The resurgence of methenamine hippurate in the prevention of recurrent UTIs in women- a systematic review.

PURPOSE OF REVIEW: Recurrent urinary tract infections (rUTIs) in women are prevalent and difficult to manage. The rise of antimicrobial resistance makes it prudent to re-investigate the role of nonantimicrobial agents in the prevention of RUTIs. We wanted to evaluate randomised controlled trials (RCTs) that employed methenamine hippurate as a therapy or prophylactic in adult women with rUTIs. RECENT FINDINGS: Relevant databases were searched for RCTs using Cochrane methodology and reporting items for systematic reviews and meta-analyses (PRISMA) checklist, comparing the efficacy of methenamine hippurate to either an antibiotic or a placebo for the prophylaxis of rUTI in women.Six trials involving 322 patients taking methenamine and 419 patients receiving antibiotics in total were evaluated. The duration of the trials ranged from 12-24 months. Studies reported that methenamine was effective in extending the mean period between symptomatic episodes of urinary tract infections (UTIs), keeping the patient symptom- and infection-free, and reducing the number of UTI episodes. The newer studies reported that methenamine reduced the incidence rates of recurrent UTIs and was not inferior to the antibiotic in this regard. SUMMARY: The outcomes of methenamine hippurate were found to be at par with the antibiotic prophylaxis. It might serve as a suitable alternative nonantibiotic prophylaxis for females with rUTIs.

Methenamine for Recurrent Urinary Tract Infections in Solid Organ Transplantation.

INTRODUCTION: Recurrent urinary tract infections remain a challenge in solid organ transplant and have a negative impact on morbidity/mortality. PROJECT AIM: The purpose of this program evaluation was to determine the impact of methenamine on recurrent urinary tract infection in kidney and liver-kidney transplant recipients. DESIGN: This retrospective review included patients > 18 years of age who received a kidney or liver-kidney transplant. Patients were divided into the following groups: (1) Methenamine therapy initiation received methenamine for ≥ 180 days or (2) Non-methenamine therapy: did not receive recurrent urinary tract infection prophylaxis. A total of 60 patients were included. RESULTS: When comparing outcomes between methenamine therapy initiation and non-methenamine therapy group, a significant reduction in the rate of recurrent urinary tract infection was reported in the methenamine therapy initiation group (0.6 vs 1.3 per 180 patient days follow-up, P = 0.0005). A significant reduction was also noted with rate of asymptomatic bacteriuria, treatment failures, bacteremia, hospitalizations due to recurrent urinary tract infection, multi-drug resistant organism isolated, and the average duration of antibiotic use. A significant difference in the time to failure of methenamine therapy initiation versus non-methenamine therapy is noted up to 180 patient-days follow-up (RR 1.56, P = 0.0019). CONCLUSION: This evaluation supported methenamine therapy for recurrent urinary tract infection in kidney and liver-kidney transplant. The most significant impact of methenamine recurrent urinary tract infection was seen in the first 30 days after initiation.

Methenamine hippurate compared with trimethoprim for the prevention of recurrent urinary tract infections: a randomized clinical trial.

INTRODUCTION AND HYPOTHESIS: The objective was to find an alternative treatment to a low-dose antibiotic for the prevention of recurrent urinary tract infections (UTI) and to evaluate the difference in rates of reinfection within 1 year when treated with methenamine hippurate for prophylaxis compared with trimethoprim. METHODS: We present a non-blinded randomized trial comparing methenamine hippurate with trimethoprim for the prevention of recurrent UTI at 12 months after starting treatment. Women over 18 who had at least two culture-positive UTI in the prior 6 months or three in the prior year were included. Ninety-two patients met enrollment criteria and were randomized to receive daily prophylaxis with methenamine hippurate or trimethoprim for a minimum of 6 months. Both intent-to-treat and per-protocol analyses if patients received the alternative drug after randomization were analyzed using Student's t test, Mann-Whitney U test, Kaplan-Meier curves, log-rank test, and a logistic and multivariate regression model. The primary outcome of this study was culture-proven UTI recurrence by 12 months after initiating prophylaxis. RESULTS: In the intent-to-treat analysis, we found no difference between groups in recurrent UTI, with a 65% (28 out of 43) recurrence in the trimethoprim group versus 65% (28 out of 43) in the methenamine hippurate group (p = 1.00). In the per-protocol analysis, 65% (26 out of 40) versus 65% (30 out of 46) of patients had UTI recurrences in the trimethoprim group versus the methenamine hippurate group (p = 0.98). CONCLUSIONS: Methenamine hippurate may be an alternative for the prevention of recurrent UTI, with similar rates of recurrence and adverse effects to trimethoprim.

