Objective
We performed a systematic review and meta-analysis to determine whether D-mannose reduces urinary tract infection recurrence (ie, cumulative incidence) in adult women with recurrent urinary tract infection compared with other prevention agents. Secondary outcomes included side effects and compliance with D-mannose use.
Data Sources
Ovid Medline 1946-, Embase 1947-, Scopus 1823-, Cochrane Library, Web of Science 1900-, and ClinicalTrials.gov were searched through 4/15/2020.
Study Eligibility Criteria
Systematic review inclusion: randomized controlled trials, prospective cohorts, and retrospective cohorts written in English of women ≥18 years old with recurrent urinary tract infection in which D-mannose was utilized as an outpatient prevention regimen. Systematic review exclusion: lab or animal-based research, study protocols only, and conference abstracts. Meta-analysis inclusion: stated D-mannose dose, follow-up time ≥6 months, a comparison arm to D-mannose, and data available from women ≥18 years of age.
Study Appraisal and Synthesis Methods
Two independent reviewers made abstract, full text, and data extraction decisions. Study methodologic quality was assessed using the Cochrane Risk of Bias tool. Relative risks, confidence intervals, and heterogeneity were computed.
Results
Searches identified 776 unique citations. Eight publications met eligibility: 2 using D-mannose only; 6 using D-mannose combined with another treatment. Seven studies were prospective: 2 randomized controlled trials, 1 randomized cross-over trial, and 4 prospective cohort studies. One retrospective cohort study was included. Three studies met meta-analysis eligibility (1 randomized controlled trial, 1 randomized cross-over trial, and 1 prospective cohort). Pooled relative risk of urinary tract infection recurrence comparing D-mannose to placebo was 0.23 (95% confidence interval, 0.14–0.37; heterogeneity=0%; D-mannose n=125, placebo n=123). Pooled relative risk of urinary tract infection recurrence comparing D-mannose to preventative antibiotics was 0.39 (95% confidence interval, 0.12–1.25; heterogeneity=88%; D-mannose n=163, antibiotics n=163). Adverse side effects were reported in 2 studies assessing D-mannose only (1 study (n=10) reported none; the other reported a low incidence (8/103 participants) of diarrhea). Two studies reported compliance, which was high.
Conclusion
D-mannose appears protective for recurrent urinary tract infection (vs placebo) with possibly similar effectiveness as antibiotics. Overall, D-mannose appears well tolerated with minimal side effects—only a small percentage experiencing diarrhea. Meta-analysis interpretation must consider the small number of studies with varied study design and quality and the overall small sample size.
Eleven percent of women in the United States report at least 1 physician-diagnosed urinary tract infection (UTI) per year. Up to half of women will experience an additional UTI within the first year after initial infection. , In the US, annual societal costs of UTIs in all patients are estimated to be at least $2.4 billion, , with some estimates upwards of $3.5 billion. In addition to the financial implications, UTIs can negatively impact patients’ work productivity, personal and family responsibilities, quality of life, and sexual well-being.
Why was this study conducted?
This study aimed to systematically review and combine data from original published literature evaluating the effectiveness, side effects, and compliance of D -mannose for recurrent urinary tract infection prevention in adult women.
Key findings
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Small number of studies: 8 in systematic review with 3 in meta-analysis.
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In the meta-analysis, D-mannose appears protective for recurrent urinary tract infection vs placebo with possibly similar effectiveness as preventative antibiotics.
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D-mannose appears well tolerated with minimal adverse side effects.
What does this add to what is known?
This is the first systematic review and meta-analysis of the effectiveness of D-mannose for recurrent urinary tract infection prevention.
Recurrent UTI (rUTI) is defined as 2 UTI episodes in 6 months, or 3 UTI episodes in 12 months. Historically, antibiotics have been used as the primary method to prevent rUTI. These medications are associated with a wide range of side effects, including diarrhea, nausea, headache, vaginal burning, and candidiasis. , Although less common, more serious side effects can occur. For example, long-term nitrofurantoin use has been associated with pulmonary and hepatic toxicity and trimethoprim-sulfamethoxazole has been associated with numerous serious cutaneous reactions, including Stevens-Johnson syndrome, blood dyscrasias, and drug interactions. Long-term antibiotic use can also lead to alteration of normal flora and antibiotic resistance, making it difficult to treat future UTI. For all these reasons, nonantibiotic rUTI prevention regimens, such as D-mannose, have increasingly been the subject of research.
The most common rUTI uropathogen is Escherichia coli . E. coli has specific virulence factors that promote infection through adhesion to urothelial cells; the most commonly expressed virulence factor is type 1 fimbriae. , Also known as type 1 pili, these virulence factors promote bacterial adhesion to urothelial cells and an early inflammatory response by recruiting neutrophils to the urinary tract. D-mannose is a promising nonantibiotic prevention strategy because it binds to the tip of type 1 pili and saturates the adhesin FimH, thereby preventing bacterial adhesion to the urothelium. , , FimH interaction with the urothelium is also believed to initiate a signaling cascade promoting uropathogenic E. coli urothelial invasion. Saturation of FimH by D-mannose should theoretically prevent this invasion by preventing induction of the signaling cascade. New research suggests that D-mannose may also act as an immune modulator. Most research surrounding type 1 fimbriae and UTIs focuses on E. coli . However, type 1 pili have been documented on other members of the Enterobacteriaceae family, including Klebsiella pneumoniae , Shigella flexneri , Salmonella typhimurium , Serratia marcescens , and Enterobacter cloacae . , Many of these are common rUTI uropathogens.
Our objective was to systematically review and combine data from published original literature evaluating the effectiveness of D-mannose compared with other agents for rUTI prevention in adult women. Secondary objectives were to evaluate side effects and compliance with D-mannose use. A systematic review and meta-analysis (SRMA) is needed to provide a compiled source of evidence to guide clinical practice. We hypothesized D-mannose would have similar efficacy as antibiotics in preventing rUTI and that it would be well tolerated.
Methods
This SRMA was submitted to the Washington University in St Louis School of Medicine institutional review board and determined to not be human subjects research. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. An a priori protocol was written and followed.
Information sources and search strategy
A comprehensive literature search was performed with a medical librarian using search strategies, standardized terms, and keywords for the concepts of recurrent UTI and mannose. These strategies were executed in Ovid Medline 1946-, Embase 1947-, Scopus 1823-, Cochrane Library, Web of Science 1900-, and ClinicalTrials.gov . All searches were completed on February 5, 2018, March 5, 2019, and again on April 15, 2020. Database-supplied English-language limits were applied. Endnote was used for deduplication. Manual checks and comparisons were also performed to determine whether abstracts were unique or duplicates. If there was any uncertainty at the abstract level, 2 authors (SL and MB) reviewed the full text article and came to consensus. The full search strategies can be found in the Appendix and they followed a similar strategy as the one used for Ovid Medline April 2020 search: (exp urinary tract infections/) or (urinary adj1 tract adj1 infection∗) or bacteriuria or pyuria or schistosomiasis haematobia or cystalgia or cystitis or pyelocystitis or exp cystitis/ or (recurrent adj1 urinary adj1 tract adj1 infection∗) AND (mannose/ or mannose or mannosides or exp mannosides/ or methylmannosides or d-mannose).
Study selection and eligibility criteria
Abstracts and full text publications were screened with a predetermined list of eligibility criteria. Inclusion criteria were as follows: (1) original clinical research (Randomized controlled trials [RCTs], including cross-over trials, prospective cohorts, and retrospective cohorts—not including case reports, case series, or conference abstracts) for women receiving care in an outpatient setting for rUTI (defined as at least 2 UTI in 6 months or at least 3 UTI in 12 months); (2) participant age ≥18 years; and (3) a study arm including D-mannose as a UTI prevention intervention. Exclusion criteria included the following: (1) laboratory or animal-based research; (2) publications written in languages other than English; (3) duplicate publications; and (4) published study protocols. If a study met all criteria, it was included. For our meta-analysis (MA), we only included studies with clearly stated D-mannose dosing, follow-up time ≥6 months, and a comparator arm. Studies that lacked follow-up, a comparator arm, or combined D-mannose with additional supplements were included in the systematic review (SR) but not the MA.
Abstract and full text review, data extraction, and quality assessment
Abstracts from the systematic literature search were independently screened by 2 authors (SL and MB) using the stated eligibility criteria. Full text of selected abstracts were independently reviewed by the same 2 authors. Data extraction was also independently performed by 2 authors. In the event of disagreement, the 2 authors reviewed the study together and a third reviewer was available if a consensus could not be made. Each of the ClinicalTrials.gov search results was reviewed to ensure that any known unpublished data were included in our MA. At the beginning of data extraction, an application for Prospero registration was submitted with our a priori protocol. Owing to the extended timeline for processing and reviewing the application, this study was not selected to be registered as the registry felt the study was too close to completion by the time the application was reviewed.
