D Mannose in Recurrent Urinary Tract Infections
Condition: Recurrent Urinary Tract Infection
MeSH terms: Infections; Communicable Diseases; Urinary Tract Infections; Recurrence
Study type: Interventional
Phase: Phase 3

Summary: 
      Background- In recurrent urinary tract infections (RUTIs) usual prophylactic antibiotic
      regimes do not change the long term risk of recurrence.

      Objective- D-Mannose is a sugar, it sticks to E. coli bacteria, the aim of the study was to
      evaluate its efficacy in the treatment and prophylaxis of recurrent UTIs.

      Design, setting and participants- : In this crossover trial female patient were eligible for
      the study if they had recurrent UTIs, that is three ore more episodes during the preceding 12
      months. Suitable patients were randomly assigned to antibiotic treatment with
      trimethoprim/sulfamethoxazole or to a regimen of oral D Mannose for 24 weeks, and received
      the other intervention in the second phase of the study.

      Outcome measurements and statistical analysis- The time to recurrence of UTI, bladder pain
      (VAS p) and urinary urgency (VAS u) were evaluated at the end of antibiotic therapy and at
      the and of 24 weeks fo D Mannose. 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 analyze differences of time of recurrence, VAS pain, Vas urgency and
      number of voidings between treatment. Data analysis was performed with STATA statistical
      package (release 11,1, 2010, Stata Corporation, College Station, Texas, USA).
    

Detailed description: 
      INTRODUCTION Urinary tract infections (UTIs) are among the most common infectious diseases,
      with a substantial financial burden to society. In Europe data on the presence of various
      types of UTIs indicate a high impact on quality of life of people affected, it is important
      the impact of urinary tract infections on the economy in general and on the health system in
      particular. In the U.S. urinary tract infections account for more than 7 million doctor
      visits each year, including more than 2 million visits for cystitis. The bacterium E. coli,
      which is the source of 90% of urinary tract infections, shows an incredible ability to
      survive in the human body, and is able to change rapidly to survive antibiotics. An infection
      of the urinary tract must be stopped before it begins to migrate to the kidneys, where it can
      cause serious infections. Women with frequent reinfections have a rate of 0.13 to 0.22 UTIs
      per month (1.6 to 2.6 infections per year). For premenopausal, healthy, and active females,
      recurrent UTIs are a major healthcare concern. Recurrent urinary tract infection (RUTI) is
      defined as three episodes of urinary tract infection (UTI) with 3 positive urine cultures in
      the previous 12 months or two episodes in the last six months. The usual present strategies
      employing a prophylactic antibiotic regime to prevent recurrent UTIs include long-term
      low-dose prophylactic antimicrobial treatment or postcoital antibiotic treatment. However, 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 pre-treatment rates when
      prophylaxis is stopped . Long-term antibiotics do not appear to positively affect the
      patient's basic susceptibility to infections. The cell wall of E. coli bacteria has tiny
      finger-like projections that contain complex molecules called lectins on their surface. These
      lectins act as a cellular glue that binds the bacteria to the bladder wall so they cannot be
      easily rinsed out by urination . In this pilot study the aim was to evaluate if oral D
      Mannose could be used as a safe and effective treatment and as a prophylactic measure for
      recurrent UTIs in adult women.

      PATIENTS AND METHODS Suitable female patients with recurrent urinary tract infections who
      were visited at the outpatient Clinic of our Urology Department were eligible for study. The
      work has been conducted in accordance with the principles of the Declaration of Helsinki of
      World Medical Association. Patients were enrolled in the study after treatment for the most
      recent urinary tract infection if they had positive urinary cultures at that time.

      Each participant entering the trial was assigned to one of the following treatments in a
      random sequence:

        1. A regimen of five-day antibiotic therapy with trimethoprim/sulfamethoxazole 160 mg/800
           mg twice a day. Then 1 week of antibiotic every 4 weeks for the following 23 weeks

        2. A regimen of oral D Mannose 1 gr. 3 times a day, every 8 hours for 2 weeks, and
           subsequently 1 gr. twice a day for 22 weeks. D-Mannose has the best activity when 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 gr. b.i.d. as
           alkalinizing agents if pH was <7.

      Patients were randomly assigned to antibiotic treatment with trimethoprim/sulfamethoxazole or
      to a regimen of oral D Mannose for 24 weeks, and received the other intervention in the
      second phase of the study.