GPR109A mediates the effects of hippuric acid on regulating osteoclastogenesis and bone resorption in mice.

The G protein-coupled receptor 109 A (GPR109A) is robustly expressed in osteoclastic precursor macrophages. Previous studies suggested that GPR109A mediates effects of diet-derived phenolic acids such as hippuric acid (HA) and 3-(3-hydroxyphenyl) propionic acid (3-3-PPA) on promoting bone formation. However, the role of GPR109A in metabolic bone homeostasis and osteoclast differentiation has not been investigated. Using densitometric, bone histologic and molecular signaling analytic methods, we uncovered that bone mass and strength were significantly higher in tibia and spine of standard rodent diet weaned 4-week-old and 6-month-old GPR109A gene deletion (GPR109A-/-) mice, compared to their wild type controls. Osteoclast numbers in bone and in ex vivo bone marrow cell cultures were significantly decreased in GPR109A-/- mice compared to wild type controls. In accordance with these data, CTX-1 in bone marrow plasma and gene expression of bone resorption markers (TNFα, TRAP, Cathepsin K) were significantly decreased in GPR109A-/- mice, while on the other hand, P1NP was increased in serum from both male and female GPR109A-/- mice compared to their respective controls. GPR109A deletion led to suppressed Wnt/ß-catenin signaling in osteoclast precursors to inhibit osteoclast differentiation and activity. Indeed, HA and 3-3-PPA substantially inhibited RANKL-induced GPR109A expression and Wnt/ß-catenin signaling in osteoclast precursors and osteoclast differentiation. Resultantly, HA significantly inhibited bone resorption and increased bone mass in wild type mice, but had no additional effects on bone in GPR109A-/- mice compared with their respective untreated control mice. These results suggest an important role for GPR109A during osteoclast differentiation and bone resorption mediating effects of HA and 3-3-PPA on inhibiting bone resorption during skeletal development.

Black Raspberries Suppress Colorectal Cancer by Enhancing Smad4 Expression in Colonic Epithelium and Natural Killer Cells.

Innate immune cells in the tumor microenvironment have been proposed to control the transition from benign to malignant stages. In many cancers, increased infiltration of natural killer (NK) cells associates with good prognosis. Although the mechanisms that enable NK cells to restrain colorectal cancer (CRC) are unclear, the current study suggests the involvement of Smad4. We found suppressed Smad4 expression in circulating NK cells of untreated metastatic CRC patients. Moreover, NK cell-specific Smad4 deletion promoted colon adenomas in DSS-treated ApcMin/+ mice and adenocarcinomas in AOM/DSS-treated mice. Other studies have shown that Smad4 loss or weak expression in colonic epithelium associates with poor survival in CRC patients. Therefore, targeting Smad4 in both colonic epithelium and NK cells could provide an excellent opportunity to manage CRC. Toward this end, we showed that dietary intervention with black raspberries (BRBs) increased Smad4 expression in colonic epithelium in patients with FAP or CRC and in the two CRC mouse models. Also, benzoate metabolites of BRBs, such as hippurate, upregulated Smad4 and Gzmb expression that might enhance the cytotoxicity of primary human NK cells. Of note, increased levels of hippurate is a metabolomic marker of a healthy gut microbiota in humans, and hippurate also has antitumor effects. In conclusion, our study suggests a new mechanism for the action of benzoate metabolites derived from plant-based foods. This mechanism could be exploited clinically to upregulate Smad4 in colonic epithelium and NK cells, thereby delaying CRC progression.

