewardship. Considering this background information and considering the lack of a general consensus about the management of rUTIs, we aimed to compare the effectiveness and safety profile of XHP in women with uncomplicated cystitis, by performing a systematic review and meta-analysis of relevant randomized controlled trials.

Research Questions
We put forth two research queries: 1.
Is XHP able to obtain significant pre-clinical data in order to justify its clinical use in the management of patients affected by uncomplicated cystitis? 2.
Is XHP able to obtain a clinical and/or microbiological cure in women affected by uncomplicated cystitis?

Results
Our research produced 21 potentially relevant articles. After the screening, three preclinical studies and four clinical trials were considered. All the papers were published after 2015. The detailed selection process of the included trials has been displayed in Figure 1.

Pre-Clinical and Non-Randomized Clinical Studies
Three pre-clinical studies were included: one in vitro study and two animal model studies. One prospective non-randomized clinical study has been included in the systematic review but not in the meta-analysis. Table 1 shows characteristics of all of the pre-clinical and non-randomized clinical studies. Three RCTs were considered eligible to be included in the meta-analysis, recruiting a total of 178 patients. One study was performed with a combination of xyloglucan, hibiscus and propolis, and two studies were performed with a combination of an equivalent mucoprotectant (reticulated gelatin), hibiscus and propolis. The Jadad score was 4 for two papers and 5 for one paper. One paper also includes an account of all patients, and for this reason, the trialists assigned the score of 5. The risk of publication bias and small-study effects has been evaluated with funnel plot analysis. The characteristics of all RCTs included in the systematic review and meta-analysis are described in Table 2.

Characteristics of Studies Included in the Meta-Analysis
In two studies, the medical device is used in the management of acute uncomplicated cystitis treatment as adjuvant therapy in association with an antimicrobial agent. In one study, the medical device is used in the management of acute uncomplicated cystitis treatment alone. In two studies, the medical device is used in association with an antimicrobial agent and used for 2 months. On the other hand, in one study, the medical device is used only for 5 days in acute setting. The follow-up period ranges from 11 days to 2 months.

Clinical Cure
We considered all three RCTs for the evaluation of a clinical cure. A statistically significant difference has been found in terms of clinical resolution between the medical device and the comparator (3 RCTs, 178 patients, OR: 0.13; 95% CI: 0.05-0.33; p < 0.0001). Figure 2 shows the clinical success (improvement/cure) in women with cystitis who were treated with the medical device compared to other antibiotic agents. Funnel plots were generated to analyze publication bias and small-study effects. The funnel plots analysis did not suggest the exclusion of any study (Figure 3).

Safety Outcomes
No significant difference has been found in terms of adverse effects (3 RCTs, 178 patients, OR: 0.14; 95% CI: 0.03-0.67; p = 0.001) (Figure 4). The most common reported adverse effects were of the gastrointestinal type (abdominal pain, diarrhea). In one study, the high prevalence of adverse effects is related to the antimicrobial agents and not to the placebo. No study withdrawal due to adverse events occurred in either of the compared treatment groups in the three trials that provided relevant data.

Main Findings
Here, we demonstrated that the medical device containing xyloglucan, hibiscus and propolis is superior to comparator regimens in terms of clinical effectiveness in adult women with microbiologically confirmed or clinical suspicion of uncomplicated cystitis and is associated with a high patient compliance.

