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Oral D-mannose in recurrent urinary tract infections in women: A pilot study

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Background In recurrent urinary tract infections (UTIs) usual prophylactic antibiotic regimes do not change the long-term risk of recurrence. Our aim was to evaluate the efficacy of D-mannose in the treatment and prophylaxis of recurrent UTIs. Methods In this randomized cross-over trial female patients were eligible for the study if they had an acute symptomatic UTI and three or more recurrent UTIs during the preceding 12 months. Suitable patients were randomly assigned to antibiotic treatment with trimethoprim/sulfamethoxazole or to a regimen of oral D-mannose 1 g 3 times a day, every 8 hours for 2 weeks, and subsequently 1 g twice a day for 22 weeks. They received the other intervention in the second phase of the study, with no further antibiotic prophylaxis. The primary endpoint was evaluation of the elapsed time to recurrence; secondary endpoints were evaluation of bladder pain (VASp) and urinary urgency (VASu). Results The results for quantitative variables were expressed as mean values and SD as they were all normally distributed (Shapiro–Wilk test). In total, 60 patients aged between 22 and 54 years (mean 42 years) were included. Mean time to UTI recurrence was 52.7 days with antibiotic treatment, and 200 days with oral D-mannose ( p < 0.0001). Conclusions Mean VASp, VASu score, and average numbers of 24-hour voidings decreased significantly. D-mannose appeared to be a safe and effective treatment for recurrent UTIs in adult women. A significant difference was observed in the proportion of women remaining infection free versus antibiotic treatment.
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Journal of Clinical Urology
2014, Vol. 7(3) 208 –213
© British Association of
Urological Surgeons 2014
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DOI: 10.1177/2051415813518332
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Introduction
Recurrent UTI (rUTI) is defined as three episodes of uri-
nary tract infection (UTI) with three positive urine cultures
in the previous 12 months or two episodes in the last 6
months.1 Usual strategies include long-term low-dose pro-
phylactic antimicrobial treatment or postcoital antibiotic
treatment, but it seems that these strategies do not alter the
long-term risk of recurrence. Patients with frequent UTIs
who take prophylactic antimicrobial agents for extended
periods decrease their infections during prophylaxis, but
the rate of infection returns to pretreatment rates when
Oral D-mannose in recurrent urinary
tract infections in women: a
pilot study
D Porru1, A Parmigiani1, C Tinelli2, D Barletta1, D Choussos1,
C Di Franco1, V Bobbi1, S Bassi1, O Miller1, B Gardella3, RE
Nappi3, A Spinillo3 and B Rovereto1
Abstract
Background: In recurrent urinary tract infections (UTIs) usual prophylactic antibiotic regimes do not change the
long-term risk of recurrence. Our aim was to evaluate the efficacy of D-mannose in the treatment and prophylaxis of
recurrent UTIs.
Methods: In this randomized cross-over trial female patients were eligible for the study if they had an acute symptomatic
UTI and three or more recurrent UTIs during the preceding 12 months. Suitable patients were randomly assigned to
antibiotic treatment with trimethoprim/sulfamethoxazole or to a regimen of oral D-mannose 1 g 3 times a day, every 8
hours for 2 weeks, and subsequently 1 g twice a day for 22 weeks. They received the other intervention in the second
phase of the study, with no further antibiotic prophylaxis. The primary endpoint was evaluation of the elapsed time to
recurrence; secondary endpoints were evaluation of bladder pain (VASp) and urinary urgency (VASu).
Results: The results for quantitative variables were expressed as mean values and SD as they were all normally distributed
(Shapiro–Wilk test). In total, 60 patients aged between 22 and 54 years (mean 42 years) were included. Mean time to UTI
recurrence was 52.7 days with antibiotic treatment, and 200 days with oral D-mannose (p < 0.0001).
Conclusions: Mean VASp, VASu score, and average numbers of 24-hour voidings decreased significantly. D-mannose
appeared to be a safe and effective treatment for recurrent UTIs in adult women. A significant difference was observed
in the proportion of women remaining infection free versus antibiotic treatment.
Keywords
Antibiotic treatment, cystitis, D-mannose, recurrent urinary tract infections, prophylaxis
Date received: 30 October 2013; revised: 24 November 2013; accepted: 2 December 2013
1 Urology Department, Fondazione IRCCS Policlinico San Matteo, Pavia,
Italy
2 Clinical Epidemiology and Biometric Unit, Fondazione IRCCS
Policlinico San Matteo, Pavia, Italy
3 Obstetrics and Gynecologic Clinic, Fondazione IRCCS Policlinico San
Matteo, Pavia, Italy
Corresponding author:
Daniele Porru, Urology Department, Fondazione IRCCS Policlinico San
Matteo, Viale Golgi 19, Pavia 27100, Italy.
Email: danieleporru@tin.it
518332URO0010.1177/2051415813518332D-mannose in recurrent UTIs in adult womenPorru et al.
research-article2014
Original Article
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Porru et al. 209
prophylaxis is stopped.2,3 Long-term antibiotics do not
appear to positively affect the patient’s basic susceptibility
to infections.4
The cell wall of Escherichia coli bacteria has tiny fin-
ger-like projections that contain complex molecules called
lectins on their surface. Lectins act as a cellular glue that
binds the bacteria to the bladder wall so they cannot be
easily rinsed out by urination, adhering to mannose recep-
tors of the bladder wall.5 D-mannose (Figure 1) is a simple
sugar structurally related to glucose; it is found in several
fruits and is also produced in the body.