Should I stay or should I go? A qualitative study exploring participation in a urology clinical trial.

INTRODUCTION AND HYPOTHESIS: The aim of this study was to identify modifiable factors to improve recruitment in a urology clinical trial of women with recurrent urinary tract infection (rUTI). An embedded qualitative study was conducted with patients and recruiting clinicians in the first 8 months of the trial. We present a matrix of factors influencing how patients make decisions about trial participation. METHODS: This was a qualitative study using telephone interviews. When they were first approached about the trial, women were asked to complete an expression of interest form if they wished to be contacted for an interview. Data were analysed thematically. NVivo 10 software (Qualitative data analysis software. 10th ed: QSR International Pty Ltd; 2012) was used as a management tool. RESULTS: Thirty patients and 11 clinicians were interviewed. Influences on patient participation included the impact of rUTI on quality of life (QoL), understanding of antibiotic resistance, and previous experiences with antibiotics either positive or negative. Very few women who declined the trial agreed to be interviewed. However, some of those who participated had reservations about it. These included the perceived risk of trying a new treatment, trial length, and the burden of participating. One person interviewed left the trial because of repeated infections and difficulties getting general practitioner appointments. CONCLUSIONS: A combination of factors worked to influence women to decide to participate, to remain in, or to leave the trial. A better understanding of how these factors interact and work can assist in the recruitment and retention of individual trial participants.

ALternatives To prophylactic Antibiotics for the treatment of Recurrent urinary tract infection in women (ALTAR): study protocol for a multicentre, pragmatic, patient-randomised, non-inferiority trial.

BACKGROUND: At least half of all adult women will experience infective cystitis (urinary tract infection: UTI) at least once in their life and many suffer from repeated episodes. Recurrent urinary tract infection (rUTI) in adult women is usually treated with long-term, low-dose antibiotics and current national and international guidelines recommend this as the 'gold standard' preventative treatment. Although they are reasonably effective, long-term antibiotics can result in bacteria becoming resistant not only to the prescribed antibiotic but to other antimicrobial agents. The problem of antimicrobial resistance is recognised as a global threat and the recent drive for antibiotic stewardship has emphasised the need for careful consideration prior to prescribing antibiotics. This has led clinicians and patients alike to explore potential non-antibiotic options for recurrent UTI prevention. DESIGN /METHODS: This is a multicentre, pragmatic, patient-randomised, non-inferiority trial comparing a non-antibiotic preventative treatment for rUTI in women, methenamine hippurate, against the current standard of daily low-dose antibiotics. Women who require preventative treatment for rUTI are the target population. This group is comprised of those with a diagnosis of rUTI, defined as three episodes in 1 year or two episodes in 6 months, and those with a single severe infection requiring hospitalisation. Participants will be recruited from secondary care urology / urogynaecology departments in the UK following referral with rUTI. Participants will be followed up during a 12-month period of treatment and in the subsequent 6 months following completion of the prophylactic medication. Outcomes will be assessed from patient recorded symptoms, quality of life questionnaires and microbiological examination of urine and perineal swabs. The primary outcome is the incidence of symptomatic antibiotic-treated UTI self-reported by participants during the 12-month period of preventative treatment. Health economic outcomes will also be assessed to define the cost-effectiveness of both treatments. A qualitative study will be conducted in the first 8 months of the trial to explore with participants/non-participants' and recruiting clinicians' views on trial processes and identify potential barriers to recruitment, reasons for participating and non-participation and for dropping out of the study. DISCUSSION: The study was commissioned and funded by the National Institute for Health Research (NIHR) and approved under the Medicines and Healthcare products Regulatory Agency (MHRA) notification scheme as a 'Type A' study. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number (ISRCTN), registry number: ISRCTN70219762 . Registered on 31 May 2016.

