Efficacy of Fosfomycin-Trometamol in Urinary Tract Infection Prophylaxis After Kidney Transplantation
Condition: Urinary Tract Infection; Asymptomatic Bacteriuria; Allograft Rejection; Microbiologic Resistance; Hospitalization
MeSH terms: Infections; Communicable Diseases; Urinary Tract Infections; Bacteriuria
Study type: Interventional
Phase: Phase 4

Summary: 
      Urinary tract infections (UTI) are the most common complications after kidney
      transplantation. Most series have reported incidence between 20 to 50% during the first year.
      In the most recent report from our center the incidence was 36.6% during the first 6 months
      after transplantation.

      The clinical consequence in the graft survival and the association with immunological
      rejection has not been well defined. Nevertheless, the association of UTI with high rate of
      hospitalization and their costs are widely recognized. There is paucity of trials, specially
      randomized and controlled, comparing antibiotic prophylaxis in this group of patients. In a
      recently published metaanalysis Green et al. (Transpl Infect Dis. 2011 Oct;13(5):441-7) found
      only 6 clinical trials well designed, the conclusion was that antibiotic prophylaxis reduced
      the incidence of UTI and the risk of sepsis. Based in this information, the KDIGO guidelines
      in transplantation recommend the prophylaxis for UTI with sulfamethoxazole-trimethoprim
      (SMT). Nevertheless, the rate of bacterial resistance to SMT has been reported above 50% in
      almost all the series.

      Fosfomycin-trometamol (FT) is a wall antibiotic (piruvil-tranferase inhibitor) that has shown
      a good bioavailability, especially in the urinary tract. It has shown a wide antibacterial
      spectrum, but the important target seems to be enteric bacilli particularly Escherichia coli
      (the most prevalent cause of UTI). FT has also shown a very good activity against E. coli
      producer of Extended Spectrum Betalactamases. Recently, the rate of these multi-drug
      resistant bacteria has increased in our center as evidence of worldwide distribution. In
      addition, the rate of FT resistance has been stable during the last years (<3%). This
      phenomenon could be explained because of the properties of this antibiotic, the most
      important one seems to be related with the unique mechanism of action and the lack to
      propagate the mechanisms of resistance at least in E. coli. There is only one clinical trial
      (randomized and controlled), which compared FT with placebo in UTI prophylaxis; 317 women
      with recurrent UTI (three by year) were included. They found rates of 0.14 and 2.9
      episodes/patient/year, respectively (p<0.001). Furthermore, there was no FT resistance during
      the follow up.

      Our hypothesis is that in the first six months after kidney transplantation, UTI prophylaxis
      with FT will show greater efficacy in comparison with SMT. Considering the incidence of UTI
      in our center (36.6%) and the rate of UTI in the unique trial of prophylaxis with FT (14%),
      65 patients will be needed by group of treatment to demonstrate a difference of 22% in the
      incidence of UTI, with a power of 80% and confidence level of 95%. The primary outcome is the
      incidence and rate of UTI during the first six months after kidney transplantation. The
      secondary outcomes are, the hospitalization rate, antibiotic resistance rate, rejections and
      titer and number of de novo donor specific antibodies.

      The investigators propose a randomized, double blind, placebo controlled trial to compare FT
      with SMT in the efficacy and safety to prevent UTI during the first six months after kidney
      transplantation. The investigators will include patients from two tertiary-care transplant
      centers. Recruiting and the randomization will be carried out separately by center and gender
      (because female patients have a greater risk of UTI). The medical visits will be scheduled
      monthly and include general laboratory, urine culture and information gathering about
      antibiotic side effects as well as adherence. Rejection rate and the number and titers of de
      novo donor specific antibodies (secondary outcome) will be obtained according to the standard
      of care of the institutional kidney transplantation follow up. These include kidney biopsy at
      days 0 and 90 after transplantation, as well as determination of donor specific antibodies
      after sixth months of follow up. Graft biopsy is also performed whenever graft dysfunction
      exists in the absence of an identifiable cause (infection, urinary graft obstruction).
    


Intervention name(s): Fosfomycin-Trometamol; Sulfamethoxazole trimethoprim
Intervention type(s): Drug; Drug
Intervention MeSH terms: Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination; Sulfamethoxazole; Fosfomycin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention