Phytotherapy in Adults With Recurrent Uncomplicated Cystitis

A systematic review

Background: Uncomplicated urinary tract infections are among the commonest bacterial infections. Because antibiotic resistance is on the rise, there is growing interest in alternative, non-antimicrobial treatment options. This systematic review presents the current evidence on phytotherapy for the treatment and prevention of recurrent uncomplicated cystitis.

Methods: A systematic search of the relevant literature from January 2011 to August 2021 was carried out in the MEDLINE, Embase, and Cochrane Library databases and in two clinical trial registries. The trials included in the present review are randomized controlled trials (RCTs) of phytotherapeutic agents as monotherapy or combination therapy, in comparison to placebo, no treatment, non-pharmacological treatment, or drug treatment without any phytotherapeutic component. Two of the authors independently selected the publications, extracted the data, and estimated the risk of bias using the Cochrane Risk of Bias Tool.

Results: 12 RCTs with a total of 1797 female patients were included. A trial of acute therapy with Chinese plant-based medicine revealed non-inferiority to antibiotic treatment. Six trials of prophylaxis with cranberry products yielded mixed results with regard to efficacy against recurrent urinary tract infections. A trial of Seidlitzia rosmarinus for the prevention of cystitis showed that its use was associated with a lower cystitis rate than placebo (at 6 months: 33 vs. 73%, p <0.001). In all trials but one, the risk of bias was unclear or high. No standardized assessment of adverse events was carried out.

Conclusion: Phytotherapeutic agents are an option for the treatment and prevention of recurrent cystitis in women. Given the heterogeneous state of the evidence on phytotherapy, no dependable recommendations can now be made for the clinical management of these patients with respect to phytotherapeutic agents.

There are an estimated 150 million urinary tract infections worldwide each year (1). Approximately 40% of all women have at least one UTI in their lifetime (2). Uncomplicated infections take a benign, self-limiting course; complicated ones are more likely to worsen or recur (3). By definition, UTIs are classified as uncomplicated when there are no relevant functional or anatomic abnormalities in the urinary tract, no relevant renal dysfunction, and no relevant pre-existing or concomitant diseases that promote UTI or serious complications (4). Uncomplicated urinary tract infections may be isolated, sporadic, or recurrent. The term “recurrent UTI” refers to two or more symptomatic episodes within six months or three or more symptomatic episodes within 12 months (4). The risk of recurrence in women is 30–50% per year for cystitis and 9% per year for pyelonephritis. Sexually active and postmenopausal women are particularly affected (5).

Because antibiotic resistance is increasing around the world, creating major challenges and costs for health care (6) and damage to the microbiome, there is growing public interest in alternative, non-antimicrobial treatment options and preventive measures (7, 8). A wide range of non-antibiotic alternatives is available (9, 10):

• behavior modification
• nutritional supplements
• nonsteroidal anti-inflammatory drugs
• probiotic agents
• D-mannose
• methenamine hippurate
• estrogens
• intravesical glycosaminoglycans
• immune stimulants
• hyaluronic acid
• acupuncture
• herbal medicines

Herbal medicines, also called phytotherapeutic agents, are already used to treat recurrent uncomplicated cystitis, but the published data are inconsistent in part (11, 12), making it difficult to derive any evidence-based recommendations for clinical practice.

In this review, we aim to pool the current evidence concerning phytotherapeutic agents in the treatment and prevention of recurrent uncomplicated cystitis in adults.

Methods

Research question and inclusion criteria

The research question was operationalized by means of a detailed a priori specification of the trial population, comparison arms, and endpoints to be considered. The inclusion and exclusion criteria are shown in Table 1. This systematic review was registered in the PROSPERO database (registration number CRD42021236008).

Table 1

Inclusion and exclusion criteria

Endpoints

The following patient-related primary endpoints were defined:

• cure or symptom relief
• adverse events
• recurrent cystitis during follow-up
• health-related quality of life

Additional endpoints included restriction of everyday activities, symptom duration, antibiotic use in the intervention group, and patient satisfaction with treatment.

Search strategy

A systematic literature search was conducted in the MEDLINE, Embase, and Cochrane Library databases for the period January 2011 to August 2021 and was supplemented by a manual search. Searches were also performed for unpublished data and ongoing trials in clinical trials registries (clinicaltrials.gov; World Health Organization International Clinical Trials Registry Platform: www.who.int/ictrp). Detailed information on the search strategy can be found in eMethods.