Nonantibiotic prevention and management of recurrent urinary tract infection.

Urinary tract infections (UTIs) are highly prevalent, lead to considerable patient morbidity, incur large financial costs to health-care systems and are one of the most common reasons for antibiotic use worldwide. The growing problem of antimicrobial resistance means that the search for nonantibiotic alternatives for the treatment and prevention of UTI is of critical importance. Potential nonantibiotic measures and treatments for UTIs include behavioural changes, dietary supplementation (such as Chinese herbal medicines and cranberry products), NSAIDs, probiotics, D-mannose, methenamine hippurate, estrogens, intravesical glycosaminoglycans, immunostimulants, vaccines and inoculation with less-pathogenic bacteria. Some of the results of trials of these approaches are promising; however, high-level evidence is required before firm recommendations for their use can be made. A combination of these agents might provide the optimal treatment to reduce recurrent UTI, and trials in specific population groups are required.

Lower urinary tract infections in women.

In her lifetime, a woman is highly likely to develop at least one lower urinary tract infection. Early detection and treatment are key. Being aware of predisposing factors for infection and understanding appropriate diagnosis and treatment regimens will help nurses in both primary and acute care manage these patients correctly. This will not only benefit patients but will also help prevent incorrect antimicrobial management and avoid unplanned admissions. This aim of this article is to provide nurses with the information they need to best advise both colleagues and patients on how to manage lower urinary tract infections in women.

Methenamine: a forgotten drug for preventing recurrent urinary tract infection in a multidrug resistance era.

In the era of multidrug resistance, it is critical to utilize antibiotics in an appropriate manner and to identify new treatments or revisit the use of 'forgotten' drugs. Because urinary tract infections (UTIs) are common, particularly in an increasing elderly population, the 'forgotten' drug, methenamine, may become important as a preventive therapy for recurrent UTIs. Methenamine, a urinary antibacterial agent, can be used as methenamine hippurate or methenamine mandelate preparations and is United States Food and Drug Administration-approved. This article discusses the place of preventive therapy for recurrent UTIs, chemistry, mechanism of action, pharmacology, clinical uses, dosage, adverse reactions and safety, and drug interactions of methenamine. Because of its unique antiseptic property, the authors suggest that methenamine should be considered when more commonly used antibiotics fail to suppress recurrent UTIs.

Urinary tract analgesics for the treatment of patients with acute cystitis: where is the clinical evidence?

Acute cystitis is one of the most common health-related problems in the female population. Over the last few decades, a number of drugs labeled as 'urinary tract analgesics' were released; these are available over the counter and are gaining widespread resonance among the North American population. The main representatives of this class of drugs are phenazopyridine and methenamine hippurate. Methenamine's efficacy and side effects have been well studied in a recent systematic review. On the other hand, in contrast to its widespread use, the published clinical evidence regarding phenazopyridine's effectiveness and safety is scarce. In addition, consumers (potentially patients) appear to ignore the limitations of this kind of treatment. In this article, concerns regarding the use of over-the-counter uroanalgesics, with a focus on the relevant clinical evidence, are discussed.

Methenamine hippurate for preventing urinary tract infections.