We hypothesized that urinary D-mannose may be able
to bind and eliminate bacteria such as E. coli by acting as
a competitor for E. coli adhesion to bladder epithelial
cells.6-8
In the management of rUTIs in women it is common
practice to fight E. coli resistance by varying the type of
antibiotic, or increasing the dose and duration of therapy.
However, in doing so the bacteria become even more
resistant to broad-spectrum antibiotics. It is likely that part
of the old colony of bacteria in the urinary tract probably
survive; some bacteria probably remain latent and are
reactivated by various favourable conditions, therefore
persistent recurrences may not be true re-infections.9
In this randomized cross-over study the aim was to
evaluate if oral D-mannose could be used as a safe and
effective treatment for UTIs and also as a prophylactic
measure for rUTIs in adult women.
Methods
Female patients were eligible for study if they were aged
18 years or older and had an acute symptomatic UTI and
three or more UTIs documented with culture of midstream
urine specimen at inclusion and in the preceding 12
months, had not taken antimicrobials within 4 weeks and
were not pregnant or contemplating pregnancy. Exclusion
criteria were: upper UTI and/or temperature higher than
38°C, flank/lumbar pain or tenderness, renal disease, ana-
tomical abnormalities, prior gynaecological surgery,
immunosuppressive medications or diseases (Table 1). All
patients gave their written consent to the study. The work
was conducted in accordance with the principles of the
Declaration of Helsinki of World Medical Association.
Each participant entering the trial was assigned to one of
the following treatments in a random sequence: (a) A regi-
men of 5-day antibiotic therapy with trimethoprim/sul-
famethoxazole 160 mg/800 mg twice a day, followed by a
single dose at bedtime for 1 week each month in the fol-
lowing 23 weeks; (b) A regimen of oral D-mannose 1 g
three times a day, every 8 hours for 2 weeks, and subse-
quently 1 g twice a day for 22 weeks. D-mannose activity
is best when the urine has neutral pH; therefore, patients
were instructed to measure urinary pH using dipsticks and
use oral sodium bicarbonate 250 mg b.i.d. or potassium
citrate 1 g b.i.d. as alkalinizing agents if pH was <7.
There were two groups of 30 patients; the first group
received antibiotic first, and the second D-mannose first.
The cross-over point was at 24 weeks in both groups A and
B. Therefore patients in group A switched to group B at
Figure 1. Chemical structure of D-glucose and D-mannose.
Table 1. Inclusion and exclusion criteria.
Inclusion criteria Exclusion criteria
female > 18 years upper urinary tract infection and/or
temperature > 38°C
acute symptomatic UTI flank/lumbar pain/tenderness
3 UTIs with positive urine culture in the preceding 12 months renal disease
no antimicrobials within 4 weeks anatomical abnormalities
not pregnant/not contemplating pregnancy prior gynaecological surgery
immunosuppressive medications or diseases
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210 Journal of Clinical Urology 7(3)
week 24, and vice versa. Data of patients in both groups
who had a symptomatic UTI and returned for at least one
follow-up visit were included in the analysis of treatment
outcome and adverse effects.
Main outcome measures
Bacteriuria with symptoms of UTI was defined as signifi-
cant if voided urine culture was positive with at least
100,000 uropathogens per ml. Urine cultures were repeated
whenever symptoms appeared and at the end of the study.
The 24-hour number of voidings was obtained by comple-
tion of a voiding diary before and at the end of treatment in
both treatment groups. The elapsed time to UTI recurrence
(time to recurrence (TTR)) was evaluated and a compari-
son was made between the two groups of treatment; fol-
low-up of the study was 12 months.
Primary outcome of the study was the TTR of UTI; the
TTR after antibiotic treatment and with D-mannose treat-
ment was appraised and compared. UTI was defined as
an acute flare of urinary symptoms + positive urine cul-
ture. Secondary outcomes were visual analogue scale
(VAS) pain and VAS urgency, both recorded during epi-
sodes of UTI.
Statistical analysis
The results for quantitative variables were expressed as
mean values and SD as they were all normally distributed
(Shapiro–Wilk test); t-test for paired data was used to ana-
lyse differences in TTR, VAS pain, VAS urgency and num-
ber of voidings between treatments.
Data analysis was performed with STATA statistical
package (release 11.1, 2010, Stata Corporation, College
Station, Texas, USA).
Results
In total, 60 patients aged between 22 and 54 years (mean
42 years) who visited at the outpatient clinic of our urol-
ogy department were included in the study.
A significant difference in the elapsed time to develop
an infection was found between patients on antibiotic
treatment and those on treatment with D-mannose. The
results of urine cultures of patients under treatment in both
groups are shown in Table 2, and risk factors for UTIs are
reported in Table 3.
Following antibiotic treatment, all patients had a nega-
tive urine culture 1 week after the end of treatment, and the
mean time to UTI recurrence was 52.7 days (SD: 11.2;
95% Confidence Interval); under D-mannose treatment the
mean TTR was 200 days (SD: 50.7) (Figure 2); the differ-
ence was statistically significant (p < 0.0001).
Of the 60 patients, 45 (75%) had one recurrence during
the 24-week course of antibiotic treatment, 10/60 (16.6%)
had two recurrences, and 5/60 (8.3%) had no recurrent
infection. Twelve out of 60 patients (20%) had positive
urine culture during treatment with D-mannose before
completing the 24-week treatment, and 48 (80%) remained
UTI free. Urine pH ranged between 6.5 and 7.5.
