Women with recurrent urinary tract infections: antibiotic resistance and non-antibiotic prophylaxis Beerepoot, M.A.J.

Transcription

1 UvA-DARE (Digital Academic Repository) Women with recurrent urinary tract infections: antibiotic resistance and non-antibiotic prophylaxis Beerepoot, M.A.J. Link to publication Citation for published version (APA): Beerepoot, M. A. J. (2013). Women with recurrent urinary tract infections: antibiotic resistance and non-antibiotic prophylaxis General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 17 Nov 2018

2 Chapter 2 Non-antibiotic prophylaxis for recurrent urinary tract infections: a systematic review and metaanalysis of randomized controlled trials M.A.J. Beerepoot¹, S.E. Geerlings¹, E.P van Haarst³, N. Mensing van Charante ², G. ter Riet 4 ¹ Department of Internal Medicine, Division of Infectious Diseases, Academic Medical Center, Amsterdam, The Netherlands. ² Department of Gynecology, Academic Medical Center, Amsterdam, The Netherlands. ³ Department of Urology, Sint Lucas Andreas Hospital, Amsterdam, The Netherlands. 4 Department of General Practice, Academic Medical Center, Amsterdam, The Netherlands. Submitted for publication

3 Chapter 2 Abstract Purpose Increasing antimicrobial resistance has stimulated interest in non-antibiotic prophylaxis of recurrent urinary tract infections (rutis). We assessed effectiveness, tolerability and safety of non-antibiotic prophylaxis in adults with rutis. Materials and Methods MEDLINE, EMBASE, the Cochrane Library and reference lists of relevant reviews were searched to September 2011 for relevant English language citations. Two reviewers selected randomized controlled trials that met the predefined criteria for population, interventions and outcomes. The difference in the proportions of patients with at least one UTI was calculated for individual studies and pooled risk ratios were calculated using random and fixed effects models. Adverse event rates were also extracted. The Jadad-score was used to assess risk of bias (0-2 high risk ; 3-5 low risk ). Results We identified 4,834 records and included 17 studies with data for 2,165 patients. The oral immunostimulant OM-89 reduced UTI recurrence (4 trials; n= 891; median Jadad-score 3; RR=0.61, 95%CI ) and had a good safety profile. The vaginal vaccine Urovac slightly reduced UTI recurrence (3 trials; n=220; Jadadscore 3; RR 0.81, 95%CI ), and primary immunization followed by booster immunization increased time to re-infection. Vaginal estrogens decreased UTI recurrence (2 trials; n=201; Jadad-score 2.5; RR=0.42, 95%CI ), but vaginal irritation occurred in 6 to 20% of women. Cranberries decreased UTI recurrence (2 trials; n=250, Jadad-score 4; RR 0.53, 95%CI ). Acupuncture reduced recurrences (2 open-label trials; n=165; Jadad-score 2; RR 0.48, 95%CI ). Oral estrogens and lactobacilli prophylaxis did not decrease UTI recurrence. Conclusions The evidence for the effectiveness of the oral immunostimulant, OM-89, is promising. Pooled findings for the other interventions, although sometimes statistically significant, should be considered tentative until corroborated by more research. Large head-to-head trials should be performed to optimally inform clinical decision-making. 18

4 Review and meta-analysis non-antibiotic UTI prophylaxis Introduction Urinary tract infections (UTI) are common and are among the most frequent medical conditions requiring outpatient treatment. Approximately 80% of all UTIs occur in women. 5 Approximately 20-30% of the women with a UTI will have a recurrence. The recurrence rate varies widely from patient to patient. 6 In individuals with recurrent UTIs, i.e. three or more UTIs per year, low dose antibiotic prophylaxis for several months can be recommended. 7 However, antibiotics are the main driving force in the development of antibiotic resistance and can lead to resistance of not only the causative microorganisms, but also of the commensal flora. 8 The increasing prevalence of Escherichia coli isolates (the most prevalent uropathogen) that are resistant to antimicrobial agents has stimulated interest in non-antibiotic methods for the prevention of UTIs. Health care providers who are interested in the therapeutic potential of non-antibiotic prophylaxis require evidence of effectiveness from randomized controlled trials. This article reviews evidence from randomized controlled trials (RCTs) on the effectiveness, tolerability and safety of non-antibiotic prophylaxis in adults with recurrent UTIs (rutis). Materials and Methods Search strategy and inclusion criteria On the electronic databases Pubmed/MEDLINE, EMBASE and the Cochrane Library were searched for relevant trials using the terms prevention and control OR prophylaxis AND urinary tract infections OR cystitis OR pyelonephritis OR uti. In addition, reference lists of relevant (Cochrane) reviews 9-13 were screened for relevant trials. Only English language articles published after 1984 were included. Our search strategy and analysis complied with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. 14 All RCTs in adults with rutis, mostly community-dwelling women, comparing non-antibiotic prophylaxis to placebo or no treatment were included. RUTIs were defined as at least 3 UTIs in the year preceding the start of the trial or rutis by the author s definition. In trials where patients with at least 1 UTI were included, baseline results had to show a mean of at least 3 UTIs per year in all trial arms. Since carryover effects due to post-prophylaxis benefits of non-antibiotic alternatives cannot be ruled out, we excluded crossover trials. In addition, trials evaluating curative treatment, perioperative antibiotic prophylaxis, prevention of nosocomial infections, the effect of lifestyle interventions or the use of devices (e.g. urinary catheter policies, intravesical installations) were excluded. The primary outcome of interest was the proportion of patients with at least one symptomatic UTI. In addition, we assessed the mean number of symptomatic UTIs during followup. In most trials examined, the authors reported the mean number of UTIs, the proportions without or with at least one UTI or described the actual number of 19