      VAS score for bladder pain (VASp) and for urgency (VASu) was evaluated before starting D
      Mannose and at 24 weeks. The 24 hour number of voidings was obtained filling a voiding diary
      before and at the end of treatment with D Mannose. Cure was defined as the resolution of
      symptoms and no post-treatment bacteriuria at the 24 week follow-up visit. Cure with
      recurrence was defined as having resolution of symptoms with negative cultures at 12 week
      followed by significant UTI with bacteriuria before 24 weeks. Failure was defined as having
      persistent symptoms and significant bacteriuria before 24 weeks. The cure rate was determined
      for patients who met infection criteria, returned for the follow-up visits and had been
      treated with an antimicrobial for recurrent urinary tract infection occurring twice or more
      times during the 6 months preceding the 24 weeks course of daily oral D Mannose. The time to
      recurrence of UTI, VAS pain and VAS urgency were evaluated at the end of antibiotic therapy
      and at the end of 24 week treatment with oral D Mannose. 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 analyze differences of
      time of recurrence, VAS pain, Vas urgency and number of voidings between treatment. Data
      analysis was performed with STATA statistical package (release 11,1, 2010, Stata Corporation,
      College Station, Texas, USA).

      DISCUSSION- The approach in the management of recurrent urinary tract infections is usually
      to treat adequately an episode of infection and after the completion should document complete
      eradication with a urine culture; if infection reoccurs or persists then imaging is required.
      In the management of recurrent UTIs in women it is a common practice to fight the resistance
      of the bacterium E. coli by varying the type of antibiotics, or increasing the dose and
      duration of therapy. However, in doing so the bacteria become even more resistant to broad
      spectrum antibiotics. Moreover, the resistance of the bacterium would not increase if the
      infection was due to a new E. coli contamination of the faeces or to sexual contact. What
      actually appears to occur is the survival of a part of the old colony of bacteria in the
      urinary tract, they remain latent and are reactivated by various favourable conditions, the
      relentless recurrences are therefore not considered as reinfection. It could be learnt a lot
      from patients and from research done on the causes of repeated urinary tract infections,
      especially due to the bacterium E. coli. Uropathogenic Escherichia coli (UPEC) strains may
      contain virulence factors that allow the bacteria to penetrate into the transitional cells
      and form quiescent intracellular reservoirs (QIRs). Establishment of QIRs throughout the
      underlying transitional epithelium may predispose an individual to an increased likelihood of
      recurrence and may account for some of the frequent same-strain recurrences that are seen
      clinically despite appropriate antibiotic therapy. A difficult aspect of treating urinary
      tract infections in women is the high likelihood of recurrence. In a series of trials a group
      of susceptible women averaged 2.6 infections per patient per year despite the apparent
      effectiveness of short-term therapy. While long-term prophylaxis was relatively effective in
      that series, resistance to trimethoprim-sulfamethoxazole by urinary pathogens increased to
      19% in a 5-year period. Although there is debate regarding the duration of antibiotic
      therapy, emergence of drug-resistant organisms has to be considered with prolonged antibiotic
      use, even in healthy women with uncomplicated UTIs. A number of triggers lead to the
      reactivation of dormant E.coli already in the bladder, or the release of E.coli pods from
      behind biofilms in the bladder. When a first UTI is caused by E. coli, the risk of a second
      infection within 6 months is greater than when a first infection is cause by another
      uropathogen. Although E. coli was the most frequently isolated microorganism in our group of
      patients, the limited number of patients studied could not confirm this assumption. The
      chemical structure of D-Mannose causes it to stick to E. coli bacteria, maybe even more
      tenaciously than E. coli adheres to human cells. Although the mechanism of how it works is
      complicated, theoretically, if enough D-mannose is present in the urine, it binds to the
      bacteria and prevents them from attaching to the urinary tract lining. Our clinical
      experience shows that D Mannose represents a useful choice to address the problem of
      recurrent UTIs. The time required to develop a new infection, or for the re-emergence of the
      bacterial reservoir, as can be assumed from new data, is significantly longer with a
      prolonged course of oral D Mannose than with antibiotic treatment, even when these are used
      for long periods at a low dose, or in cycles. We actually know mannose has no bactericidal
      properties, and it might well be that the dosage and duration of therapy have to be
      individualized according to bacterial growth and replication speed in the bladder and urinary
      tract. The major part of mannose ingested is eliminated with urine and works by binding to
      bacteria concentrated in infected urine and attempting to perpetuate infection by binding to
      mannose receptors of urothelial bladder cells, this mechanism being the one involved in most
      cases of recurrences. In most cases recurrences are wrongly regarded as re-infections: it is
      highly likely that bactericidal molecules not possessing the same properties cannot produce
      the same consistent effect, that is the elimination of more and more loads of bacteria with
      urine, "alive" albeit inactivated, motionless, devoid of pathogenic potential due to mannose
      linked to them.
    

Intervention name(s): D Mannose; trimethoprim/sulfamethoxazole
Intervention type(s): Dietary Supplement; Drug
Intervention description(s): 1 gr. every 8 hours; one cp b.i.d. for 5 days. Then one week of antibiotic every 4 weeks for the following 23 weeks
Other intervention name(s): sugar; trimethoprim/sulfamethoxazole 160 mg/800 mg
Intervention MeSH terms: Trimethoprim; Sulfamethoxazole
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: recurrent urinary tract infections; D Mannose; cystitis; antibiotic treatment