<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03235947</url>
  </required_header>
  <id_info>
    <org_study_id>1649</org_study_id>
    <nct_id>NCT03235947</nct_id>
  </id_info>
  <brief_title>Perioperative Fosfomycin in the Prophylaxis of Urinary Tract Infection in Kidney Transplant Recipients</brief_title>
  <acronym>PERIFOS</acronym>
  <official_title>Perioperative Disodium Fosfomycin in the Prophylaxis of Urinary Tract Infection in Kidney Transplant Recipients. Controlled Clinical Trial (PERIFOS Trial)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Laboratorios Senosiain, S.A. de C.V.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      A clinical controlled, randomized and double blind trial that included adult patients (≥18&#xD;
      years) receiving kidney transplantation (KT) at the INCMNSZ.&#xD;
&#xD;
      The intervention group will receive disodium fosfomycin 4 g intravenously in three moments:&#xD;
      preoperative of transplant surgery, prior to removal of the urinary catheter and finally&#xD;
      prior to removal of ureteral catheter. The control group will receive placebo in the same&#xD;
      moments.&#xD;
&#xD;
      Both groups will receive prophylaxis standard for urinary tract infection (UTI), with&#xD;
      trimethoprim/sulfamethoxazole 160/800 mg per day. This prophylaxis will be administered once&#xD;
      the estimated glomerular filtration rate is greater than 30 mL/min/1.73m2.&#xD;
&#xD;
      The primary objective is to compare the average number of episodes of UTI´s and asymptomatic&#xD;
      bacteriuria in both groups after 7 weeks of follow-up. The secondary objectives are to know&#xD;
      the incidence of asymptomatic bacteriuria, the incidence of hospitalizations for IVU, the&#xD;
      days of hospital stay, the pattern of bacterial resistance, the safety of disodium&#xD;
      fosfomycin, and assessment of the function of the graft and rejection rate.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In the context of development UTI in receptors of KT, some microbiological factors have&#xD;
      raised great importance, mainly the antimicrobial drug resistance, which has been reported&#xD;
      for TMP/SMX as high as 60 to 100%. Furthermore, it is also of increasing importance the&#xD;
      recent isolation of multidrug-resistant bacteria, in particular ESBL-producing Escherichia&#xD;
      coli and ampicillin-resistant Enterococcus. This phenomenon increases the rate of&#xD;
      hospitalizations as well as the costs of hospital stay and antibiotic therapy. (1-3) In our&#xD;
      institution, in receptors of KT the rate of TMP/SMX resistance is 89% and ESBL-production&#xD;
      about 32% among E. coli recovered from urine. (4)&#xD;
&#xD;
      Because of the increase in the rate of TMP-SMX resistance, there is a lot of interest to use&#xD;
      other antibiotics for the prevention of UTI among different populations. In this sense,&#xD;
      fosfomycin is an agent with a unique mechanism of action that does not share with other&#xD;
      families of known antibiotics, this characteristic provides advantages to use this antibiotic&#xD;
      alone or, even, synergistically in combination with other antibiotics. Fosfomycin (FOS) is a&#xD;
      wall antibiotic (pyruvyl-transferase inhibitor) that has shown a good bioavailability,&#xD;
      especially in the urinary tract. It has shown a wide antibacterial spectrum, but the&#xD;
      important target seems to be enteric bacilli particularly Escherichia coli (the most&#xD;
      prevalent cause of UTI). FOS has also shown a very good activity against E. coli producer of&#xD;
      Extended Spectrum Betalactamases.&#xD;
&#xD;
      Multiple clinical studies have shown FOS efficacy in the treatment of UTI's and especially in&#xD;
      multiple-drug-resistant bacteria. (5) With regard to its use as a perioperative prophylaxis,&#xD;
      in a systematic review with 8 trials, FOS proved to be effective to prevent health&#xD;
      care-associated UTI's, however only one study showed no benefit. The oral dose regularly used&#xD;
      is FOS 3 g, 3 hours before and 24 hours after the surgical procedure. (6)&#xD;
&#xD;
      Our hypothesis is that in the seven weeks after kidney transplantation, perioperative&#xD;
      prophylaxis with FOS will show greater efficacy in comparison with standard prophylaxis&#xD;
      (TMP/SMX). Considering that the mean number of UTI and BA episodes per patient in the first&#xD;
      seven weeks is 0.8 episodes / patient, if we want to decrease it to 0.4 episodes per patient,&#xD;
      using the means comparison formula will require 40 patients per arm per treatment, this&#xD;
      considering a power of 80% and confidence intervals of 95%. The primary outcome will be to&#xD;
      compare the mean number of episodes of urinary tract infection and asymptomatic bacteriuria&#xD;
      per patient in each treatment arm. Secondary outcomes refer to the development of&#xD;
      UTI-associated sepsis, pyelonephritis, recurrent UTI and asymptomatic bacteriuria. Safety&#xD;
      outcomes included hematological and gastrointestinal side effects, the acute rejection rate,&#xD;
      glomerular filtration rate, graft loss and patient death.&#xD;
&#xD;
      Patients eligible for a kidney transplant will be invited to participate in the study, prior&#xD;
      to renal transplant surgery. They are given an informed consent, which is reviewed and&#xD;
      approved by the ethics and research committees of our institution. The arms of the study are&#xD;
      discussed in detail below. The study followed the Declaration of Helsinki recommendations and&#xD;
      was approved by the Institutional Review Board (Ref: 1649). Randomization was conducted&#xD;
      centrally by stratifying according to gender, with specific software (www.randomization.com).&#xD;
      Patients were assigned to one of two parallel groups in a 1:1 ratio and in blocks of 4.&#xD;
&#xD;
      Subjects will be followed up for 7 weeks from renal transplant surgery. The outcome variables&#xD;
      are defined as follows:&#xD;
&#xD;
        -  Positive urine culture: The isolated germ will be defined depending on international&#xD;
           standards. For enterobacteria and gram positive ≥100,000 colony-forming unit (CFU) / mL.&#xD;
&#xD;
        -  Urinary tract infection: Positive urine culture plus presence of associated signs or&#xD;
           symptoms.&#xD;
&#xD;
        -  Significant Asymptomatic Bacteriuria: Will be identified from isolation ≥100,000 CFU/mL.&#xD;
           In the case of women, the same insulation should be corroborated in a second urine&#xD;
           culture sample.&#xD;
&#xD;
        -  Asymptomatic Bacteriuria not significant: It will be identified from isolation of ≥1000&#xD;
           CFU/mL and will not be given antibiotic treatment.&#xD;
&#xD;
        -  Hospitalization due to UTI: It will be defined as any UTI event that warrants&#xD;
           hospitalization or that, having another reason for hospitalization, develop IVU that&#xD;
           requires intravenous antimicrobial treatment.&#xD;
&#xD;
      The urine cultures will be taken from the first urine in the morning, obtaining the sample of&#xD;
      medium jet with an approximate volume to collect of 25 to 50 mL. Urine samples were processed&#xD;
      within the first hour after obtention.&#xD;
&#xD;
      The sample was inoculated in human blood agar and McConkey agar with a 1 microliter&#xD;
      calibrated loop, and incubated at 35ºC, overnight. The report included the number of CFU. All&#xD;
      clinical isolates were identified with the gram-negative and gram-positive identification&#xD;
      cards by Vitek 2 (BioMérieux, Lyon, France) following the manufacturer´s instructions.&#xD;
      AST-285 Vitek2 cards were used for gram-negative bacilli and the AST-591 Vitek2 card for&#xD;
      gram-positive cocci (BioMérieux, Lyon, France); they were incubated and then interpreted by&#xD;
      an expert in the system (version 7.01) and according to the Clinical &amp; Laboratory Standards&#xD;
      Institute (CLSI) M100-S24 (2014) guideline (20). Susceptibility to fosfomycin was determined&#xD;
      by disk diffusion on cation-supplemented Müeller Hinton agar plates (CLSI, M07-A9); a&#xD;
      bacterial suspension was inoculated in 0.5 mL Mc Farland, and a fosfomycin disk (200&#xD;
      micrograms [mcg]) supplemented with glucose-6-phosphate was used (50 mcg). Interpretation of&#xD;
      inhibition halos in E. coli and Enterococcus faecalis isolates was based on CLSI M100-S24&#xD;
      (2014) criteria. The following were used as controls: E. coli ATCC 25922, E. coli ATCC 35218,&#xD;
      Staphylococcus aureus ATCC 29213 and S. aureus ATCC 43300. Antimicrobial sensitivity to&#xD;
      fosfomycin was determined with the microdilution broth method in E. coli, Klebsiella&#xD;
      pneumoniae and Enterococcus spp. isolates. Müeller Hinton broth supplemented with&#xD;
      glucose-6-phosphate (25 mcg/ml) was used, E. coli ATCC 25922, S. aureus ATCC 29213 and&#xD;
      Pseudomonas aeruginosa ATCC 27853 were included as controls and results were interpreted&#xD;
      according to the CLSI (M07-A10) and European Committee on Antimicrobial Susceptibility&#xD;
      Testing (EUCAST) 2015 criteria (20,21).&#xD;
&#xD;
      Urine culture will be performed in the following situations: 1.- 48 hrs after the removal of&#xD;
      the urinary catheter. 2.- Prior to removal of the ureteral catheter. 3.- At 4 weeks after&#xD;
      renal transplantation. 4.- At 6 weeks after renal transplantation. 5.-In case of urinary&#xD;
      storage symptoms suggestive of UTI or elevated creatinine (If the emergency department&#xD;
      approach requires it). 6.- After antibiotic treatment of urinary tract infection or&#xD;
      significant asymptomatic bacteriuria. In the case of women who have an episode of significant&#xD;
      asymptomatic bacteriuria, this should be corroborated in two consecutive urine cultures.&#xD;
&#xD;
      Subjects will have the following follow-up visits: before ureteral catheter removal (first&#xD;
      visit), 4 weeks of renal transplantation (second visit), 6 weeks (third visit) and one final&#xD;
      visit at week 7.&#xD;
&#xD;
      Both follow-up visits and reports of urine cultures are recorded in the CRFs for each&#xD;
      patient. In the follow-up consultations, adverse events will also be registered, if they are&#xD;
      reported, are notified to the institutional committees and to the regulatory institutions of&#xD;
      the health system of Mexico. An intermediate analysis will be carried out to determine both&#xD;
      the effectiveness and safety of the interventions.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 7, 2016</start_date>
  <completion_date type="Actual">November 6, 2017</completion_date>
  <primary_completion_date type="Actual">November 6, 2017</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>This is a randomized, parallel-group, controlled clinical trial conducted in a single center that will include renal transplant recipients over the age of 18 to assess the efficacy and safety of disodium fosfomycin in the perioperative period of renal transplantation. The intervention group will receive intravenous fosfomycin 4 g disodium three hours prior to: renal transplant surgery, removal of the urinary catheter and withdrawal of the ureteral catheter. The control group will receive placebo at the same time. Both groups will receive standard prophylaxis consisting of trimethoprim / sulfamethoxazole (160/800 mg) orally every 24 hours when the GFR is greater than 30 mL / min / 1.73m2.</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>To compare the efficacy of Fosfomycin-disodium/Trimethoprim-sulfamethoxazole with Placebo/Trimetoprim-sulfamexazol in the prophylaxis of urinary tract infection or significant asymptomatic bacteriuria among kidney transplantation recipients.</measure>
    <time_frame>7-weeks after transplantation</time_frame>
    <description>The primary outcome in this clinical trial is the comparison of the mean number of episodes of urinary tract infection or significant asymptomatic bacteriuria, per patient in both arms of treatment among kidney transplantation recipients during the first seven weeks after surgery.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>The elapsed time period until the first urinary tract infection or asymptomatic bacteriuria developed</measure>
    <time_frame>7-weeks after transplantation</time_frame>
    <description>Refers to the elapsed time period until the first urinary tract infection or asymptomatic bacteriuria developed during the first 7 weeks post-KT</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Incidence of urinary tract infection</measure>
    <time_frame>7-weeks after transplantation</time_frame>
    <description>The number of patients that develope tract urinary infection in the first seven weeks after transplantation in each group, divided by the number of patients allocated in each group at randomization.</description>
  </other_outcome>
  <other_outcome>
    <measure>Incidence of asymptomatic bacteriuria</measure>
    <time_frame>7-weeks after transplantation</time_frame>
    <description>The number of patients that develope asymptomatic bacteriuria in the first seven weeks after transplantation in each group, divided by the number of patients allocated in each group at randomization.</description>
  </other_outcome>
  <other_outcome>
    <measure>Incidence of bacteremia</measure>
    <time_frame>7-weeks after transplantation</time_frame>
    <description>The number of patients that develope bacteremia in the first seven weeks after transplantation in each group, divided by the number of patients allocated in each group at randomization.</description>
  </other_outcome>
  <other_outcome>
    <measure>Incidence of hospitalization for urinary tract infection</measure>
    <time_frame>7-weeks after transplantation</time_frame>
    <description>The number of patients that develope hospitalization for urinary tract infection in the first seven weeks after transplantation in each group, divided by the number of patients allocated in each group at randomization.</description>
  </other_outcome>
  <other_outcome>
    <measure>Incidence of Clostridium difficile infection</measure>
    <time_frame>7-weeks after transplantation</time_frame>
    <description>The number of patients that develope Clostridium difficile infection in the first seven weeks after transplantation in each group, divided by the number of patients allocated in each group at randomization.</description>
  </other_outcome>
  <other_outcome>
    <measure>Incidence of multidrug resistant bacteria colonization</measure>