5 Chapter 2 IDENTIFICATION SCREENING ELIGIBILTY INCLUDED 4834 records identified by database searching 1982 records after duplicates removed 1982 records screened 119 full-text articles assessed for eligibility 17 studies included in qualitative synthesis 16 studies included in a quantitative synthesis (meta-analysis) 49 of additional records identified through other sources 1863 records excluded after review of titles and/or 102 full-text articles excluded, reason: - double publication (n=2) 1;2 - no RCT (n=33) - other patient population, e.g. no rutis or children (n=24) - other intervention (e.g. curative) or active control (n=18) - other outcome (n=6) - non-english and/or published before 1984 (n=17) - insufficient data (n=2) 3;4 Figure 1. PRISMA Flow diagram of stages in the systematic review of non-antibiotic prophylaxis for recurrent urinary tract infections. RCT=randomized controlled trial, rutis= recurrent urinary tract infections. 1 Because of the similarity of data, design and outcomes, it was concluded that two studies were duplicate publications. 20

6 Review and meta-analysis non-antibiotic UTI prophylaxis UTIs experienced by the participants, which then could be transformed into the corresponding means and proportions. If data on our primary outcomes were not reported or could not be calculated, we contacted the authors. Our secondary outcome was adverse events. To assess tolerability we extracted adverse events (AE) and adverse reactions (AR) observed. To assess safety we describe serious adverse events (SAE) and, suspected unexpected serious adverse reactions (SUSAR) reported. Definitions of the different types of adverse events can be found elsewhere. 15 Data extraction All selected articles were checked independently against the inclusion criteria and study design by two reviewers (MB and NM, or MB and EH). In case of discordance a third reviewer was consulted (SG). Data extraction from eligible studies was performed independently by MB and NM, or MB and EH. A third reviewer was consulted to review discrepancies in data extraction (SG or GR). Assessment of methodological quality The internal validity of included trials was assessed by the same reviewers using the Jadad score. 16 The Jadad scale assigns scores from 0 to 5 (best quality trial) based on the following items: 1) the study is randomized; 2) the intervention is double blind; 3) study withdrawals are accounted for and described; 4) the randomization procedure is adequately performed using an appropriate method such as computer generated random numbers; and 5) blinding is also adequately performed using identical-looking placebo.² Concealment of treatment allocation was also evaluated for adequacy. If the descriptions of the procedures were such that investigators were likely to be unaware of each participant s allocation at the time of allocation, concealment was considered adequate. Statistical analysis For comparison of the proportion of patients with at least one symptomatic UTI and the mean number of symptomatic UTIs between non-antibiotic prophylaxis and control we used the risk ratio and the mean difference, respectively. We performed random and fixed effects meta-analyses on the risk ratios of at least one UTI with non-antibiotic prophylaxis compared to the control group using Dersimonian-Laird and Mantel-Haenszel weights, respectively using Stata software (version 10.1). Heterogeneity was assessed using the I-squared (I 2 ) statistic. 17 Publication bias could not be investigated due to small numbers of trials. Results Description of studies The PRISMA flow diagram summarizes the number of records screened and included (Figure 1). Characteristics and methodologic quality of included studies 21

7 Chapter 2 1st author Year of publication Index n/n Control n/n Jadad score RR (95% CI) OM89 Tammen Schulman Magasi Bauer /61 29/82 19/58 93/231 49/59 54/78 42/54 122/ D+L Subtotal (I-squared = 69.3%, p = 0.021) M-H Subtotal. Urovac Uehling Uehling Hopkins /61 22/36 32/50 22/30 14/18 21/ D+L Subtotal (I-squared = 0.0%, p = 0.787) M-H Subtotal. Oral oestriol Kirkengen Cardozo /20 24/36 9/20 20/ D+L Subtotal (I-squared = 2.6%, p = 0.311) M-H Subtotal. Vaginal oestriol Raz Eriksen /50 27/53 27/43 44/ D+L Subtotal (I-squared = 85.3%, p = 0.009) M-H Subtotal. Lactobacilli Baerheim Kontiokari /25 21/49 11/22 19/ D+L Subtotal (I-squared = 0.0%, p = 0.985) M-H Subtotal. Cranberries Kontiokari Stothers /50 19/100 18/50 16/ D+L Subtotal (I-squared = 0.0%, p = 0.540) M-H Subtotal. Acupuncture Aune Alraek /27 18/67 11/26 13/ D+L Subtotal (I-squared = 0.0%, p = 0.418) M-H Subtotal (0.60, 0.94) 0.51 (0.37, 0.71) 0.42 (0.28, 0.63) 0.73 (0.60, 0.89) 0.61 (0.48, 0.78) 0.64 (0.56, 0.73) 0.87 (0.65, 1.16) 0.79 (0.55, 1.13) 0.76 (0.58, 1.00) 0.81 (0.68, 0.96) 0.81 (0.68, 0.96) 0.78 (0.36, 1.68) 1.20 (0.83, 1.74) 1.10 (0.78, 1.56) 1.07 (0.76, 1.50) 0.25 (0.13, 0.50) 0.64 (0.47, 0.86) 0.42 (0.16, 1.10) 0.48 (0.36, 0.64) 1.12 (0.65, 1.93) 1.13 (0.70, 1.82) 1.12 (0.78, 1.61) 1.12 (0.78, 1.62) 0.44 (0.21, 0.93) 0.59 (0.34, 1.05) 0.53 (0.34, 0.84) 0.53 (0.33, 0.83) 0.35 (0.13, 0.96) 0.56 (0.32, 0.97) 0.50 (0.31, 0.81) 0.48 (0.29, 0.79) favours non-antibiotic prophylaxis favours placebo or no treatment Figure 2. Forest plot showing risk ratios and 95% confidence intervals of the probability to experience at least one UTI for 17 trials on non-antibiotic prophylaxis of rutis, and pooled estimates using random and fixed effects methods. Abbreviations: M-H = Mantel- Haenszel (fixed-effects method); D+L = DerSimonian and Laird (random-effects method). I-squared quantifies inconsistency (percentage of variability in effect estimates that is due to heterogeneity rather than chance). 1 because of the difference in intervention and effect size, we decided to report summary measures for the comparison of acupuncture (not sham acupuncture) and control only. 22