BACKGROUND: Methenamine salts are often used as an alternative to antibiotics for the prevention of urinary tract infection (UTI). This review was first published in Issue 1, 2002 and updated in Issue 4, 2007. OBJECTIVES: To assess the benefits and harms of methenamine hippurate in preventing UTI. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL in The Cochrane Library), MEDLINE (from 1950), EMBASE (from 1980), reference lists of articles and abstracts from conference proceedings without language restriction. Manufacturers' of methenamine salts were contacted for unpublished studies and contact was made with known investigators.Date of last search: June 2012 SELECTION CRITERIA: Randomised controlled trials (RCT) and quasi-RCTs of methenamine hippurate used for the prevention of UTIs in all population groups were eligible. A comparison with a control/no treatment group was a prerequisite for selection. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. Statistical analyses were performed using the random effects model and the results expressed as risk ratio (RR) for dichotomous outcomes with 95% confidence intervals (CI). An exploration of heterogeneity and a detailed description of results, grouped by population, was undertaken. MAIN RESULTS: Thirteen studies (2032 participants) were included. Six studies (654 patients) reported symptomatic UTI and eight studies (796 patients) reported bacteriuria. Overall, study quality was mixed. The overall pooled estimates for the major outcome measures were not interpretable because of underlying heterogeneity. Subgroup analyses suggested that methenamine hippurate may have some benefit in patients without renal tract abnormalities (symptomatic UTI: RR 0.24, 95% CI 0.07 to 0.89; bacteriuria: RR 0.56, 95% CI 0.37 to 0.83), but not in patients with known renal tract abnormalities (symptomatic UTI: RR 1.54, 95% CI 0.38 to 6.20; bacteriuria: RR 1.29, 95% CI 0.54 to 3.07). For short-term treatment duration (1 week or less) there was a significant reduction in symptomatic UTI in those without renal tract abnormalities (RR 0.14, 95% CI 0.05 to 0.38). The rate of adverse events was low. AUTHORS' CONCLUSIONS: Methenamine hippurate may be effective for preventing UTI in patients without renal tract abnormalities, particularly when used for short-term prophylaxis. It does not appear to work in patients with neuropathic bladder or in patients who have renal tract abnormalities. The rate of adverse events was low, but poorly described.There is a need for further large well-conducted RCTs to clarify this question, particularly for longer term use for people without neuropathic bladder.

Sensibilidad antimicrobiana de cepas hipurato-negativas de Campylobacter spp. y de Helicobacter pullorum aisladas de enfermos con diarrea / Antimicrobial sensitivity of hippurate-negative Campylobacter and Helicobacter pullorum strains isolated from patients with diarrhea

El género Campylobacter, tanto C. jejuni como algunas especies hipurato-negativas y géneros relacionados, son la principal causa de gastroenteritis en nuestro entorno a lo largo de todo el año. El objetivo del presente estudio es determinar la sensibilidad de cepas hipurato negativas de Campylobacter spp. y de Helicobacter pullorum aislados de heces diarreicas humanas. Se estudiaron 39 cepas de Campylobacter coli, dos de C. lari y cinco de Helicobacter pullorum identificadas por espectrometría de masas MALDI-TOF. La sensibilidad a amoxicilina- clavulánico, eritromicina, azitromicina, gentamicina, ciprofloxacino, levofloxacino, tetraciclina, tigeciclina y cloranfenicol se determinó por E-test. La mayoría de las cepas de Campylobacter hipurato-negativos y H. pullorum estudiadas presentaron una elevada resistencia a las dos fluoroquinolonas probadas y a la tetraciclina. Por otro lado, todas las cepas fueron sensibles a amoxicilina-clavulánico, a tigeciclina y a cloranfenicol, mientras que la mayoría lo fueron a los macrólidos y a la gentamicina(AU)

C. jejuni as well as some hippurate-negative Campylobacter species and related diarrheagenic organisms, are the leading cause of gastroenteritis in our environment all throughout the year. The aim of the present study was to determine the sensitivity of hippurate-negative Campylobacter and Helicobacter pullorum strains isolated from the stools of patients with diarrhea. We tested 39 Campylobacter coli, two C. lari and five Helicobacter pullorum strains identified by mass spectrometry analysis. The sensitivity to amoxicillin-clavulanic acid, erytrhomycin, azithromycin, gentamicin, ciprofloxacin, levofloxacin, tetracycline, tigecycline and chloramphenicol was tested by E-test. Most hippurate-negative Campylobacter and H. pullorum isolates studied showed high resistance to tetracycline and to the two fluorquinolones tested. On the other side, all strains were sensitive to amoxicillin-clavulanic acid, tigecycline and chloramphenicol, while most of them were sensitive to both macrolides tested and to gentamicin(AU)

Methenamine hippurate for preventing urinary tract infections.