Literatur screening

Two of the authors (JL, UK) independently screened the titles, abstracts, and full texts of the identified publications. Discrepant judgments were discussed with a third person (SS). Reasons for exclusion of full texts were documented for each of the publications that were not included (eFigure).

eFigure

PRISMA flowchart for the different phases of this systematic review. For more information, see: www.prisma-statement.org.

Data extraction

Data from the included trials were entered into an a priori extraction table with the following categories: trial characteristics, patient characteristics, treatment groups, and endpoints. Data extraction was performed by one author (UK) and reviewed by another (JL). Discrepancies were discussed with a third author (SS). In case of incomplete data, the authors of the corresponding publication were contacted and asked to provide additional information.

Quality assessment

Two authors (JL, UK) independently assessed the risk of bias with the Cochrane risk-of-bias tool (13). Disagreements were resolved by involving a third author (SS).

Results

Trial selection

1421 references were identified by the database searches. Twelve RCTs involving a total of 1797 patients met the inclusion criteria (eFigure). No trial included men or pregnant women. Chinese herbal medicines were studied in one trial (14), cranberry products in six (15, 16, 17, 18, 19, 20), Seidlitzia rosmarinus in one (21), and combined preparations in four (22, 23, 24, 25). Phytotherapeutic agents were used to treat acute episodes of recurrent cystitis in two trials (14, 23) and to prevent recurrent uncomplicated cystitis in ten (15, 16, 17, 18, 19, 20, 21, 22, 24, 25). Patient satisfaction and restrictions in daily living were not considered as endpoints in any of the included trials. The extracted trial data are given in Tables 2 and 3. More detailed information on the included trials can be found in the electronic supplement: the relevant trials that were identified from the trial registries are listed in eTable 1.

Table 2

Evidence table for therapeutic trials

Table 3

Evidence table for prevention trials

eTable 1

Findings of the trial register search

Risk of bias

One trial was assessed as having a low risk of bias in all domains (21), while all others were found to have a high or unclear risk of bias (Table 4). In two trials, the subjects were not blinded (23, 25). In three, missing data on endpoints led to a high risk of bias. Data were missing for various reasons: a high dropout rate (15), a summarized presentation of data on patients taking different doses of medication (18), and the retrospective exclusion of trial subjects during the analysis (19). One trial was considered to be at high risk of bias because of selective endpoint reporting: symptom improvement was rated on a 5-point scale, but it was not explained how these scores were incorporated into the grouped rating of percent symptom improvement (14). Seven trials were rated at high risk of bias for other factors because UTIs and recurrent UTIs were defined only partially (16, 17, 22, 24) or not at all (19, 23), or the dosage of phytotherapeutic ingredients was not indicated (25).

Table 4

Assessment of the risk of bias (trials listed alphabetically)

Therapeutic trials

Two therapeutic trials were found that compared phytotherapeutic agents with antibiotics. Liu et al. treated 122 women suffering from an acute episode of recurrent cystitis with either Chinese herbal medicine (a mixture of nine phytotherapeutic agents and one mineral agent) combined with a sham antibiotic (n = 61) or else antibiotics (levofloxacin 200 mg twice daily, amoxicillin/clavulanic acid 500 mg three times daily, or another test-matched antibiotic) combined with sham Chinese herbal medicine (n = 61) (14). Cai et al [23] compared an herbal combined preparation (400 mg L-methionine, 100 mg Hibiscus sabdariffa, 100 mg Boswellia serrata) with short-term antibiotic therapy according to the EAU guideline (23, 26) in 93 women with an acute episode of recurrent cystitis. The non-inferiority trial by Liu et al. revealed no inferiority of Chinese herbal medicine to antibiotics (14). The trial by Cai et al. also showed comparable results in terms of clinical improvement, but there was a statistically significant association of antibiotic treatment with a better quality of life at 90 days (23) (23) (Table 2).