Mean VAS pain was 4.4 (SD: 1.1) before D-mannose
treatment and 2.2 (SD: 0.5) after its course. Mean VAS
urgency score decreased from 4.6 (SD: 1.1) to 2.6 (SD:
0.7) before and after treatment (Figure 2). Mean number
of voidings was 7.1 (SD: 1.7) before D-mannose, and
4.7 (SD: 1.0) at the end of D-mannose treatment (Figure
3). All differences were statistically significant (p <
0.001).
Discussion
Because of the need for alternatives to antibiotics in rUTIs,
other treatment or prophylaxis regimens have been
Table 2. Results at 6, 12 and 24 weeks with treatment. Oral D-mannose treatment 1 g every 8 h in 60 patients. Number of
patients with positive urine culture at time 0, 6, 12 and 24 weeks after starting treatment.
Urine culture Time 0 6 weeks 12 weeks 24 weeks
E. Coli 40 28 20 10
Klebsiella pneumonia 10 12 6 2
Proteus 4 4 6 0
Streptococcus agalactiae 4 2 0 0
Enterococcus 2 0 0 0
No. of patients 60 46 32 12
Table 3. Risk factors for UTIs in 60 patients.
Irritable bowel syndrome 5
Constipation 26
UTI 24–48 hours after
intercourse
24
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Porru et al. 211
suggested, such as intravaginal estriol, oral cranberry juice
or lactobacilli vaginal suppositories.10-12
E. coli strains adhere to the normally sterile human
urothelium using type 1 pili.13 It has been observed that,
initially, invasion of bladder superficial cells provides
uropathogenic E. coli with a protective, but transient, envi-
ronment in which the bacteria can replicate.14 Subsequently,
bacteria that manage to avoid rapid clearance from the uri-
nary tract can invade the underlying epithelium,15 where
they can establish a more stable bacterial reservoir. This
reservoir can persist for several weeks in a quiescent state,
seemingly undetected by immune surveillance mechanisms
and protected from antibiotics,16 possibly by virtue of the
permeability barrier maintained by the bladder epithelium.
Intracellular uropathogenic E. coli appear to be better pro-
tected from a number of antibiotics, including cefuroxime,
gentamicin, and trimethoprim-sulfamethoxazole.17-19
The chemical structure of D-mannose causes it to
adhere to E. coli bacteria, perhaps even more tenaciously
than E. coli adheres to human cells. Although the mecha-
nism of action is complicated, we could hypothesize that if
enough D-mannose is present in the urine, it may bind to
the bacteria and prevent them from attaching to the urinary
tract lining.20
Our trial compares two different treatment methods for
addressing the issue of rUTIs in the female population,
usually non-complicated UTIs, over a similar time-frame
of 6 months. We randomly compared the results of
D-mannose with antibiotics; our experience shows that
D-mannose represents a useful choice to address the prob-
lem of treating acute UTIs and also preventing rUTIs. The
justification for not performing a placebo-controlled cross-
over trial is that an acute UTI may result in severe clinical
symptoms including pain, which may be addressed by one
300
250
200
150
100
50
0
mean_time to_recurrence
AB _MANNOSE
p < 0.0001
Means (error bars: 95% CI for mean)
Figure 2. Time to recurrence in 60 female patients with
recurrent UTIs with antibiotic treatment: 52.7 days (SD: 11.2),
and with treatment with D-mannose for 24 weeks: 200 days
(SD: 50.7). All differences were statistically significant
(p < 0.001).
Means (error bars: 95% CI for mean)
10
8
6
4
2
0
-2
-4
p < 0.001
Vas
pain
Vas
pain_mann
Vas
urg
Vas
urg_mann
freq_24h freq_mann diff_pain diff_vas
urg
diff_freq
p < 0.001
p < 0.001
Figure 3. VAS pain, VAS urgency and 24-hour frequency with antibiotic treatment and during 24-week treatment with oral
D-mannose. Mean VAS pain from 4.4 (SD: 1.1) to 2.2 (SD: 0.5). Mean VAS urgency score from 4.6 (SD: 1.1) to 2.6 (SD: 0.7). Mean
number of voidings from 7.1 (SD: 1.7) to 4.7. All differences were statistically significant (p < 0.001).
by guest on October 13, 2015uro.sagepub.comDownloaded from
212 Journal of Clinical Urology 7(3)
the two treatment methods chosen. There are no compara-
ble studies with the same characteristics using D-mannose;
when examining previous results21-23 we should question
whether long-term antibiotic prophylaxis has real advan-
tages over a prolonged regimen with D-mannose, possibly
promoting further representative studies.
As control group we thought that a continuous daily
prophylactic antibiotic for 6 months, more commonly
used,21 would probably “sterilize” urine by eliminating
microorganisms; however, its continuous and prolonged
use would probably also reduce normal vaginal and intes-
tinal bacterial flora, facilitating new UTI recurrences in
patients at risk.24 Therefore a weekly intermittent adminis-
tration of trimethoprim/sulfamethoxazole was chosen in
the control group, based on previous experience;25 limited
evidence suggests that weekly prophylaxis is better than
monthly prophylaxis.26
Mannose is involved in an extensive series of metabolic
transformations, being incorporated into glycoproteins and
glycolipids or formed into fructose that is then incorpo-
rated into glycoproteins. The primary source of mannose is
glucose. Mannose occurs as the free sugar in peaches,
apples, and oranges but is absorbed from the gastrointesti-
nal tract of rats at only about 12% of the rate of glucose.