BACKGROUND: Methenamine salts are often used as an alternative to antibiotics for the prevention of urinary tract infection (UTI). OBJECTIVES: To assess the benefits and harms of methenamine hippurate in preventing UTI. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL in The Cochrane Library), MEDLINE (from 1950), EMBASE (from 1980), reference lists of articles and abstracts from conference proceedings without language restriction. Manufacturers' of methenamine salts were contacted for unpublished studies and contact was made with known investigators. Date of last search: September 2006 SELECTION CRITERIA: Randomised controlled trials (RCT) and quasi-RCTs of methenamine hippurate used for the prevention of UTIs in all population groups were eligible. A comparison with a control/no treatment group was a prerequisite for selection. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. Statistical analyses were performed using the random effects model and the results expressed as relative risk (RR) for dichotomous outcomes with 95% confidence intervals (CI). An exploration of heterogeneity and a detailed description of results, grouped by population, was undertaken. MAIN RESULTS: Thirteen studies (2032 participants) were included. Six studies (654 patients) reported symptomatic UTI and eight studies (796 patients) reported bacteriuria. Overall, study quality was mixed. The overall pooled estimates for the major outcome measures were not interpretable because of underlying heterogeneity. Subgroup analyses suggested that methenamine hippurate may have some benefit in patients without renal tract abnormalities (symptomatic UTI: RR 0.24, 95% CI 0.07 to 0.89; bacteriuria: RR 0.56, 95% CI 0.37 to 0.83), but not in patients with known renal tract abnormalities (symptomatic UTI: RR 1.54, 95% CI 0.38 to 6.20; bacteriuria: RR 1.29, 95% CI 0.54 to 3.07). For short-term treatment duration (1 week or less) there was a significant reduction in symptomatic UTI in those without renal tract abnormalities (RR 0.14, 95% CI 0.05 to 0.38). The rate of adverse events was low. AUTHORS' CONCLUSIONS: Methenamine hippurate may be effective for preventing UTI in patients without renal tract abnormalities, particularly when used for short-term prophylaxis. It does not appear to work in patients with neuropathic bladder or in patients who have renal tract abnormalities. The rate of adverse events was low, but poorly described. There is a need for further large well-conducted RCTs to clarify this question, particularly for longer term use for people without neuropathic bladder.

Spinal-injured neuropathic bladder antisepsis (SINBA) trial.

OBJECTIVE: To determine whether Methenamine Hippurate (MH) or cranberry tablets prevent urinary tract infections (UTI) in people with neuropathic bladder following spinal cord injury (SCI). STUDY DESIGN: Double-blind factorial-design randomized controlled trial (RCT) with 2 year recruitment period from November 2000 and 6 month follow-up. SETTING: In total, 543 eligible predominantly community dwelling patients were invited to participate in the study, of whom 305 (56%) agreed. METHODS: Eligible participants were people with SCI with neurogenic bladder and stable bladder management. All regimens were indistinguishable in appearance and taste. The dose of MH used was 1 g twice-daily. The dose of cranberry used was 800 mg twice-daily. The main outcome measure was the time to occurrence of a symptomatic UTI. RESULTS: Multivariate analysis revealed that patients randomized to MH did not have a significantly longer UTI-free period compared to placebo (HR 0.96, 95% CI: 0.68-1.35, P=0.75). Patients randomized to cranberry likewise did not have significantly longer UTI-free period compared to placebo (HR 0.93, 95% CI: 0.67-1.31, P=0.70). CONCLUSION: There is no benefit in the prevention of UTI from the addition of MH or cranberry tablets to the usual regimen of patients with neuropathic bladder following SCI.