    <time_frame>7-weeks after transplantation</time_frame>
    <description>The number of patients that develope multidrug resistant bacteria colonization infection in the first seven weeks after transplantation in each group, divided by the number of patients allocated in each group at randomization.</description>
  </other_outcome>
  <other_outcome>
    <measure>Incidence of acute rejection</measure>
    <time_frame>3-months after transplantation</time_frame>
    <description>The number of patients that develope acute rejection in the first seven weeks after transplantation in each group, divided by the number of patients allocated in each group at randomization.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">82</enrollment>
  <condition>Urinary Tract Infection</condition>
  <condition>Asymptomatic Bacteriuria</condition>
  <arm_group>
    <arm_group_label>Fosfomycin disodium</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Fosfomycin disodium 4 g intravenously: 3 hours before kidney transplant surgery, 3 hours before urinary catheter removal and 3 hours prior to ureteral catheter removal.&#xD;
Trimethoprim / Sulfamethoxazole (160/800 mg) 1 tablet orally every 24 hours.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Trimethoprim / Sulfamethoxazole</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Trimethoprim / Sulfamethoxazole (160/800 mg) 1 tablet orally every 24 hours.&#xD;
Intravenous placebo solution at the same time of application of fosfomycin disodium in the experimental arm.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fosfomycin disodium</intervention_name>
    <description>Fosfomycin disodium 4 g intravenously dissolved in 100 mL of normal saline 0.9% three times in the perioperative period of renal transplant surgery.</description>
    <arm_group_label>Fosfomycin disodium</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Trimethoprim / Sulfamethoxazole</intervention_name>
    <description>Trimethoprim / Sulfamethoxazole (160/800 mg) orally every 24 hours during the study follow-up (7 weeks)</description>
    <arm_group_label>Fosfomycin disodium</arm_group_label>
    <arm_group_label>Trimethoprim / Sulfamethoxazole</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Intravenous placebo</intervention_name>
    <description>Normal saline 0.9% 100 mL intravenous administered three times in the perioperative period of the renal transplant, at the same times corresponding to disodium fosfomycin</description>
    <arm_group_label>Trimethoprim / Sulfamethoxazole</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients transplanted in the Instituto Nacional de Ciencias Medicas y Nutricion&#xD;
             Salvador Zubiran.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Allergy to Fosfomycin disodium or Trimethoprim / Sulfamethoxazole&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>José Sifuentes-Osornio, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran</name>
      <address>
        <city>Mexico City</city>
        <zip>14080</zip>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Mexico</country>
  </location_countries>
  <reference>
    <citation>Linares L, Cervera C, Cofan F, Ricart MJ, Esforzado N, Torregrosa V, Oppenheimer F, Campistol JM, Marco F, Moreno A. Epidemiology and outcomes of multiple antibiotic-resistant bacterial infection in renal transplantation. Transplant Proc. 2007 Sep;39(7):2222-4. doi: 10.1016/j.transproceed.2007.06.061.</citation>
    <PMID>17889144</PMID>
  </reference>
  <reference>
    <citation>Kawecki D, Kwiatkowski A, Sawicka-Grzelak A, Durlik M, Paczek L, Chmura A, Mlynarczyk G, Rowinski W, Luczak M. Urinary tract infections in the early posttransplant period after kidney transplantation: etiologic agents and their susceptibility. Transplant Proc. 2011 Oct;43(8):2991-3. doi: 10.1016/j.transproceed.2011.09.002.</citation>
    <PMID>21996207</PMID>
  </reference>
  <reference>
    <citation>Senger SS, Arslan H, Azap OK, Timurkaynak F, Cagir U, Haberal M. Urinary tract infections in renal transplant recipients. Transplant Proc. 2007 May;39(4):1016-7. doi: 10.1016/j.transproceed.2007.02.060.</citation>
    <PMID>17524879</PMID>
  </reference>
  <reference>
    <citation>Figueroa-Sánchez G, Arreola-Guerra JM, Morales-Buenrostro LE. Time of presentation and antimicrobial resistance pattern of urinary tract infection in the early period after kidney transplantation. Rev Mex Traspl 2016; 5: 20-26.</citation>
  </reference>
  <reference>
    <citation>Falagas ME, Kastoris AC, Karageorgopoulos DE, Rafailidis PI. Fosfomycin for the treatment of infections caused by multidrug-resistant non-fermenting Gram-negative bacilli: a systematic review of microbiological, animal and clinical studies. Int J Antimicrob Agents. 2009 Aug;34(2):111-20. doi: 10.1016/j.ijantimicag.2009.03.009. Epub 2009 Apr 28.</citation>
    <PMID>19403273</PMID>
  </reference>
  <reference>