Our data reveal that D-mannose provides both preven-
tative and therapeutic effects, and we think its properties
can be greatly improved. We know that mannose has no
bactericidal properties, and it might well be that the dosage
and duration of therapy have to be individualized accord-
ing to bacterial growth and replication speed in the bladder
and urinary tract. It has been described that the majority of
ingested mannose works by binding to bacteria concen-
trated in infected urine, and perpetuating infection, by
binding to the mannose receptors of urothelial bladder
cells.5 This mechanism is the one involved in most cases of
recurrences of UTIs.
In most cases recurrences are wrongly regarded as re-
infections: it is likely that the clinical results of d man-
nose are obtained with the elimination of progressive
bacterial loads in urine, “alive” albeit inactivated,
motionless, and devoid of pathogenic potential due to
mannose linked to them.18,19 This is the main reason for
performing a cross-over trial with a sufficiently long
D-mannose treatment period; a much longer time is
required for D-mannose than for antibiotic treatment in
order to improve its effectiveness and obtain an adequate
infection-free time period. Further studies should clarify
the positive effect of reducing the rate of recurrences of
microorganisms other than E. coli, such as Klebsiella and
Proteus (Table 2), which are not known to act by means
of pili on urothelial tissues.
No significant side effects limiting long-term consump-
tion of mannose have been reported. D-mannose has been
shown to reduce bacteria in rats in a dose-dependent manner.
Basic microbiological data from in vitro experiments are
lacking. However, D-mannose was found to significantly
reduce bacteria in 1 day,23,27,28 and in a murine cystitis model
the potential of ligand-based design of antagonists of UTIs is
determined by structural mimicry of natural epitopes, and
extends into blocking of bacterial invasion, intracellular
growth and capacity to fluxing and of recurrence of the
infection.23
Conclusions
In our study oral D-mannose appeared to be a safe and
promising treatment choice for acute and recurrent UTIs
in adult women, which represent a significant burden on
their sexual life. This was the first experience in the
clinical setting, the previous data coming from animal
studies. A statistically significant difference was seen in
the proportion of women remaining infection free dur-
ing an average course of 24-week treatment, both for
treatment of acute episodes and as a safe, preventative
therapy of UTI recurrences, compared with targeted
antibiotic treatment.
Future research and clinical studies are needed in a
wider population to establish and confirm D-mannose as a
practical, safe, and effective therapy.
Conflict of interest
None declared.
Funding
This research received no specific grant from any funding agency
in the public, commercial, or not-for-profit sectors.
Note
1. ClinicalTrials.gov Identifier: NCT01808755.
https://register.clinicaltrials.gov/prs/app/action/SelectProto
col?sid=S00043DV&selectaction=Edit&uid=U0001954&t
s=5&cx=ht023
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... In total, 416 studies were retrieved in the search and eight were deemed eligible for inclusion according to our predefined search criteria. Four studies were randomised controlled trials (RCTs) [3][4][5][6], two were prospective cohort studies [7,8], and two were laboratory studies [9,10] (Table 1 and Supplementary Fig. 1). Outcomes for the six clinical studies were recorded for a total of 695 individuals with a mean age of 46 yr (range 42-50) [3][4][5][6][7][8]. ...
... Four studies were randomised controlled trials (RCTs) [3][4][5][6], two were prospective cohort studies [7,8], and two were laboratory studies [9,10] (Table 1 and Supplementary Fig. 1). Outcomes for the six clinical studies were recorded for a total of 695 individuals with a mean age of 46 yr (range 42-50) [3][4][5][6][7][8]. Three studies included only women [3,4,6]. ...
... Outcomes for the six clinical studies were recorded for a total of 695 individuals with a mean age of 46 yr (range 42-50) [3][4][5][6][7][8]. Three studies included only women [3,4,6]. Overall, 292 patients received D-mannose (Table 1 and Supplementary Table 1) [3][4][5][6][7][8]. ...
Article
The inexorable rise of antimicrobial resistance reinforces the need for alternative approaches to both treat and prevent urinary tract infections (UTIs). A potential approach is administration of D-mannose, an inert monosaccharide that is metabolised and excreted in urine and acts by inhibiting bacterial adhesion to the urothelium. We performed a systematic review to assess the effect of D-mannose in the prevention of recurrent UTIs. Of the eight studies reporting on D-mannose in this context, six were clinical and included 695 individuals. Three studies reported that time to UTI recurrence was longer with D-mannose. D-Mannose improved quality of life and significantly reduced recurrent UTIs in both catheter and non-catheter users. D-Mannose was effective in reducing the incidence of recurrent UTIs and prolonging UTI-free periods, which consequently increased quality of life. Patient summary D-Mannose is a sugar that seems to reduce the incidence of recurrent urinary tract infections and associated bothersome symptoms. It also leads to a longer duration between episodes of recurrences and consequently improves patient quality of life. D-Mannose can be used as a supplementary or alternate treatment for recurrent urinary tract infections.
... It exists in certain fruits such as cranberries, apples, and blueberries. D-mannose has been used as a treatment for urinary tract infections due to its antiadhesive effect against bacteria (12,13). Importantly, D-mannose also has antiinflammatory properties (14)(15)(16)(17)(18). ...
