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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).
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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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