8 Review and meta-analysis non-antibiotic UTI prophylaxis are presented in Table 1. We included 17 studies with data for 2165 patients, most were between 20 and 50 years of age. The sample size varied between 44 and 453 and follow-up between 20 weeks and 12 months. In most studies only women were included. In the studies by Tammen 18, Schulman et al. 19 and Magasi et al. 20 about 10-20% of participants were men. Unfortunately, the analyses were not stratified by sex. A UTI was mostly defined as symptoms suggestive of a UTI and bacteriuria. The cut-off point for a microbiologically confirmed UTI varied from 10 3 cfu/ml to 10 5 cfu/ml. The median (interquartile range) quality score was 3 (2.5-4) and seven trials (41%) were judged as having adequate allocation concealment. Effectiveness, tolerability and safety of non-antibiotic UTI prophylaxis Immunoactive prophylaxis Various bacterial extracts have been used in the management of rutis. To be effective a bacterial extract must be able to stimulate the host s immune system to produce antibodies and cytokines. 12 OM-89 The oral immunostimulant OM-89 (Uro-Vaxom ), an extract of five different serotypes of heat-killed uropathogenic E. coli, stimulates the immune system by the activation of monocyte-derived dendritic cells, resulting in an increase in TNF-alpha and interleukin-6 production. The activation of immune cells is likely to be mediated via Toll like receptors. 21 We included 4 studies with a total of 891 participants ;22 Participants took oral OM-89 or a placebo capsule daily. In the meta-analysis, the risk ratio for developing at least one UTI was significantly lower in the OM-89 group (RR 0.61, 95% confidence interval (CI) ; see Figure 2). The mean number of UTIs was about half compared to placebo (Table 2). Bauer et al. 22 reported 161 AEs in 75 women in the OM-89 group compared to 192 AEs in 71 women in the placebo group. In both groups 13% of AEs were considered to be related to the study medication. Headache and gastro-intestinal complaints were the most frequent AEs, with 17% and 15% in both groups, respectively. The SAEs reported (mostly hospitalizations), 11 in the OM-89 and 4 in the placebo group, were deemed unrelated to the study medication. In the study by Schulman et al out of 82 patients (2.4%) from the OM-89, compared to 5 out of 78 patients (6.4%) from the placebo group experienced AEs. The AEs reported by Tammen 18 were an allergic reaction, diarrhea and headache in the OM-89 group and nausea and erythema in the placebo group. Magasi et al. 20 reported no AEs. Vaginal vaccine Urovac is a vaginal vaccine, which contains 10 heat-killed uropathogenic bacteria, including six different serotypes of uropathogenic E. coli, and one strain each of Proteus vulgaris, Klebsiella pneumoniae, Morganella morganii and Enterococcus 23

9 Chapter 2 faecalis. This vaccine induces primarily immunoglobulin G and immunoglobulin A in the urogenital tract, thereby reducing potential colonization of the vagina and bladder with uropathogens. 23 The exact mechanisms of protection and immunological basis are still unclear. In one trial 24 with 91 women primary immunization was compared to placebo. Primary immunization consisted of 3 vaginal vaccine suppositories at weekly intervals (with 1 (low dose) or 2 (high dose) ampules of 2 x10 9 heat-killed organisms per suppository). In this study no significant differences were found in the proportion of women with at least one UTI and the mean number of UTIs during the 20 weeks of follow-up (Table 2). In two smaller studies 23;25 the addition of booster vaccinations was evaluated. Booster immunization consisted of 3 additional vaccine suppositories (with 1 x or 2 x10 9 killed organisms 25 ) at monthly intervals. The time until first reinfection, the proportion of women experiencing a UTI, and the mean number of UTIs during the follow-up were all in favor of the booster immunization group, compared to those receiving placebo or primary immunization only (Table 2). In the meta-analysis of the three studies, Urovac appeared to slightly reduce UTI recurrence rates (RR 0.81, 95%CI , Figure 2). In all studies using the vaginal vaccine some women experienced vaginal irritation shortly after suppository insertions. In the two studies by Uehling et al. 24;25 3 out of 61 (4.9%) and 5 out of 18 (27.8%) women experienced this AR. Hopkins et al. 23 reported this AR in 6 out of 50 patients (12%) who received the vaginal vaccines, but this proportion was the same in the placebo group (3 out of 25 patients). Estrogen prophylaxis The main factors associated with ruti in postmenopausal women are vesical prolapse, cystocele, post-voidal residual volume and urinary incontinence. All these abnormalities are associated with a decrease in estrogen. Given this evidence estrogens have been proposed as a strategy for the prevention of UTI in postmenopausal women. 13 In addition, in a placebo-controlled trial the use of vaginal estrogens was associated with a significant increase in vaginal colonization with lactobacilli, which may protect the vagina against the colonization with potential uropathogens. 26 Oral estrogens In the study by Kirkengen et al. 27 the women were treated with 3 mg estriol orally per day or corresponding placebo for four weeks, followed by 1 mg per day for 8 weeks. The intervention in the study by Cardozo et al. 28 consisted of oral estriol, 3 mg per day, or placebo for six months. In the individual studies, nor in the meta-analysis, did oral estrogens reduce the proportion of women experiencing a UTI (Table 2, Figure 2). In the study by Kirkengen et al. 1 patient died due to a myocardial infarction. Kirkengen did not report ARs. 27 Cardozo et al. reported breast tenderness in 7 out of 36 patients (19.4%) and mild vaginal bleeding in 3 patients (8.3%) 24

10 Review and meta-analysis non-antibiotic UTI prophylaxis receiving oral estrogens. 28 In the placebo arm each AR occured once. SAEs were hospital admission, bleeding, stroke and depression in the estrogen group and femur fracture, sepsis, stroke and left arm paresis in the placebo group. 28 In both studies the likelihood of a causal relation between each of these events and the study medication was not reported. However, nowadays oral estrogens are not longer recommended in older postmenopausal women and to those at high risk of coronary heart disease (CHD) because in these groups the long-term use of oral estrogens has been found to be associated with a higher risk of venous thromboembolism, breast cancer, stroke and CHD. 29;30 Vaginal estrogens In a trial performed by Raz and Stamm 26 women were randomly assigned to 0.5 mg of estriol in vaginal cream, to be used each night for 2 weeks, followed by twice-weekly use for 8 months. In a study by Eriksen 31 women received an estradiol-releasing vaginal ring with 2 mg of estradiol (Estring) or no treatment. Both studies showed that vaginal estrogens significantly reduced the proportion of women with a UTI (Table 2). However, there was significant heterogeneity and random effects meta-analysis yielded an insignificant pooled effect. (RR 0.42, 95%CI , Figure 2). Vaginal estrogen prophylaxis mainly caused vaginal irritation or local discomfort. In the study by Raz and Stamm out of 50 (20%) patients in the estriol group and 4 out of 43 (9%) patients in the placebo group withdrew due to vaginal irritation. One patient in the estriol group died due to a myocardial infarction. In the study by Eriksen 31 there were 3 SAEs in the estradiol group, compared to 1 SAE in the placebo group. For all SAEs a causal relationship with the study medication was deemed unlikely. Lactobacilli prophylaxis Specific lactobacilli strains can interfere with the adherence, growth and colonization of the urogenital human epithelium by uropathogenic bacteria. This interaction is believed to be important in the maintenance of a normal urogenital flora and in the prevention of infection in women. 9 Vaginal application of L. casei v rhamnosus In the study by Baerheim et al women were randomized to vaginal suppositories containing L. casei v rhamnosus, twice weekly for 26 weeks, or placebo. The authors did not show an advantage in terms of UTI prevention compared to placebo (Table 2). The most commonly reported AR was vaginal discharge after taking the suppositories. This occurred in 4 out of 25 women (16%) from the lactobacilli group, compared to 1 out of 22 women (4.5%) in the placebo group. Lactobacillus GG drink The study from Kontiokari et al. 33 was an open randomized trial in 150 women who had a UTI caused by E. coli. After being treated with antibacterials for the 25

11 Chapter 2 UTI episode, they were randomly allocated to one of three groups. The first group received cranberry lingonberry juice 50mL per day for 6 months, the second group took 100 ml Lactobacillus GG (4 x10 10 cfu) drink 5 days per week for 1 year, and a third group received no further treatment. In the lactobacillus group 21 out of 49 women (42.9%) had had a UTI at 12 months, which was similar to the 19 out of 50 women (38.0%) in the group without treatment (Table 2). There were no ARs. Cranberry prophylaxis Cranberries have been used in the prevention of UTIs for many years. The mechanism of action has not been completely elucidated, but cranberries contain type A proanthocyanidins (PACs), which in urine can inhibit the adherence of P fimbriae of E. coli to the uroepithelial cell receptors. 34 We identified two studies that compared cranberry products to placebo or no treatment in women with at least 3 UTIs in the year before inclusion. In our metaanalysis cranberry products reduced UTI recurrences (RR 0.53, 95%CI , Figure 2). In the study by Kontiokari et al. 33, mentioned above, for the women in the cranberry lingonberry juice group the intervention was stopped prematurely after 6 months because the manufacturer stopped producing the juice. After 6 months 8 out of 50 women (16%) in the cranberry group and 18 out of 50 women (36%) in the control group had had at least one UTI (RR 0.44, 95%CI , Table 2). There were only occasional complaints about the bitter taste of the cranberry juice. Stothers 35 compared cranberry juice as well as cranberry tablets to placebo. The study was double dummy double blind. Tablets were taken twice and 250 ml of juice three times daily. Both cranberry juice and cranberry tablets significantly decreased the proportion of women experiencing at least one symptomatic UTI during the 12-months of follow-up (Table 2). In the cranberry juice group 3 out of 50 women (6%) receiving cranberry juice reported gastro esophageal reflux, 2 of whom dropped out due to this problem. Ten out of 50 women (20%) in the cranberry tablet group complained about the size of the tablets, but this did not lead to their withdrawal. In addition, 4 out of 50 women (8%) in the cranberry tablet group and 2 out of 50 women (4%) in the placebo group experienced mild nausea. Miscellaneous Angocin Albrecht et al. 36 conducted a double-blind placebo controlled trial to verify the effectiveness and safety of Angocin Anti-Infekt N, which is a herbal medicinal product (film-coated tablets) containing two active ingredients: horseradish root (Armoraciae rusticanae radix) 80 mg and nasturtium (Tropaeoli majoris herba) 200 mg. For these two active ingredients antimicrobial effectiveness has been proven in vitro, which is based on the isothiocyanates (mustard oils). Patients 26