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Inflammation drives the pathology of many neurological diseases. d -mannose has been found to exert an antiinflammatory effect in peripheral diseases, but its effects on neuroinflammation and inflammatory cells in the central nervous system have not been studied. We aimed to determine the effects of d -mannose on key macrophage/microglial functions—oxidative stress and phagocytosis. In murine experimental autoimmune encephalomyelitis (EAE), we found d -mannose improved EAE symptoms compared to phosphate-buffered saline (PBS)-control mice, while other monosaccharides did not. Multiagent molecular MRI performed to assess oxidative stress (targeting myeloperoxidase [MPO] using MPO-bis-5-hydroxytryptamide diethylenetriaminepentaacetate gadolinium [Gd]) and phagocytosis (using cross-linked iron oxide [CLIO] nanoparticles) in vivo revealed that d -mannose–treated mice had smaller total MPO-Gd ⁺ areas than those of PBS-control mice, consistent with decreased MPO-mediated oxidative stress. Interestingly, d -mannose–treated mice exhibited markedly smaller CLIO ⁺ areas and much less T2 shortening effect in the CLIO ⁺ lesions compared to PBS-control mice, revealing that d -mannose partially blocked phagocytosis. In vitro experiments with different monosaccharides further confirmed that only d -mannose treatment blocked macrophage phagocytosis in a dose-dependent manner. As phagocytosis of myelin debris has been known to increase inflammation, decreasing phagocytosis could result in decreased activation of proinflammatory macrophages. Indeed, compared to PBS-control EAE mice, d -mannose–treated EAE mice exhibited significantly fewer infiltrating macrophages/activated microglia, among which proinflammatory macrophages/microglia were greatly reduced while antiinflammatory macrophages/microglia increased. By uncovering that d -mannose diminishes the proinflammatory response and boosts the antiinflammatory response, our findings suggest that d -mannose, an over-the-counter supplement with a high safety profile, may be a low-cost treatment option for neuroinflammatory diseases such as multiple sclerosis.
... Uropathogenic E. coli (UPEC) causes 80-90% of community-acquired UTIs, 30-50% of nosocomially-acquired UTIs and most recurring UTIs [1,2]. Several small clinical trials consistently indicate that D-mannose (mannose) supplementation reduces the severity and frequency of UTIs [3][4][5][6][7][8][9]. The rationale for mannose therapy is that uropathogenic bacteria bind to mannosecontaining glycolipids and glycoproteins on the bladder epithelium [10]. ...
Article
Aim: Urinary tract infections (UTIs) are increasingly antibiotic resistant, and alternate or adjunct therapies are urgently needed. Several studies suggest that D-mannose ingestion and a hypothesized increase in urinary D-mannose reduce UTI frequency. Our goal was to develop a reliable assay for urinary D-mannose, which is needed to assess the effects of supplemental D-mannose on urinary D-mannose and UTIs. Results: We developed an enzymatic assay for D-mannose in urine. Hexoses in urine were phosphorylated, sequentially isomerized and oxidized, and the increases in reduced NADPH were measured in a spectrophotometer. Urinary mannose from ten volunteers was well above the detection limit and ranged from 8 to 700 μM. Conclusion: A rapid, reliable, and sensitive assay was developed, readily detected urinary D-mannose, and is adaptable to high-throughput analysis. If urinary D-mannose is shown to correlate with susceptibility to UTIs, then the assay could assess susceptibility to UTIs and direct mannose therapy.
... 3,4 Interfering with this binding has been pursued as a new mode of antibacterial therapy, mainly due to the slow selective pressure exerted by antiadhesive agents. 5,6 Inhibition of lectin−carbohydrate binding by glyco-derived compounds has been met with promising clinical success in human urinary 7,8 and respiratory 9,10 infections, albeit hampered by the weak affinity of lectins for carbohydrates (typically in the milli-to micromolar range). Approaches to design efficient lectin inhibitors have explored two main directions: presentation of carbohydrate epitopes on multivalent scaffolds (glycodendrimers, 11 glycopeptides, 12,13 glycoclusters, 14,15 and glycofullerenes 16 ) and design of glycomimetics, compounds combining carbohydrate character with functional groups able to form specific binding interactions or provide avenues for further optimization. ...
Article
Bacterial adhesion to human epithelia via lectins constitutes a therapeutic opportunity to prevent infection. Specifically, BambL (the lectin from Burkholderia ambifaria) is implicated in cystic fibrosis, where lectin-mediated bacterial adhesion to fucosylated lung epithelia is suspected to play an important role. We have employed structure-based virtual screening to identify inhibitors of BambL-saccharide interaction with potential therapeutic value. In order to enable such discovery, a virtual screening protocol has been iteratively developed via 194 retrospective screening protocols against four bacterial lectins (BambL, BC2L-A, FimH and LecA) with known ligands. Specific attention was given to the rigorous evaluation of retrospective screening, including calculation of analytical errors for enrichment metrics. The developed virtual screening workflow used crystallographic constraints, pharmacophore filters, and a final manual selection step. The protocol was applied to BambL, predicting 15 active compounds from virtual libraries of approximately 7 million compounds. Experimental validation using fluorescence polarization confirmed micromolar inhibitory activity for two compounds, which were further characterized by isothermal titration calorimetry and surface plasmon resonance. Subsequent testing against LecB from Pseudomonas aeruginosa demonstrated binding specificity of one of the hit compounds. This report demonstrates the utility of virtual screening protocols, integrating ligand-based pharmacophore filtering and structure-based constraints, in the search for bacterial lectin inhibitors.