Prevention trials

Ten trials of preventive measures were identified (Table 3). Five of them compared cranberry products with placebo for the prevention of recurrent cystitis (16, 17, 18, 19, 20): two showed a significant lowering of the recurrence rate (16, 20), while two others showed no significant effects (18, 19). Takahashi et al. were able to show a significant lowering of the recurrence rate only in a subgroup of women aged 50 or older (cranberry: 49%, placebo: 29%; p = 0.04) (19). The report on one of these five trials contained no data on the recurrence rates in the two arms of the trial (17), and thus no conclusion can be drawn. In a Dutch trial conducted by Beerepoot et al. from 2005 to 2007, 221 healthy premenopausal women with a history of recurrent cystitis were treated with either antibiotics (480 mg trimethoprim-sulfamethoxazole [TMP-SMX] once daily) or cranberry capsules (500 mg twice daily) (15). Antibiotics were found to be significantly more effective than the cranberry product in preventing recurrent cystitis at the 12-month follow-up time point (1.8; 95% confidence interval [CI]: [0.8; 2.7] versus 4.0; [2.3; 5.6]; p = 0.02). The median number (with interquartile range) of antibiotic prescriptions in the intervention period was 0.5 (0, 1, 2) in the TMP-SMX group and 1 (0, 1, 2) in the cranberry group (15). TMP-SMX caused a serious adverse event (Stevens-Johnson syndrome) in one patient, after which the drug was discontinued (15). Three trials compared herbal combined preparations with placebo or no treatment for the prevention of recurrent cystitis in women (22, 24, 25). In a French trial conducted from 2013 to 2015, Bruyère et al. treated 42 women suffering from recurrent cystitis with a combined preparation of 400 mg propolis, 600 mg cranberry extract, and 5 mg zinc, 43 women with placebo. The recurrence rate during six months of follow-up was lower in the phytotherapy group (2.3 ± 1.8 versus 3.1 ± 1.8), but this difference was not statistically significant (p = 0.091). The groups did not differ significantly with respect to the quality of life or treatment side effects (22). In an Indian trial conducted from 2016 to 2018, a combined preparation with 18 mg of cranberry extract, 21 mg of probiotics, and 160 μg of vitamin A was compared to placebo in a cohort of 90 premenopausal women (45 women per group) (24): recurrent cystitis was significantly less common in women taking the combined drug (9% versus 33%; p = 0.005), and the combined drug also shortened the duration of acute cystitis (5 versus 12 days; p = 0.009) as well as lessening the need for antibiotics (8 versus 27%; p = 0.037) (24). Finally, in a single-center trial involving 55 premenopausal women, a combined preparation of cranberry, Lactobacillus paracasei LC11, and D-mannose was compared with no treatment. Two trial groups were defined (group 1: once daily for ten days per month for 90 days, group 2: once daily for 90 days), and episodes of recurrent cystitis up to 150 days after the start of treatment were tallied. Significantly more women in the control group developed cystitis during the trial period compared to the two treatment groups (group 1: 16%, group 2: 15.6%, control group: 52.9%; p < 0.01). There were no trial dropouts (25).

An Iranian multicenter trial conducted from 2017 to 2018 compared Seidlitzia rosmarinus with placebo for the prevention of recurrent cystitis (21). Recurrent cystitis was significantly less common in the intervention group than in the control group: 14% (8/58) versus 66% (39/59); odds ratio: 0.08; 95-% CI: [0.03; 0.20]; p < 0.001.

Adverse events

All phytotherapeutic agents had a good safety profile. In four trials, there were no adverse events in the phytotherapeutic intervention group (20, 21, 23, 25). Occasionally, serious events were reported that were considered unrelated or unlikely to be related to phytotherapeutic treatment (16, 22). Mild adverse events occurred sporadically, e.g., fever and weakness (17, 19). Gastrointestinal symptoms were most common (16, 17, 18, 19, 22, 24). For a detailed list of adverse events that occurred in the trials, see eTables 2 and 3.

eTable 2

Evidence table for therapeutic trials

eTable 3

Evidence table for prevention trials

Discussion

This systematic review of randomized controlled trials makes it clear that the available evidence on phytotherapy for the treatment and prevention of recurrent cystitis is highly heterogeneous. This review only included trials that were restricted to patients with recurrent urinary tract infections, yet the definition of recurrent cystitis among the included trials was far from uniform, varying from one or more (18) to four or more (22) cystitis episodes per year. The definition used in three of the trials (17, 19, 22, 23) was not stated at all. Moreover, the prevention trials included not only healthy women with a history of recurrent cystitis, but also women suffering from an acute episode of recurrent cystitis (17, 19). This makes it difficult to distinguish the preventive effect from the therapeutic effect.