Postoperative voiding, bacteriuria and urinary tract infection with Foley catheterization after gynecological surgery.

BACKGROUND: The use of bladder drainage to avoid urinary retention after gynecological surgery is more or less custom based, and duration of drainage varies considerably. In this paper the use of 1-day drainage by transurethral Foley catheter was investigated with regard to impaired voiding, asymptomatic bacteriuria, and urinary tract infection. Furthermore, the use of methenamine hippurate was studied with regard to postoperative asymptomatic bacteriuria and urinary tract infection. METHODS. This summary is based on six published papers totaling 917 patients. In three case series, 1-day catheterization was used in women undergoing gynecological laparotomy, colposuspension, or vaginal plastic surgery. To compare 1- and 3-day Foley catheterization, two open, randomized trials were performed on women undergoing vaginal plastic surgery or colposuspension. The last study was a double-blind trial between methenamine hippurate and placebo as prophylaxis against urinary tract infection and asymptomatic bacteriuria using 1-day catheterization. RESULTS: Postoperative voiding problems and urinary tract infection occurred infrequently with 1-day catheterization, and no more frequently than with catheterization for three days. Methenamine hippurate decreased the incidence of urinary tract infection and asymptomatic bacteriuria by 80 and 40%, respectively. CONCLUSIONS: One-day bladder drainage by transurethral Foley catheter may be used routinely in common gynecological surgery with a low rate of voiding problems, asymptomatic bacteriuria, and urinary tract infection. Methenamine hippurate prophylaxis effectively reduces postoperative urinary tract infection.

Methenamine hippurate for preventing urinary tract infections.

BACKGROUND: Methenamine salts are often used for the prevention of urinary tract infection (UTI). OBJECTIVES: To assess the effectiveness of methenamine hippurate in preventing UTI. SEARCH STRATEGY: Published and unpublished randomised controlled trials were identified from the Cochrane Controlled Trials Register, MEDLINE, EMBASE, CINAHL, Current Contents, reference lists of review articles and retrieved trials. The manufacturers' of methenamine salts were contacted for unpublished studies and contact was made with known investigators in the area. SELECTION CRITERIA: Randomised and quasi-randomised trials of methenamine hippurate used for the prevention of UTIs in all population groups were eligible for inclusion. A comparison with a control (no treatment) group was a prerequisite to selection. DATA COLLECTION AND ANALYSIS: Two reviewers (BL and TB) performed independent assessment and data extraction using a standardised format. Discrepancies, methodological and interpretative issues were discussed with JS or JC. An exploration of heterogeneity as well as a detailed description of results grouped by population was conducted. MAIN RESULTS: Eleven studies met the inclusion criteria. All trials were included in a descriptive analysis. Seven trials were included in meta-analyses. Four trials (199 patients) studied symptomatic bacteriuria and six trials (341 patients) studied bacteriuria as an outcome measure. Overall, trial quality was poor. The direction of six of the pooled trials was towards a favourable treatment effect from methenamine hippurate. Interpretation of the pooled estimates was not done in view of underlying heterogeneity. The study by Pettersson 1989 explained some, but not all, of the underlying heterogeneity. This study differed from all others by including patients with known upper renal tract abnormalities. Adverse reactions were mentioned by 10 studies. The rate of adverse events was low. REVIEWER'S CONCLUSIONS: There is not enough evidence to conclusively support the use of methenamine hippurate for urinary prophylaxis. An exploration of heterogeneity raises the (hypothesis generating) possibility that methenamine hippurate may have some efficacy in patients without but not in patients with known upper renal tract abnormality (with asymptomatic bacteriuria as the outcome measure). Due to the small sample size and methodological problems within the studies involved, interpretation of these data should be done cautiously. The rate of adverse events reported by the trials was low, which suggests that current usage is unlikely to be causing significant harm.