Article
Objectives: d-Mannose is a promising nonantibiotic prophylaxis for recurrent urinary tract infection (rUTI). Recurrent UTI is common in postmenopausal women and may be especially prevalent in those with cystitis cystica (CC) lesions found on cystoscopy. Our objectives were to determine whether CC lesions are associated with a higher UTI incidence rate and whether d-mannose reduces this rate in women with CC. Methods: This is a retrospective cohort study of patients with rUTI who underwent cystoscopy at our institution (from which CC status was identified) and who were treated with d-mannose as a single agent for UTI prophylaxis. Participants were required to have at least 1 year of follow-up for UTIs both before and after d-mannose initiation to allow for a pre-post comparison. Results: Twenty-seven patients were included in the analysis (13 with CC, 14 without CC). Most patients (88.9%) were postmenopausal. Patients with CC had a higher UTI incidence rate than patients without CC (4.69 vs 2.93 UTIs/year before starting d-mannose prophylaxis, P = 0.021). After initiating d-mannose prophylaxis, the UTI incidence rate decreased significantly in patients with CC (rate decrease = 2.23 UTIs/year, P = 0.0028). This decrease was similar in magnitude to that observed in patients without CC (rate decrease = 1.64 UTIs/year, P = 0.0007; P interaction = 0.58). Conclusions: Patients with rUTI with CC had more frequent UTI episodes than patients without CC. Patients in both groups had fewer UTI episodes after beginning d-mannose prophylaxis. These findings add to the body of literature supporting d-mannose for the prevention of rUTI in women, including those with CC.
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The results of several studies reveal that antibiotics may promote treatment resistance by causing alterations in the intestinal flora. The development of a gut reservoir of resistant bacteria promotes the development of UTIs through autoinfection. This review aims to address clinical reliability, efficacy and safety of long-term treatment with oral D mannose for the prevention of Recurrent Urinary Tract Infections (RUTI) in females. A comprehensive MEDLINE, Embase, Scopus and Cochrane search was performed for English language reports published before December 2018 using the term “recurrent urinary tract infections and D mannose” was carried out. We searched Medline, Embase, Scopus and the Cochrane Register of Controlled Trials from January 2010 to December 2018. Eligible studies did not include non-oral therapy, local (vaginal) treatment in women with recurrent UTIs. We identified eligible original articles. A few limitations of the review are the heterogeneity of the available studies, their different rational and aim, the assumption of D mannose for prophylaxis or treatment of recurrent UTIs. Oral D mannose performs well in the prevention of UTIs recurrences, significant improvement of urinary symptoms was observed, the disease- free time was longer in the groups of patients under prophylaxis with D mannose in comparison with control groups (no treatment, antibiotic prophylaxis, prophylaxis with Proanthocyanidin (PAC) etc. The review has limitations, as the studies are heterogeneous, the meta-analysis requires classifications that can also be arbitrary. Furthermore, single-arm studies are not included. Some of the authors found this evidence inconclusive, which results as a limitation of the study. D mannose prolonged the recurrence-free interval of recurrent UTIs, thus reducing the prolonged or cyclical use of antibiotics, improving clinical symptoms, with a significant difference between treatment and control groups (no treatment, antibiotic prophylaxis, prophylaxis with Proanthocyanidin). However, most clinical trials used an association of different substances commingled with D mannose, dosages and regimens of D mannose were different. For this reason, the evidence of the efficacy of D mannose remains low.
Article
Introduction Treatment of recurrent Urinary tract infections (UTIs) has become challenging because of the dramatic increase in the rates of recurrent infection andof multidrug-resistant (MDR) infections. Areas covered The authors review recurrent UTIs(rUTI) management in women. Expert opinion Continuous or post-coital prophylaxis with low-dose antimicrobials or intermittent self-treatment has all been demonstrated to be effective in managing rUTIs in women. Intravaginal estrogen therapy , shows potential toward preventing rUTI. Oral vaccine Uro-Vaxom seems to reduce the number of UTIs. There is evidence that other therapies (e.g. cranberry, Methenamine hippurate, oral D-mannose) may decrease the number of symptomatic UTIs. The treatment of CRE-UTIs is focused on a colistin backbone. Carbapenems are considered first-line agents for UTIs caused by ESBL, but their use is associated with increased MDR. The usage of non-carbapenem for the treatment of ESBL UTIs is necessary. Cefepime, Piperacillin-Tazobactam, Ceftolozane-Tazobactam, and Ceftazidime-Avibactam are justified options. Oral therapy with Pivmecillinam, Fosfomycin, and Nitrofurantoin can be used against uncomplicated UTIs due to ESBL infection.
Article
OBJECTIVE We performed a systematic review and meta-analysis to determine whether D-mannose reduces urinary tract infection (UTI) recurrence (i.e. cumulative incidence) in adult women with recurrent UTI compared to 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 Clinicaltrial.gov were searched through 4/15/2020. STUDY ELIGIBILITY CRITERIA Systematic review inclusion: randomized controlled trials (RCTs), prospective cohorts, and retrospective cohorts written in English of women ≥18 years old with recurrent UTI 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 (RRs), confidence intervals (CIs), and heterogeneity (I²) 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 RCTs, 1 randomized cross-over trial, and 4 prospective cohort studies. One retrospective cohort study was included. Three studies met meta-analysis eligibility (1 RCT, randomized cross-over trial, prospective cohort). Pooled RR of UTI recurrence comparing D-mannose to placebo was 0.23 (95%CI: 0.14-0.37; I²=0%; D-mannose n=125, placebo n=123). Pooled RR of UTI recurrence comparing D-mannose to preventative antibiotics was 0.39 (95%CI: 0.12-1.25; I²=88%; D-mannose n=163, antibiotics n=163). Adverse side effects were reported in 2 studies assessing D-mannose only (one study (n=10) reported none; the other reported a low incidence (8/103 participants) of diarrhea). Two studies reported compliance, which was high. CONCLUSIONS D-mannose appears protective for recurrent UTI (versus 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.