The trials on the treatment of recurrent urinary tract infections are of limited informative value. The prevailing opinion at present is that acute UTIs should be treated in the same way regardless of whether they are recurrent or non-recurrent. Both of the treatment trials had short follow-up periods of six and three months, respectively (14, 23), and, in one of them, no definition of recurrent UTI was given (23). The data in these reports do not enable us to determine whether acute episodes of recurrent UTIs should be treated differently than non-recurrent UTIs, or whether phytotherapeutic agents are suitable in such cases. The trials concerning non-recurrent UTIs show that phytotherapeutic agents can be used for treatment instead of antibiotics (27, 28). In the prevention trials, too, the period of follow-up after therapy administered was often short: three months (15), a median of 168 days (18), or limited to the time that the patient was taking the drug (16, 17, 19, 20, 22, 24). Six of the ten prevention trials that were identified included cranberry-based single agents or combined preparations, with different mode of administration: beverages (16, 18, 19), capsules (15, 17, 20, 24), or sachets (25). The quantities of various ingredients were sometimes not stated (25) or varied widely across trials: for example, proanthocyanidin levels ranged from 1.4 mg per capsule (20) to 40 mg per drink (19). Because of this marked heterogeneity a meta-analysis for cranberry products was not possible. Most of the trials involving cranberry-based single or combination products that are included in the present review revealed a lower recurrence rate with cranberry products than with no treatment or placebo (16, 20, 24, 25). Two meta-analyses confirmed this preventive effect for women with recurrent UTIs (11, 29), although a Cochrane review published in 2012 did not find any such effect (12). The trials included in these three meta-analyses were markedly heterogeneous, and their results must therefore be interpreted with caution (11, 12, 29). One option discussed in a systematic review was to use cranberry products as an adjuvant preventive measure (29). More recent trials mainly used combined preparations of cranberries and lactobacilli (24, 25), which also lessen the recurrence rate (24, 25). The effect of lactobacilli alone on recurrent cystitis has already been reviewed in two meta-analyses, without any clear superiority to placebo or cranberry monotherapy (30, 31). The trials did not investigate whether the preventive effect is due to phytotherapeutic agents or, for example, to lactobacilli. In this review, a combined product (600 mg cranberry extract, 400 mg propolis, 5 mg zinc) without lactobacilli was considered: this was not associated with any difference in the incidence of recurrent cystitis compared to placebo, but it did prolong the mean time to the first cystitis episode to a statistically significant extent (69.9 ± 45.8 days versus 43.3 ± 45.9 days with placebo; p = 0.0258) (22).

Aside from the cranberry trials, a trial involving Seidlitzia rosmarinus was identified that had a low risk of bias; the incidence of cystitis was lower with this treatment than with placebo, even four months after the two months of treatment were over. Seidlitzia rosmarinus was previously studied in a pilot trial in men with benign prostatic hyperplasia, in which it led to a significant improvement of urologic symptoms (32).

The present review has a number of limitations. All of the included trials were restricted to women with recurrent cystitis, and their results cannot be extrapolated to men. The ten-year search period was chosen to take account of current developments, such as the use of combined drugs. Moreover, only RCTs that were published in either German or English were considered. One may assume, however, that these inclusion criteria succeeded in identifying the most relevant trials with the best available evidence on efficacy.

Overview

This systematic review shows that phytotherapeutic agents are a valid option for the prevention and treatment of recurrent cystitis in women, with few associated adverse events. The use of cranberry products as single agents or in combination was found to lower the recurrence rate in some trials. Because of the marked heterogeneity among trials, the evidence does not yet permit any conclusion about the efficacy of phytotherapeutic agents against recurrent cystitis. Further, methodologically improved trials should be conducted.

Conflict of interest statement
PD Dr. med. habil. Kranz has served as a paid consultant for, and received lecture honoraria from, Bionorica. Prof. Dr. med. Wagenlehner has served as a paid consultant for, and received lecture honoraria and reimbursement of travel expenses from, the same company, of whose advisory board he is a member.