We performed an SRMA to determine whether D-mannose reduces UTI recurrence (ie, cumulative incidence) in adult women with rUTI compared with other prevention agents. Secondary outcomes included side effects and compliance with D-mannose use. The primary outcome was defined as the proportion of participants experiencing at least one UTI in a 6-month or greater time frame of treatment (cumulative incidence). We referred to the first UTI during study follow-up as the incident UTI. Extracted information included title, year of publication, author names, study information and duration, including timing of measurements, demographics, and baseline characteristics, information about the intervention and/or control arms, treatment outcomes, side effects reported in participants using D-mannose, and compliance with D-mannose use.
We assessed the methodologic quality of each study using predefined criteria from a three-tier system in which studies were graded as good, fair, or poor on the basis of scientific merit, the likelihood of biases, and the completeness of reporting. This grading was completed according to the Cochrane Risk of Bias tool (as either high, low, or unclear) and relevant questions from the Newcastle-Ottawa Scale. , Selective study reporting within studies was assessed as part of the risk of bias assessment.
Data synthesis and analysis
Aggregate data from published reports were used to determine the effect of D-mannose compared with other treatments (such as a placebo or antibiotic). At minimum, 2 studies were required for each MA performed. Our a priori protocol had initially planned for relative risks (RRs) to be computed using a fixed effects model where published estimates are combined using a weighted average (weighted according to the number of participants in each study). However, owing to the small number of studies identified for this MA, the decision was made to compute RRs using a random effects model with robust variance estimation because I 2 can be falsely low with a small number of studies. Confidence intervals (CI) for the log RRs were determined and then exponentiated to obtain the confidence interval for the RR. These were computed and graphed in R, using the metafor and forestplot libraries. Two separate MAs were done: an MA of D-mannose vs placebo, and MA of D-mannose vs antibiotics. Data are presented similarly to other SRMA with comparable primary outcomes.
Results
The literature search yielded 776 unique abstracts, of which 17 were reviewed in full text ( Figure 1 , PRISMA diagram). Of the 17 full text publications reviewed, 3 were conference abstracts only (no accompanying full text), 1 was non-English (only abstract was written in English), and 1 was a duplicate study; leaving 12 full text articles for further review and data extraction. Four of the 12 articles evaluated patient populations other than adult women with rUTI, leaving a total of 8 articles that met the SR eligibility criteria ( Table 1 ). Seven studies were prospective: 2 RCTs, 1 randomized cross-over trial, and 4 prospective cohort studies. The other study was a retrospective cohort study. Cochrane assessment of bias of each study ( Table 2 ) was used to determine each study’s grade of evidence. Evaluation of selective reporting within studies is shown in Table 2 . The definition of rUTI and incident UTI as defined in each study is outlined in Table 3 as well as the study follow-up time. Of note, the authors identified a few additional studies during abstract and full text review that demonstrated possible additional uses of D-mannose for preventing UTI after urodynamic office procedures and for treating UTI and urinary stones. These were not included in the SRMA as they did not use D-mannose for prevention of recurrent uncomplicated infections. An additional article was found to be written in Italian, despite an English abstract. Ten studies were identified in our clinicaltrials.gov search, including 2 rUTI studies evaluating D-mannose that are still currently recruiting and 2 studying nonantibiotic rUTI prevention regimens that have not yet begun recruiting. No other studies were relevant. All completed relevant studies were included in our SRMA.