12 Review and meta-analysis non-antibiotic UTI prophylaxis were randomized to receive either the study drug or placebo twice daily for 90 days. The authors concluded that, based on a per-protocol analysis in 103 patients, the product Angocin was effective in the prevention of rutis. They found that the mean number of UTIs during the follow-up of 180 days was 0.43 in the Angocin compared to 0.77 in the placebo group (p=0.035, one-sided). The statistical significance disappeared when a two-sided p-value was calculated. However, in the intention-to-treat analysis on 174 patients, the mean numbers of UTIs were 0.65 and 0.64 respectively (p=0.476, one-sided). Thirty-six of 84 patients in the Angocin group (43%) and 37 of 90 patients (41%) in the placebo group reported an AE. SAEs were reported in 1 and 2 patients, respectively. The SAEs were not related to the study medication. Acupuncture Acupuncture has traditionally been used in the treatment and prevention of many clinical conditions. We identified 2 open trials 37;38, by the same group of investigators, on the use of acupuncture in the prevention of rutis in women. In the real acupuncture group needles were inserted to the correct depth at known acupuncture points, the qi sensation was obtained, and needles were manipulated by hand. In the sham acupuncture group needles were inserted superficially, outside known acupuncture points and without manipulation. All treatments were administered twice weekly for 4 weeks. Acupuncture, significantly reduced the proportion of women experiencing a UTI (RR 0.48, 95%CI , see figure 2 and Table 2). In the study by Aune et al. 38 the most common ARs, reported in the acupuncture and the sham acupuncture group, were gastroenteral discomfort and a warm feeling in the legs. Alraek et al. 37 did not report adverse events, but in another paper about the same study loose stools, anxiety, depression, cold hands and feet were reported. 1 Discussion Among the different forms of non-antibiotic prophylaxis described in this systematic review the oral immunostimulant OM-89 appears to be the most promising to prevent rutis. Four trials with 891 participants showed effectiveness in reducing UTIs (RR 0.61, 95%CI ) and a good safety profile. In postmenopausal women there was a trend towards fewer UTI recurrences with vaginal estrogens, which was not seen with oral estrogens. Vaginal estrogens are already used for many years worldwide. However, vaginal irritation occurred frequently and affected adherence. Although there was a significant decrease in UTI recurrence with the vaginal vaccine Urovac, cranberries and acupuncture, the pooled finding for these nonantibiotic forms of prophylaxis are based on a small number of studies and are not necessarily robust. Therefore, confirmation by larger studies by independent investigators seems necessary. 27

13 Chapter 2 Vaginal application of L. casei v rhamnosus and L. rhamnosus GG drink did not appear to be effective. Various in vitro and animal studies led to the conclusion that L. rhamnosus GR-1 and L. reuteri RC-14 possess optimal properties to prevent UTIs. 39 However, identified trials using L. rhamnosus GR-1 and L. reuteri RC-14 could not be included in this review because they did not meet the predefined inclusion criteria. One trial compared vaginal suppositories with lactobacilli to vaginal suppositories with Lactobacillus growth factor 40, another compared the lactobacilli with trimethoprim-sulfamethoxazole. 8 One trial evaluated the effectiveness of probiotic vaginal suppositories after antimicrobial therapy for an acute UTI. 41 Another strain, L. crispatus given as intravaginal suppositories, reduced recurrences after antimicrobial treatment of a symptomatic UTI in premenopausal women. 42 Both cranberry juice and tablets reduced the occurrence of UTIs compared to placebo. However, cranberry tablets were tolerated better. The greatest challenge in the field of cranberry research is to determine the optimum dose of proanthocyanidins (PAC) to prevent UTIs in vivo. In 2010 Howell et al. concluded, based on an ex-vivo study in urine samples of volunteers who consumed cranberry powder, that 72 mg of PAC per day might offer some protection against bacterial adhesion and virulence in the urinary tract. 34 In earlier studies often the chemical composition of available cranberry products was not standardized, neither was the description of the dose. In addition, the bioequivalence between the juice and capsules or tablets is not clear. These factors make it difficult to compare studies and draw conclusions. 10;43 A recent Cochrane Review 10 concluded that cranberry products did not significantly reduce the occurrence of symptomatic UTI in women with recurrent UTI. This conclusion was based on a meta-analysis of 4 studies. Two of these were also included in this meta-analysis, two others were not. In one study 44 the premenopausal women included did not have recurrent UTIs but started drinking cranberry juice after an acute UTI. The women did not experience a decrease in the 6-month incidence of a second UTI, compared with those drinking placebo juice. In the other trial 45 cranberry capsules were given to women with a history of recurrent UTI, who were currently culture positive with mild symptoms of UTI, with the goal to ameliorate symptoms and to reduce the uropathogen load in urine samples. Since the meta-analysis from the Cochrane did include studies in women without recurrent UTIs, it is incorrect to conclude that cranberry products did not reduce the occurrence of symptomatic UTI in women with recurrent UTI. Two studies 37;38, by the same group of investigators, suggest that acupuncture might prevent rutis. However, these results should be interpreted cautiously due to low quality scores (median JADAD score of 2) and small numbers. In addition, the mechanism of action remains unclear. 28