Evidence and Implications for Clinical Practice
In recent years, the use of phytotherapy and nutraceuticals-based medications has gained popularity among non-antibiotic prophylaxis of rUTIs in urological practice [9]. Nowadays, the progressive introduction of phytotherapy and nutraceuticals drugs for the management of symptomatic UTI recurrences represents a reasonable, cost-effective alternative to obviate the massive and reckless use of antibiotics [10]. Xyloglucan, hibiscus and propolis as well as hibiscus and propolis combinations have recently emerged as alternative non-antibiotic approaches in the management of women affected by acute uncomplicated cystitis and rUTIs [5][6][7][8]. The clinical efficacy of XHP on uncomplicated cystitis both in the acute phase and for the prevention of recurrence is due to the following properties: -Mechanical barrier protection (mucoprotectant effect) on intestinal cell mucosa.
-Environmental changes in urine (mild decrease of pH) that prevent bacteria proliferation in the urinary tract.
These properties are related to the components in the medical device. Xyloglucan, extracted from the seeds of the tamarind tree (Tamarindus indica), is a 'mucosal protector' with the capability to produce a defensive barrier on human epithelial tissues. In vitro studies highlighted how xyloglucan could be efficacious for the management of UTIs by lowering the intestinal reservoirs of uropathogens colonizing the lower intestinal tract, as well as by interfering in the process by which microorganisms contact uroepithelial cell receptors [11][12][13][14].
On the other hand, Hibiscus sabdariffa and propolis have been shown to modify the urine environment, preventing bacteria proliferation and colonization of the urinary tract [15,16].
Several studies have already presented the effects of different mucoprotectant-containing products in women at increased risk for UTIs [5,8]. Herein, we undertook this systematic review and meta-analysis to evaluate the available evidence on medical devices containing a mucoprotectant, hibiscus and propolis, in the management of rUTIs. In this scenario, we selected trials that focused on the efficacy and safety profile of these medications in the prophylaxis of symptomatic recurrences and for improving UTI-related urinary symptoms. Indeed, we included in the selection process all 'in vitro' or 'in vivo' studies on rat models which evaluated the mechanism of action of mucoprotectants on intestinal epithelial cells [11][12][13]17]. Despite the limited available literature, the results of our study suggest that XHP may represent a promising, non-antibiotic approach to the management of acute UTI and rUTIs. To our knowledge, this is the first meta-analysis to focus on a novel combination of nutraceutical agents as a therapeutical option to manage UTIs. Three RCTs were considered eligible, considering a decrease in symptomatic UTI as the primary endpoint [6][7][8]. The series were comparable in terms of the number of patients considered and the secondary endpoints considered (safety profile or urinary symptoms improvement). Only one study reported the drop-out rate (24%), while only one series required either an active UTI or history of UTI at study entry, although varying criteria and validated tools to define rUTIs were used. Despite the concept of 'culture-negative' UTI having emerged, which recognizes the demonstrated effect of antibiotics to resolve UTI symptoms in women who did not demonstrate a culture growth of uropathogens or who had low colony-count infections, it is common in clinical practice to initiate treatment without or before culture results are available, creating a significant bias [18]. In all clinical series, the medical device was adequately tolerated, resulting in excellent compliance, as negligible side effects were registered [19]. Moreover, it showed remarkable results since patients reported a notable clinical improvement of urinary symptoms at 6 months ranging between 19.4-85% [5,6,8].

Study Strengths and Limitations
This meta-analysis is not free from limitations. Firstly, the small observational timeframes and the lack of validated tools for estimating urinary symptoms may represent an intrinsic bias. Furthermore, the restricted number and gender of patients enrolled should be considered a limitation. Moreover, in several series, only patients with an active UTI and unknown history were enrolled and the subsequent UTI was considered a recurrent UTI. Notwithstanding these limitations, our meta-analysis suggests that XHP may represent a potential non-pharmacologic approach for women affected by uncomplicated UTI.
Longer-term follow-up and further multicentric series would be necessary to definitively establish the long-term benefits of XHP.