Article
Many women will experience one or more urinary tract infection (UTI) during their life. The most unfortunate will have many. Men presenting with infections, and women with recurrent episodes, require further investigation. A diagnosis of a UTI is often based on a typical spectrum of symptoms, with confirmatory urine cultures lagging a few days behind. Unfortunately, symptoms of a UTI may not be typical, and other conditions can manifest similarly. Treatment of UTI with antibiotics is usually required, but there is increasing awareness of the need for antimicrobial stewardship to avoid the misuse and overuse of antibiotics, even as patients are increasingly reluctant to take them. Recurrent UTI can cause significant morbidity and disruption to daily activities yet investigations rarely demonstrate a reversible cause. There are a host of different antibiotic and non-antibiotic interventions that aim to lower the risk of further infections. However, these are not reliably effective, bring side effects of their own and are often proposed to this desperate population of patients on the back of weak evidence of efficacy.
Article
Introduction The aim of this systematic review is to compare chemotherapeutic agents commonly used in treating recurrent urinary infection in nonpregnant women by their efficacy, tolerability, adverse effects, and cost employing network meta-analysis. Materials and Methods We used three online databases, i.e., PubMed, ScienceDirect, and Cochrane Central Registry of Clinical Trials. Randomized controlled trials (RCTs) on the use of prophylactic chemotherapeutic agents used in treating nonpregnant women with recurrent urinary tract infections (RUTIs) published between 2002 and 2016 were selected. Only published papers in English were assessed for study quality, and meta-analyses were performed using fixed-effects model with NetMetaXL. Results Six RCTs fulfilled the criteria. When all three variables, i.e., efficacy, adverse effects and cost were considered, nitrofurantoin 50 mg once daily for 6 months appears to rank high for prophylaxis against RUTI. When efficacy was the only factor, fosfomycin had the highest superiority compared to D-mannose, nitrofurantoin, estriol, trimethoprim–sulfamethoxazole, and cranberry juice, respectively. However, fosfomycin was also ranked highest by adverse events. When cost alone is considered, nitrofurantoin appeared the most cost-effective agent while placed third for efficacy alone. Conclusion Selecting appropriate chemotherapeutic agents for RUTI will need to factor in effectiveness, adverse effects, and cost. While it is difficult to select an ideal drug, evaluation using network analysis may guide choice of medication for best practice.
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Uncomplicated Urinary tract infections are common in adult women across the entire age spectrum, with mean annual incidence of 15% and 10% in those aged 15-39 and 40-79 years, respectively. Urinary tract infection (UTI), with its diverse clinical syndromes and affected host groups, remains one of the most common but widejly misunderstood and challenging infectious diseases encountered in clinical practice. Recurrent urinary tract infections (UTIs) present a significant problem for women and a challenge for the doctors who care for them. The diagnosis of uncomplicated UTI can be achieved best by a thorough assessment of patient symptoms with or without the addition of a urine dipstick test. Treatment should be based on the most recent guidelines, taking into account resistance patterns in the local community. The patient who suffers from recurrent UTIs can be treated safely and effectively with continuous antibiotic prophylaxis, post-coital therapy, or self-initiated treatment. This review article covers the latest trends in the management of recurrent UTI among women. Further research is needed regarding rapid diagnosis of UTI, accurate presumptive identification of patients with resistant pathogens, and development of new antimicrobials for drug-resistant UTI.
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The mannose-binding activity of several isolates of Escherichia coli was monitored by aggregometry with mannan-containing yeast cells. The velocity of yeast cell aggregation was found to correlate with the ability of the organisms to adhere to human epithelial cells. Mannose or its derivatives specifically inhibited or reversed epithelial cell adherence and yeast cell aggregation. Most of the adherent bacteria could be displaced within 30 min from the epithelial cells with methyl alpha-d-mannopyranoside, but not with other sugars tested. Cultures of E. coli were fractionated into nonadherent and adherent populations by adsorption with epithelial cells followed by elution of the adherent bacteria with methyl alpha-d-mannopyranoside. When the methyl alpha-d-mannopyranoside-displaced organisms were washed free of the sugar, they exhibited a high degree of mannose-binding activity and were heavily piliated. In contrast, the nonadherent fraction of organisms lacked detectable mannose-binding activity and were devoid of pili. Our results suggest that the binding activity of a mannose-specific lectin on the surface of E. coli can be quantitated directly on intact organisms, and the observed variations in the amount of mannose-binding activity among human isolates accounts for the variation in adherence of the organisms to mannose residues on epithelial cells.