The remaining authors state that they have no conflict of interest.

Manuscript submitted on 21 September 2021, revised version accepted on 10 January 2022.

Translated from the original German by Ethan Taub, M.D.

Corresponding author
PD Dr. med. habil. Jennifer Kranz, FEBU, MHBA
Klinik und Poliklinik für Urologie, Uniklinik RWTH Aachen
Pauwelsstr. 30, D-52074 Aachen, Germany

Cite this as:
Kranz J, Lackner J, Künzel U, Wagenlehner F, Schmidt S:
Phytotherapy in adults with recurrent uncomplicated cystitis—a systematic review. Dtsch Arztebl Int 2022; 119: 353–60. DOI: 10.3238/arztebl.m2022.0104

►Supplementary material

eMethods, eTables, eFigure:
www.aerzteblatt-international.de/m2022.0104

References

1. Harding GK, Ronald AR: The management of urinary infections: what have we learned in the past decade? Int J Antimicrob Agents 1994; 4: 83–8

2. Butler CC, Hawking MK, Quigley A, McNulty CA: Incidence, severity, help seeking, and management of uncomplicated urinary tract infection: a population-based survey. Br J Gen Pract 2015; 65: e702–7

3. Kranz J, Wagenlehner FME, Schneidewind L: [Complicated urinary tract infections]. Urologe A 2020; 59: 1480–5.

4. Interdisziplinäre S3-Leitlinie: Epidemiologie, Diagnostik, Therapie, Prävention und Management unkomplizierter, bakterieller, ambulant erworbener Harnwegsinfektionen bei erwachsenen Patienten. AWMF Register-Nr.: 043/044 2017; Langversion 1.1–2.

5. Foxman B: Urinary tract infection syndromes: occurrence, recurrence, bacteriology, risk factors, and disease burden. Infect Dis Clin North Am 2014; 28: 1–13.

6. Wagenlehner FM, Bartoletti R, Cek M, et al.: Antibiotic stewardship: a call for action by the urologic community. Eur Urol 2013; 64: 358–60.

7. Langdon A, Crook N, Dantas G: The effects of antibiotics on the microbiome throughout development and alternative approaches for therapeutic modulation. Genome Med 2016; 8: 39.

8. Ventola CL: The antibiotic resistance crisis: part 1. P T 2015; 40: 277–83.

9. Kranz J, Schmidt S, Schneidewind L: Current evidence on nonantibiotic prevention of recurrent urinary tract infections. Eur Urol Focus 2019; 5: 17–9.

10. Sihra N, Goodman A, Zakri R, Sahai A, Malde S: Nonantibiotic prevention and management of recurrent urinary tract infection. Nat Rev Urol 2018; 15: 750–76.

11. Fu Z, Liska D, Talan D, Chung M: Cranberry reduces the risk of urinary tract infection recurrence in otherwise healthy women: a systematic review and meta-analysis. J Nutr 2017; 147: 2282–8.

12. Jepson RG, Williams G, Craig JC: Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev 2012; 10: Cd001321.

13. Higgins JPT, Altman DG, Gøtzsche PC, et al.: The cochrane collaboration’s tool for assessing risk of bias in randomised trials. BMJ 2011; 343: d5928.

14. Liu SW, Guo J, Wu WK, Chen ZL, Zhang N: Treatment of uncomplicated recurrent urinary tract infection with chinese medicine formula: a randomized controlled trial. Chin J Integr Med 2019; 25: 16–22.

15. Beerepoot MA, ter Riet G, Nys S, et al.: Cranberries vs antibiotics to prevent urinary tract infections: a randomized double-blind noninferiority trial in premenopausal women. Arch Intern Med 2011; 171: 1270–8.

16. Maki KC, Kaspar KL, Khoo C, Derrig LH, Schild AL, Gupta K: Consumption of a cranberry juice beverage lowered the number of clinical urinary tract infection episodes in women with a recent history of urinary tract infection. Am J Clin Nutr 2016; 103: 1434–42.

17. Sengupta K, Alluri KV, Golakoti T, et al.: A randomized, double blind, controlled, dose dependent clinical trial to evaluate the efficacy of a proanthocyanidin standardized whole cranberry (Vaccinium macrocarpon) powder on infections of the urinary tract. Current Bioactive Compounds 2011; 7: 39–46.