Research Strategy and Literature Search
From September 2020 to April 2021, two independent reviewers (T.C., I.T.) performed the research in PubMed database, Cochrane CENTRAL and Scopus. All disagreements between the two reviewers were resolved by a supervisor (T.B.J.). All references cited in relevant articles were also reviewed and analyzed. The search strategy used was '(xyloglucan,) AND (hibiscus) AND (propolis) AND (urinary tract infection OR cystitis)'. As filters, we used: clinical trial, humans, female, English language and adult. Titles and abstracts were used to screen for initial study inclusion. Full-text review was used where abstracts were insufficient to determine if the study met inclusion or exclusion criteria. Two authors independently performed all data abstraction, including evaluation of the study characteristics, risk of bias and outcome measures, with independent verification performed by the senior author. The limited number of studies collected did not require any other authors. The study has been performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), the recommendations of the European Association of Urology Guidelines office for conducting systematic reviews and meta-analysis and previous studies [4,20,21]. All selected pre-clinical and clinical trials were used for the systematic review. On the other hand, only clinical trials have been used for the meta-analysis.

Selection Criteria for Study Inclusion in Meta-Analysis and Data Extraction
In this meta-analysis, we included all RCTs involving female patients aged >19 years with microbiologically confirmed or clinical suspicion of uncomplicated cystitis, who were randomized to receive treatment with a medical device containing xyloglucan (or an equivalent mucoprotectant substance), hibiscus and propolis or placebo or other comparator. In line with EAU guidelines, we defined uncomplicated cystitis as acute, sporadic or recurrent cystitis limited to non-pregnant, premenopausal women with no known relevant anatomical and functional abnormalities within the urinary tract or comorbidities [4]. We excluded all male patients and patients with complicated UTIs, defined as reported in the EAU guidelines [4]. We consider for this meta-analysis only studies written in English languages. Abstracts presented at scientific conferences were not considered. Data extraction, risk of bias (RoB) assessment using the Cochrane RoB Tool and quality assessment using the Grading of Recommendations, Assessment, Development and Education (GRADE) [22] approach have been performed by two reviewers (T.C., I.T.) working independently, as described in our previous study [23].

Main Outcomes Measures
The primary endpoint was clinical or microbiological success, defined as the complete (cure) and/or non-complete (improvement) resolution of symptoms at the end of treatment, or microbiological resolutions, in line with the trialists' definition. Microbiological success (eradication) was defined as the presence of a negative urine culture at the end of treatment [23]. Secondary endpoints included the presence of adverse events, which was defined as any adverse event that was reported at any time during the study period [23].

Statistical Considerations
After extraction, data were pooled to conduct a meta-analysis. Outcomes for continuous variables were expressed as mean difference (MD) with 95% confidence intervals (CI). To analyze dichotomous data, we calculated crude (unadjusted) odds ratios (OR) and log odds ratios. The inverse variance method was used for the combination of the results. Meta-analysis and forest plot diagrams were designed using a random effect model since the sample sizes of the selected studies were different. The 'trim and fill' missing study imputation approach was applied to funnel plots, and adjusted overall effect sizes were calculated according to Duval and Tweedie [24]. The software that has been used was the Review Manager (RevMan) Version 5.4 (The Cochrane Collaboration, The Nordic Cochrane Center, Copenhagen 2014). Variations among the studies were calculated using the chi-square test. In addition, I2 was evaluated to indicate the proportion of inconsistency between the selected studies that could not be attributed to chance. Separate analyses regarding all the clinical and microbiological outcomes were performed to compare fosfomycin with each of the different types of antibiotic agent. Finally, the Jadad criteria were used to assess the methodological quality of each of the included trials [25]. The risk of bias was performed by using the Newcastle-Ottawa Scale [26].

Conclusions
A medical device containing xyloglucan, hibiscus and propolis is superior to comparator regimens in terms of clinical effectiveness in adult women with microbiologically confirmed or clinical suspicion of uncomplicated cystitis and is associated with a high patient compliance. XHP, in this sense, may represent a novel starting grid to expand the armamentarium for uncomplicated UTIs.

Conflicts of Interest:
The authors declare the following conflict of interest: Tommaso Cai received a travel and speaker grant from the Noventure-Ferrer Company, but it was not related to this manuscript.