Article
Objective. —To determine the effect of regular intake of cranberry juice beverage on bacteriuria and pyuria in elderly women.Design. —Randomized, double-blind, placebo-controlled trial.Subjects. —Volunteer sample of 153 elderly women (mean age, 78.5 years).Intervention. —Subjects were randomly assigned to consume 300 mL per day of a commercially available standard cranberry beverage or a specially prepared synthetic placebo drink that was indistinguishable in taste, appearance, and vitamin C content but lacked cranberry content.Outcome Measures. —A baseline urine sample and six clean-voided study urine samples were collected at approximately 1-month intervals and tested quantitatively for bacteriuria and the presence of white blood cells.Results. —Subjects randomized to the cranberry beverage had odds of bacteriuria (defined as organisms numbering ≥105/mL) with pyuria that were only 42% of the odds in the control group (P=.004). Their odds of remaining bacteriuric-pyuric, given that they were bacteriuric-pyuric in the previous month, were only 27% of the odds in the control group (P=.006).Conclusions. —These findings suggest that use of a cranberry beverage reduces the frequency of bacteriuria with pyuria in older women. Prevalent beliefs about the effects of cranberry juice on the urinary tract may have microbiologic justification.(JAMA. 1994;271:751-754)
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Background: Urinary tract infection (UTI) is a common health care problem. Recurrent UTI (RUTI) in healthy non-pregnant women is defined as three or more episodes of UTI during a twelve month period. Long-term antibiotics have been proposed as a prevention strategy for RUTI. Objectives: To determine the efficacy (during and after) and safety of prophylactic antibiotics used to prevent uncomplicated RUTI in adult non-pregnant women. Search strategy: We searched MEDLINE (1966-April 2004), EMBASE (1980-January 2003), Cochrane Central Register of Controlled Trials( in The Cochrane Library Issue 1, 2004) and reference lists of retrieved articles Selection criteria: Any published randomised controlled trial where antibiotics were used as prophylactic therapy in RUTI. Data collection and analysis: Two reviewers independently assessed trial quality and extracted data. Statistical analyses were performed using the random effects model and the results expressed as relative risk (RR) with 95% confidence intervals (CI). Main results: Nineteen studies involving 1120 women were eligible for inclusion. Antibiotic versus antibiotic (10 trials, 430 women): During active prophylaxis the rate range of microbiological recurrence patient-year (MRPY) was 0 to 0.9 person-year in the antibiotic group against 0.8 to 3.6 with placebo. The RR of having one microbiological recurrence (MR) was 0.21 (95% CI 0.13 to 0.34), favouring antibiotic and the NNT was 1.85. For clinical recurrences (CRPY) the RR was 0.15 (95% CI 0.08 to 0.28). The NNT was 1.85. The RR of having one MR after prophylaxis was 0.82 (95% CI 0.44 to 1.53). The RR for severe side effects was 1.58 (95% CI 0.47 to 5.28) and for other side effects the RR was 1.78 (CI 1.06 to 3.00) favouring placebo. Side effects included vaginal and oral candidiasis and gastrointestinal symptoms. Antibiotic versus antibiotic (eight trials, 513 women): These trials were not pooled. Weekly pefloxacin was more effective than monthly. The RR for MR was 0.31(95% CI 0.19 to 0.52). There was no significant difference in MR between continuous daily and postcoital ciprofloxacin. Reviewers' conclusions: Continuous antibiotic prophylaxis for 6-12 months reduced the rate of UTI during prophylaxis when compared to placebo. After prophylaxis two studies showed nodifference between groups. There were more adverse events in the antibiotic group. One RCT compared postcoital versus continuous daily ciprofloxacin and found no significant difference in rates of UTIs, suggesting that postcoital treatment could be offered to woman who have UTI associated with sexual intercourse.
Article
To determine if antibiotics used in the treatment of urinary infections alter introital gramnegative carriage after termination of therapy we analyzed 254 cultures obtained between episodes of bacteriuria in 14 women with recurrent urinary infections. Cultures obtained within the first 30 days after termination of therapy were compared to all subsequent cultures. Introital carriage in women with recurrent urinary infections was compared to 416 consecutive introital cultures from 31 control women resistant to bacteriuria. In women with recurrent bacteriuria introital colonization patterns were similar in incidence and density during the immediate post-treatment period compared to later cultures. Four volunteer controls received tetracycline for 10 days. There was no difference in introital carriage of enterobacteria before during or after tetracycline therapy. Consecutive cultures also confirmed a higher incidence and greater density of vaginal carriage of enterobacteria in patients when compared to similar cultures from women who never had a urinary infection.
Article
Fourteen patients with chronic or multiple recurrences of infection of the urinary tract have self-administered a single oral dose of one of five antibiotics after sexual intercourse for periods of 19 to 111 months for a total of 761 months. Infections did not occur among 15 of 22 treatment periods. A total of 19 infections occurred while the patients were taking prophylactic medication, significantly less than the total of 90 infections recorded during the 705 months when these patients did not take prophylactic doses of antibiotics. Patients taking nitrofurantoin, a cephalosporin, or nalidixic acid had a significant reduction in the proportion of specimens of urine containing any Gram-negative bacteria. Serious toxic effects were not encountered.
Article
Long-term, low-dose antimicrobial prophylaxis is effective for the prevention of acute uncomplicated urinary tract infection in women. Selected new antimicrobials should be assessed to determine their efficacy for this clinical use. Recommended guidelines for future studies of prophylactic therapy need to address several issues. The study population must be limited to women with recurrent symptomatic uncomplicated urinary tract infection. Antimicrobials studied should be excreted in the urine, with an in vitro spectrum that includes the common uropathogens. An extended half-life may be beneficial. Monitoring during the study should include monthly urine cultures and vaginal, periurethral and rectal colonization studies. The primary outcome measurement is symptomatic urinary tract infection. Secondary outcomes would include asymptomatic bacteriuria, adverse antimicrobial effects, colonization with potential uropathogens, and development of resistance. The comparative regimen should be one of the current standard regimens, trimethoprim/sulphamethoxazole, nitrofurantoin, or trimethoprim.
Article
Forty-one adult women with acute lower urinary tract infections (UTI) were randomly treated for three days with norfloxacin or trimethoprim/sulfamethoxazole (TMP/SMX). Infection was eradicated in 100% of norfloxacin-treated patients and in 95% of TMP/SMX-treated patients. UTI recurred in 29% of patients treated with norfloxacin and in 41% of those treated with TMP/SMX. Post-therapy vaginal administration of lactobacillus suppositories resulted in a recurrence rate of UTI of only 21%, while in patients given sterilized skim-milk suppositories the recurrence rate was 47%. This study indicates that lactobacillus vaginal suppositories are safe and may be effective in reducing the recurrence of UTI following antimicrobial therapy.