14 Review and meta-analysis non-antibiotic UTI prophylaxis Implications for further research Before recommending the widespread use of a vaginal vaccine, cranberry products or acupuncture, we think that more evidence is needed. Since UTIs can be relapsing infections and therefore often occur in clusters, intervention and follow-up periods (also after stopping the prevention method) in future trials may need to cover much longer time periods to take into account the natural course of the disease. Since, women are far more likely to have UTIs than men and pathogenesis differs by sex, we recommend to include only women to improve generalisability of findings to the circumstances most often seen in daily practice. In this review, in three trials with the oral immunostimulant OM out of 438 included patients were men (13.7%). Unfortunately, findings were not stratified by sex. For most forms of non-antibiotic prophylaxis the optimum dose to prevent UTI is unknown. We are waiting for the results of the dose finding study 43 with cranberry products that is currently underway to determine the optimal dose for future cranberry product trials. To optimally inform clinical decision-making large head-to-head trials should be performed comparing the different forms of non-antibiotic prophylaxis with each other and with antibiotic prophylaxis, which is standard of care. Up to now, only few studies have been undertaken that compared non-antibiotic prophylaxis with antibiotic prophylaxis to prevent UTIs in adults with rutis. 8;46-49 The results of a study comparing OM-89 with antibiotic prophylaxis in adults with rutis are expected in the near future. 50 Recent studies have shown that using cranberries or lactobacilli instead of antibiotic prophylaxis considerably reduces the development of antibacterial resistant micro-organisms. 8;46 In addition, for future trials it would be desirable to evaluate quality of life, patient s preferences and cost-effectiveness with each alternative. These are aspects that are important to take into account to assess which alternatives are worthwhile and likely to be adopted into practice. To easily compare alternatives and to draw conclusions, future trials should use uniform outcomes and definitions. In the trials included in this systematic review, the cut-off point for a microbiologically confirmed UTI varied from 10 3 cfu/ml to 10 5 cfu/ml. However, it is documented that as few as 10 2 cfu/ml can cause symptoms of a UTI. 31 In this systematic review we focused on non-antibiotic prophylaxis of UTIs in adults, mainly community-dwelling women, with rutis. It is known from clinical practice that these adults are at high risk of recurrences and they are increasingly asking health care professionals about the value of taking nonantibiotic products. 29

15 Chapter 2 In conclusion, the use of the oral immunostimulant OM-89 is promising. Vaginal estriol can be used to prevent rutis in postmenopausal women. Larger and better studies about the effectiveness of the vaginal vaccine Urovac, (the optimal dose of) cranberry products and acupuncture are warranted. 30

16 Review and meta-analysis non-antibiotic UTI prophylaxis References (1) Alraek T, Baerheim A. The effect of prophylactic acupuncture treatment in women with recurrent cystitis: kidney patients fare better. J Altern Complement Med 2003;9: (2) Uehling DT, Hopkins WJ, Beierle LM, Kryger JV, Heisey DM. Vaginal mucosal immunization for recurrent urinary tract infection: extended phase II clinical trial. J Infect Dis 2001;183 Suppl 1:S81-S83. (3) Frey C, Obolensky W, Wyss H. Treatment of recurrent urinary tract infections: efficacy of an orally administered biological response modifier. Urol Int 1986;41: (4) Larsson B, Jonasson A, Fianu S. Prophylactic effect of UVA-E in women with recurrent cystitis: A preliminary report. Curr Ther Res Clin Exp 1993;53: (5) Griebling TL. Urologic diseases in america project: trends in resource use for urinary tract infections in men. J UROL 2005;173: (6) Stamm WE, McKevitt M, Roberts PL, White NJ. Natural history of recurrent urinary tract infections in women. Rev Infect Dis 1991;13: (7) Albert X, Huertas I, Pereiro II, Sanfelix J, Gosalbes V, Perrota C. Antibiotics for preventing recurrent urinary tract infection in non-pregnant women. Cochrane Database Syst Rev 2004;CD (8) Beerepoot MA, Ter Riet G, Nys S et al. Lactobacilli vs antibiotics to prevent urinary tract infections: a randomized double-blind noninferiority trial in postmenopausal women. Arch Intern Med 2012;172: (9) Falagas ME, Betsi GI, Tokas T, Athanasiou S. Probiotics for prevention of recurrent urinary tract infections in women : a review of the evidence from microbiological and clinical studies. Drugs 2006;66: (10) Jepson RG, Williams G, Craig JC. Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev 2012;10:CD (11) Lee BB, Simpson JM, Craig JC, Bhuta T. Methenamine hippurate for preventing urinary tract infections. Cochrane Database Syst Rev 2007;CD (12) Naber KG, Cho YH, Matsumoto T, Schaeffer AJ. Immunoactive prophylaxis of recurrent urinary tract infections: a meta-analysis. Int J Antimicrob Agents 2009;33: (13) Perrotta C, Aznar M, Mejia R, Albert X, Ng CW. Oestrogens for preventing recurrent urinary tract infection in postmenopausal women. Cochrane Database Syst Rev 2008;CD (14) Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6:e (15) Nebeker JR, Barach P, Samore MH. Clarifying adverse drug events: a clinician s guide to terminology, documentation, and reporting. Ann Intern Med 2004;140: (16) Moher D, Jadad AR, Nichol G, Penman M, Tugwell P, Walsh S. Assessing the quality of randomized controlled trials: an annotated bibliography of scales and checklists. Control Clin Trials 1995;16: (17) Higgins JP, Whitehead A, Simmonds M. Sequential methods for random-effects meta-analysis. Stat Med 2011;30: (18) Tammen H. Immunobiotherapy with Uro-Vaxom in recurrent urinary tract infection. The German Urinary Tract Infection Study Group. Br J Urol 1990;65:6-9. (19) Schulman CC, Corbusier A, Michiels H, Taenzer HJ. Oral immunotherapy of recurrent urinary tract infections: a double-blind placebo-controlled multicenter study. J UROL 1993;150:

17 Chapter 2 (20) Magasi P, Panovics J, Illes A, Nagy M. Uro-Vaxom and the management of recurrent urinary tract infection in adults: a randomized multicenter double-blind trial. Eur Urol 1994;26: (21) Bessler WG, Puce K, vor dem EU, Kirschning C, Huber M. Immunomodulating effects of OM-89, a bacterial extract from Escherichia coli, in murine and human leukocytes. Arzneimittelforschung 2009;59: (22) Bauer HW, Alloussi S, Egger G, Blumlein HM, Cozma G, Schulman CC. A longterm, multicenter, double-blind study of an Escherichia coli extract (OM-89) in female patients with recurrent urinary tract infections. Eur Urol 2005;47: (23) Hopkins WJ, Elkahwaji J, Beierle LM, Leverson GE, Uehling DT. Vaginal mucosal vaccine for recurrent urinary tract infections in women: results of a phase 2 clinical trial. J Urol 2007;177: (24) Uehling DT, Hopkins WJ, Balish E, Xing Y, Heisey DM. Vaginal mucosal immunization for recurrent urinary tract infection: phase II clinical trial. J Urol 1997;157: (25) Uehling DT, Hopkins WJ, Elkahwaji JE, Schmidt DM, Leverson GE. Phase 2 clinical trial of a vaginal mucosal vaccine for urinary tract infections. J Urol 2003;170: (26) Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med 1993;329: (27) Kirkengen AL, Andersen P, Gjersoe E, Johannessen GR, Johnsen N, Bodd E. Oestriol in the prophylactic treatment of recurrent urinary tract infections in postmenopausal women. Scand J Prim Health Care 1992;10: (28) Cardozo L, Benness C, Abbott D. Low dose oestrogen prophylaxis for recurrent urinary tract infections in elderly women. Br J Obstet Gynaecol 1998;105: (29) Anderson GL, Limacher M, Assaf AR et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women s Health Initiative randomized controlled trial. JAMA 2004;291: (30) Hulley S, Grady D, Bush T et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998;280: (31) Eriksen B. A randomized, open, parallel-group study on the preventive effect of an estradiol-releasing vaginal ring (Estring) on recurrent urinary tract infections in postmenopausal women. Am J Obstet Gynecol 1999;180: (32) Baerheim A, Larsen E, Digranes A. Vaginal application of lactobacilli in the prophylaxis of recurrent lower urinary tract infection in women. Scand J Prim Health Care 1994;12: (33) Kontiokari T, Sundqvist K, Nuutinen M, Pokka T, Koskela M, Uhari M. Randomised trial of cranberry-lingonberry juice and Lactobacillus GG drink for the prevention of urinary tract infections in women. BMJ 2001;322:1571. (34) Howell AB, Botto H, Combescure C et al. Dosage effect on uropathogenic Escherichia coli anti-adhesion activity in urine following consumption of cranberry powder standardized for proanthocyanidin content: a multicentric randomized double blind study. BMC Infect Dis 2010;10:94. (35) Stothers L. A randomized trial to evaluate effectiveness and cost effectiveness of naturopathic cranberry products as prophylaxis against urinary tract infection in women. Can J Urol 2002;9:

18 Review and meta-analysis non-antibiotic UTI prophylaxis (36) Albrecht U, Goos KH, Schneider B. A randomised, double-blind, placebo-controlled trial of a herbal medicinal product containing Tropaeoli majoris herba (Nasturtium) and Armoraciae rusticanae radix (Horseradish) for the prophylactic treatment of patients with chronically recurrent lower urinary tract infections. Curr Med Res Opin (37) Alraek T, Soedal LI, Fagerheim SU, Digranes A, Baerheim A. Acupuncture treatment in the prevention of uncomplicated recurrent lower urinary tract infections in adult women. Am J Public Health 2002;92: (38) Aune A, Alraek T, LiHua H, Baerheim A. Acupuncture in the prophylaxis of recurrent lower urinary tract infection in adult women. Scand J Prim Health Care 1998;16: (39) Reid G, Bruce AW. Selection of lactobacillus strains for urogenital probiotic applications. J Infect Dis 2001;183 Suppl 1:S77-S80. (40) Reid G, Bruce AW, Taylor M. Instillation of Lactobacillus and stimulation of indigenous organisms to prevent recurrence of urinary tract infections. Microecol Ther 1995; (41) Reid G, Bruce AW, Taylor M. Influence of three-day antimicrobial therapy and lactobacillus vaginal suppositories on recurrence of urinary tract infections. Clin Ther 1992;14: (42) Stapleton AE, Au-Yeung M, Hooton TM et al. Randomized, -Controlled Phase 2 Trial of a Lactobacillus crispatus Probiotic Given Intravaginally for Prevention of Recurrent Urinary Tract Infection. Clin Infect Dis 2011;52: (43) ClinicalTrials.Gov. Effects of Cranberry-Containing Products in Women With Recurrent Urinary Tract Infections. www clinicaltrials gov /ct2 /show /NCT , Accessed November 25, (44) Barbosa-Cesnik C, Brown MB, Buxton M, Zhang L, DeBusscher J, Foxman B. Cranberry juice fails to prevent recurrent urinary tract infection: results from a randomized placebo-controlled trial. Clin Infect Dis 2011;52: (45) Sengupta KA. 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: (46) Beerepoot MAJ, Riet ter 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: (47) McMurdo ME, Argo I, Phillips G, Daly F, Davey P. Cranberry or trimethoprim for the prevention of recurrent urinary tract infections? A randomized controlled trial in older women. J Antimicrob Chemother (48) Raz R, Colodner R, Rohana Y et al. Effectiveness of estriol-containing vaginal pessaries and nitrofurantoin macrocrystal therapy in the prevention of recurrent urinary tract infection in postmenopausal women. Clin Infect Dis 2003;36: (49) Xu R, Wu Y, Hu Y. [Prevention and treatment of recurrent urinary system infection with estrogen cream in postmenopausal women]. [Chinese]. Chung Hua Fu Chan Ko Tsa Chih [Chinese Journal of Obstetrics & Gynecology ] 2001;36: (50) EU clinical trial register. Multicentre, double-blind, placebo controlled randomised clinical study of URO-VAXOM in female patients suffering from uncomplicated recurrent urinary tract infections. trial/ /at Accessed November 25,