18. Stapleton AE, Dziura J, Hooton TM, et al.: Recurrent urinary tract infection and urinary Escherichia coli in women ingesting cranberry juice daily: a randomized controlled trial. Mayo Clin Proc 2012; 87: 143–50.

19. Takahashi S, Hamasuna R, Yasuda M, et al.: A randomized clinical trial to evaluate the preventive effect of cranberry juice (UR65) for patients with recurrent urinary tract infection. J Infect Chemother 2013; 19: 112–7.

20. Vostalova J, Vidlar A, Simanek V, et al.: Are high proanthocyanidins key to cranberry efficacy in the prevention of recurrent urinary tract infection? Phytother Res 2015; 29: 1559–67.

21. Kamalifard M, Abbasalizadeh S, Mirghafourvand M, et al.: The effect of Seidlitzia rosmarinus (eshnan) on the prevention of recurrent cystitis in women of reproductive age: a randomized, controlled, clinical trial. Phytother Res 2020; 34: 418–27.

22. Bruyère F, Azzouzi AR, Lavigne JP, et al.: A multicenter, randomized, placebo-controlled study evaluating the efficacy of a combination of propolis and cranberry (Vaccinium macrocarpon) (DUAB®) in preventing low urinary tract infection recurrence in women complaining of recurrent cystitis. Urol Int 2019; 103: 41–8.

23. Cai T, Cocci A, Tiscione D, et al.: L-methionine associated with hibiscus sabdariffa and boswellia serrata extracts are not inferior to antibiotic treatment for symptoms relief in patients affected by recurrent uncomplicated urinary tract infections: focus on antibiotic-sparing approach. Arch Ital Urol Androl 2018; 90: 97–100.

24. Koradia P, Kapadia S, Trivedi Y, Chanchu G, Harper A: Probiotic and cranberry supplementation for preventing recurrent uncomplicated urinary tract infections in premenopausal women: a controlled pilot study. Expert Rev Anti Infect Ther 2019; 17: 733–40.

25. Murina F, Vicariotto F, Lubrano C: Efficacy of an orally administered combination of lactobacillus paracasei LC11, cranberry and D-mannose for the prevention of uncomplicated, recurrent urinary tract infections in women. Urologia 2021; 88: 64–8.

26. European Association of Urology Guidelines on Urological Infections: www.uroweb.org/guideline/urological-infections (last accessed on 21 September 2021).

27. Rechberger E, Rechberger T, Wawrysiuk S, et al.: A randomized clinical trial to evaluate the effect of canephron N in comparison to ciprofloxacin in the prevention of postoperative lower urinary tract infections after midurethral sling surgery. J Clin Med 2020; 9: 3391.

28. Wagenlehner FM, Abramov-Sommariva D, Höller M, Steindl H, Naber KG: Non-antibiotic herbal therapy (BNO 1045) versus antibiotic therapy (fosfomycin trometamol) for the treatment of acute lower uncomplicated urinary tract infections in women: a double-blind, parallel-group, randomized, multicentre, non-inferiority phase III trial. Urol Int 2018; 101: 327–36.

29. Xia JY, Yang C, Xu DF, Xia H, Yang LG, Sun GJ: Consumption of cranberry as adjuvant therapy for urinary tract infections in susceptible populations: a systematic review and meta-analysis with trial sequential analysis. PLoS One 2021; 16: e0256992.

30. Beerepoot MA, Geerlings SE, van Haarst EP, van Charante NM, ter Riet G: Nonantibiotic prophylaxis for recurrent urinary tract infections: a systematic review and meta-analysis of randomized controlled trials. J Urol 2013; 190: 1981–9.

31. Grin PM, Kowalewska PM, Alhazzan W, Fox-Robichaud AE: Lactobacillus for preventing recurrent urinary tract infections in women: meta-analysis. Can J Urol 2013; 20: 6607–14.

32. Heidari M, Hosseinabadi R, Anbari K, Pournia Y, Tarverdian A: Seidlitzia rosmarinus for lower urinary tract symptoms associated with benign prostatic hyperplasia: a pilot randomized controlled clinical trial. Complement Ther Med 2014; 22: 607–13.