| Authors, year | Study design | Study population | Inclusion criteria | Exclusion criteria | D-mannose group (dose, other components, duration) | Compared group(s) | Grade of evidence a |
|---|---|---|---|---|---|---|---|
| Meta-analysis studies | |||||||
| Domenici et al, 2016 | Prospective cohort | Women, aged 18–65 y (mean, 46.7; SD, 5.7 y) n=45 | Acute cystitis and/or history of recurrent UTIs b | Urinary tract anomalies, pregnancy/breastfeeding, symptoms of pyelonephritis, upper tract infection, hormone therapy, diabetes, use of CISC, previous antibiotic prophylaxis | All participants received oral Mannocist (D-mannose 1.5 g, sodium bicarbonate, sorbitol and silicon dioxide; Laboratori Farmaceutici Krymi, Rome, Italy) BID for 3 d, then daily for 10 d at same dosage. No antibiotics were given. | Poor | |
| Prophylaxis: oral Mannocist daily (for 1 wk every other mo)×6 mo (n=22) | Prophylaxis: none (n=21) | ||||||
| Kranjčec et al, 2014 | Randomized controlled trial | Women aged >18 y (median, 48–52; range, 29–58) n=308 | Acute cystitis and history of recurrent UTIs b | Pregnant/breastfeeding symptoms of pyelonephritis, urinary tract anomalies, diabetes, current hormone therapy/contraception, previous antibiotic prophylaxis | All participants first received oral ciprofloxacin 500 mg BID×7 days | Fair | |
| Prophylaxis: 2 g of oral D-mannose powder (diluted in 200 mL of water) daily×6 mo (n=103) | Active prophylaxis: 50 mg of Nitrofurantoin daily×6 mo (n=103) or Control prophylaxis: none (n=102) | ||||||
| Porru et al, 2014 | Randomized cross-over trial | Women aged ≥18 y (median, 42 y; range, 22–54) n=46 | Current acute symptomatic UTI and history of recurrent UTIs b | Symptoms of pyelonephritis, renal disease, anatomic abnormalities, prior gynecologic surgery, immunosuppressive medications or diseases, pregnant/breastfeeding | Oral D-mannose 1 g Prophylaxis: TID×2 wk, then BID×total 6 mo (n=30) | Oral TMP/SMX 160/800 mg BID×5 days Prophylaxis: TMP/SMX 160 mg/800 daily (1 wk each mo)×total 6 mo (n=30) | Fair |
| 6 mo: cross-over to other group for additional 6 mo | |||||||
| Other studies | |||||||
| Genovese et al, 2018 | Randomized 3-arm parallel group | Women (no ages reported) n=72 | Current acute UTI and history of recurrent cystitis b | Pregnancy/lactation, abnormalities of the upper urinary tract, permanent urinary catheter, stage 5 chronic kidney disease | A: oral D-mannose 420 mg+berberine, arbutin, birch (n=24) B: oral D-mannose 420 mg+berberine, arbutin, birch, forskolin (n=24) C: oral D-mannose 500 mg+proanthocyanidins (n=24) All (A, B, and C) for a 12-wk duration | None (all arms with D-mannose) | Poor |
| Phe et al, 2017 | Open-label feasibility, prospective study | Men or women (median, 50.0; IQR, 46.2–59.0) n=22 | Clinically stable MS ≥3 mo, history of recurrent UTIs b | Pregnancy, urinary tract anomalies, diabetes mellitus, current UTI or vaginal infection, allergies to D-mannose | Oral D-mannose 1.5 g BID×16 wk (n=22) | None | Poor |
| Del Popolo et al, 2018 | Prospective cohort | Men or women seen in neuro-urology clinic (mean age, 45.2 y; range, 22–78) Neurogenic bladder (n=33 female) Non-neurogenic bladder (n=39 female) | Symptomatic UTI, history of recurrent UTIs, b previous unsuccessful treatment with D-mannose and/or cranberry | Non- E. coli UTI at the screening, pregnancy/breastfeeding, hematuria, fever, urogenital abnormalities, allergies to salicylates and/or D-mannose, antibiotics in the last 2 wk | All participants received 1000 mg of oral D-mannose+200 mg of dry willow extract (salicin) TID for 5 d | Poor | |
| All received 700 mg oral D-mannose+50 mg (1×10 9 CFU) of oral Lactobacillus acidophilus (La-14) BID for 15 d monthly for 2 mo | |||||||
| Efros et al, 2010 | Prospective, dose-escalation trial | Women (mean age, 46.5; SD, 12.8 y) n=28 | History of History of recurrent UTIs b | Current UTI or vaginitis, allergy to cranberry, predisposition to kidneys stones, diabetes on insulin, immunosuppressive disease/corticosteroid use, catheterization, pregnant/breastfeeding, abnormalities of the urinary tract, recent prophylactic antibiotics, warfarin | Study agent of oral liquid dietary supplement UTI-STAT (3875 mg Proantinox [cranberry concentrate 4:1, ascorbic acid, D-mannose, fructo-oligosaccharides, and bromelain]/30 mL) Participants were given 15 mL of UTI-STAT with Proantinox then increasing by 15 mL to maximal dosage target of 90 mL/d (only reached 75 mL/d because of adverse events [n=28]) | Poor | |
| Marchiori et al, 2017 | Retrospective cohort study | Women (no ages reported) n=60 | History of recurrent UTIs, physiological menopause and childbearing age, breast cancer | Not reported | 1: oral D-mannose 500 mg, n-acetylcysteine 100 mg, and Morinda citrifolia fruit extract 200 mg (NDM) BID for 2 mo, then daily for 4 mo, with antibiotic regimen as needed(n=40) | 2: no prophylaxis (either Fosfomycin, nitrofurantoin, or ciprofloxacin for acute cystitis) (n=20) | Poor |
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