19 Chapter 2 Table 1. Details of studies comparing non-antibiotic prophylaxis with placebo or no treatment in recurrent UTIs. UTI= urinary tract infection. The definition of a UTI was based to the use of clinical criteria (symptoms) and/or bacteriuria (figures refer to the number of colony-forming units per milliliter). A: Immunoactive prophylaxis Reference Year of publication Jadad score Allocation concealment Study size Tammen Unknown Schulman Adequate Magasi Unknown 122 Not stated (range 16-82) Bauer Adequate Uehling Adequate Mean age Interventions Duration intervention Uehling Unknown Hopkins Unknown Oral OM-89 Oral OM-89 Oral OM-89 Oral OM-89 Vaginal Urovac, low dose (single dose) Vaginal Urovac, high dose (double dose) Vaginal Urovac Vaginal Urovac and boosters Vaginal Urovac Vaginal Urovac and boosters Follow-up Definition UTI³ 3 months 6 months months 6 months Symptoms and months 6 months Symptoms and months 12 months Symptoms and weeks 20 weeks Unclear 14 weeks 6 months Unclear 3,5 months 6 months Unclear 34

20 Review and meta-analysis non-antibiotic UTI prophylaxis B: Estrogen prophylaxis Reference Year of publication Jadad score Allocation concealment Study size Kirkengen Unknown Raz Unknown Cardozo Unknown Eriksen Unknown Mean age Interventions Duration intervention 69.0 Oral estriol Vaginal estriol Oral estriol Estradiol-releasing vaginal ring No treatment Follow-up Definition UTI 12 weeks 12 weeks Unclear 8 months 8 months Symptoms and months 12 months Symptoms and weeks 36 weeks Symptoms and 10 5 C: Lactobacilli prophylaxis Reference Year of publication Jadad score Allocation concealment Study size Baerheim Unknown Mean age Interventions Duration intervention 35.1 Kontiokari Adequate Vaginal Lactobacillus casei v rhamnosus Lactobacillus rhamnosus GG drink No treatment 26 weeks 26 weeks 12 months 12 months Follow-up Definition UTI 12 months Symptoms and 10 4 Symptoms and

21 Chapter 2 D: Cranberry prophylaxis Reference Year of publication Kontiokari 33 Jadad score Allocation concealment Study size Adequate Mean age Interventions Duration intervention 29.0 Stothers Adequate Cranberry- Lingonberry juice No treatment Cranberry juice Cranberry tablets 6 months 12 months Follow-up Definition UTI 12 months Symptoms and months 12 months Symptoms and 10 4 E: Miscellaneous Reference Year of publication Jadad score Allocation concealment Study size Aune Unknown Alraek Unknown Albrecht Adequate Mean age Interventions Duration intervention 52.3 Acupuncture Sham acupuncture No treatment Acupuncture No treatment Oral Angocin Anti- Infekt N (herbal product) Follow-up Definition UTI 4 weeks 6 months Symptoms and weeks 6 months Symptoms and days 180 days Unclear 36

22 Review and meta-analysis non-antibiotic UTI prophylaxis Table 2. Urinary tract infections and adverse events in non-antibiotic prophylaxis compared to placebo or no treatment. UTI= urinary tract infection, 95% CI=95% confidence interval. 1 Since, no difference was found in the interval until first re-infection with the low or high dose vaginal vaccine, the researchers decided to combine results of both doses for analysis of vaccine effectiveness. A: Immunoactive prophylaxis Reference Interventions n At least 1 UTI (%) Tammen 18 Oral OM-89 Schulman 19 Oral OM-89 Magasi 20 Oral OM-89 Bauer 22 Oral OM-89 Uehling 24 Vaginal Urovac¹ Uehling 25 Vaginal Urovac Vaginal Urovac and boosters Hopkins 23 Vaginal Urovac Vaginal Urovac and boosters Risk Ratio (95% CI) 0.75 ( ) ( ) ( ) ( ) ( ) ( ) 0.57 ( ) 0.89 ( ) 0.64 ( ) Mean number of UTIs Not stated Mean difference (as % of control) (-53.4) (-51.4) (-65.2) (-34.3) 0 (0) 0.20 (13.3) (-26.7) 37

23 Chapter 2 B: Estrogen prophylaxis Reference Interventions n At least 1 UTI (%) Kirkengen 27 Oral estriol Raz 26 Vaginal estriol Cardozo 28 Oral estriol Eriksen 31 Estradiol-releasing vaginal ring No treatment Risk Ratio (95% CI) ( ) ( ) Mean number of UTIs 1.17 ( ) Not stated 0.64 ( ) 1.17 Not stated C: Lactobacilli prophylaxis Reference Interventions n At least 1 UTI (%) Risk Ratio (95% CI) Mean number of UTIs Baerheim 32 Vaginal L. casei v rhamnosus Kontiokari 33 L. rhamnosus GG drink No treatment ( ) ( ) Mean difference (as % of control) (-40.9) (-91.6) Mean difference (as % of control) 0.38 (44.2) 0.04 (5.3) 38

24 Review and meta-analysis non-antibiotic UTI prophylaxis D: Cranberry prophylaxis Reference Interventions n At least 1 UTI (%) Kontiokari 33 Cranberry-Lingonberry juice No treatment Stothers 35 Cranberry juice Cranberry tablets Risk Ratio (95% CI) ( ) ( ) 0.56 ( ) Mean number of UTIs Not stated Mean difference (as % of control) (-44.7) E: Miscellaneous Reference Interventions n At least 1 UTI (%) Aune 38 Acupuncture Sham acupuncture No treatment Alraek 37 Acupuncture No treatment Albrecht 36 Oral Angocin Anti-Infekt N Not stated Risk Ratio (95% CI) 0.23 ( ) 0.66 ( ) Mean number of UTIs ( ) Mean difference (as % of control) (-63.4) (-18.3) (-59.7) 0.01 (1.6) 1 The proportion of patients with at least one UTI in the first 4 weeks of treatment. 2 The proportion of patients with at least one UTI was analyzed after 6 months of cranberry juice intake. 39