    <citation>Wagenlehner FM, Thomas PM, Naber KG. Fosfomycin trometamol (3,000 mg) in perioperative antibiotic prophylaxis of healthcare-associated infections after endourological interventions: a narrative review. Urol Int. 2014;92(2):125-30. doi: 10.1159/000355103. Epub 2013 Sep 13.</citation>
    <PMID>24051657</PMID>
  </reference>
  <reference>
    <citation>Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing; twenty-fourth informational supplement. Document M100-S24. Wayne, PA: CLSI; 2014.</citation>
  </reference>
  <reference>
    <citation>The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 6.0, 2016. http://www.eucast.org</citation>
  </reference>
  <verification_date>November 2017</verification_date>
  <study_first_submitted>June 6, 2017</study_first_submitted>
  <study_first_submitted_qc>July 31, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 1, 2017</study_first_posted>
  <last_update_submitted>November 8, 2017</last_update_submitted>
  <last_update_submitted_qc>November 8, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">November 13, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Renal transplant</keyword>
  <keyword>Antimicrobian prophylaxis</keyword>
  <keyword>Fosfomycin</keyword>
  <keyword>Urinary tract infection</keyword>
  <keyword>Asymptomatic bacteriuria</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infections</mesh_term>
    <mesh_term>Communicable Diseases</mesh_term>
    <mesh_term>Urinary Tract Infections</mesh_term>
    <mesh_term>Bacteriuria</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Trimethoprim</mesh_term>
    <mesh_term>Sulfamethoxazole</mesh_term>
    <mesh_term>Fosfomycin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>The data would be available for future analysis for possible additional multicentered studies or metaanalysis.</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03235947
org study id: 1649
nct id: NCT03235947
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
A clinical controlled, randomized and double blind trial that included adult patients (≥18
      years) receiving kidney transplantation (KT) at the INCMNSZ.

      The intervention group will receive disodium fosfomycin 4 g intravenously in three moments:
      preoperative of transplant surgery, prior to removal of the urinary catheter and finally
      prior to removal of ureteral catheter. The control group will receive placebo in the same
      moments.

      Both groups will receive prophylaxis standard for urinary tract infection (UTI), with
      trimethoprim/sulfamethoxazole 160/800 mg per day. This prophylaxis will be administered once
      the estimated glomerular filtration rate is greater than 30 mL/min/1.73m2.

      The primary objective is to compare the average number of episodes of UTI´s and asymptomatic
      bacteriuria in both groups after 7 weeks of follow-up. The secondary objectives are to know
      the incidence of asymptomatic bacteriuria, the incidence of hospitalizations for IVU, the
      days of hospital stay, the pattern of bacterial resistance, the safety of disodium
      fosfomycin, and assessment of the function of the graft and rejection rate.
In the context of development UTI in receptors of KT, some microbiological factors have
      raised great importance, mainly the antimicrobial drug resistance, which has been reported
      for TMP/SMX as high as 60 to 100%. Furthermore, it is also of increasing importance the
      recent isolation of multidrug-resistant bacteria, in particular ESBL-producing Escherichia
      coli and ampicillin-resistant Enterococcus. This phenomenon increases the rate of
      hospitalizations as well as the costs of hospital stay and antibiotic therapy. (1-3) In our
      institution, in receptors of KT the rate of TMP/SMX resistance is 89% and ESBL-production
      about 32% among E. coli recovered from urine. (4)

      Because of the increase in the rate of TMP-SMX resistance, there is a lot of interest to use
      other antibiotics for the prevention of UTI among different populations. In this sense,
      fosfomycin is an agent with a unique mechanism of action that does not share with other
      families of known antibiotics, this characteristic provides advantages to use this antibiotic
      alone or, even, synergistically in combination with other antibiotics. Fosfomycin (FOS) is a
      wall antibiotic (pyruvyl-transferase 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). FOS has also shown a very good activity against E. coli producer of
      Extended Spectrum Betalactamases.

      Multiple clinical studies have shown FOS efficacy in the treatment of UTI's and especially in
      multiple-drug-resistant bacteria. (5) With regard to its use as a perioperative prophylaxis,
      in a systematic review with 8 trials, FOS proved to be effective to prevent health
      care-associated UTI's, however only one study showed no benefit. The oral dose regularly used
      is FOS 3 g, 3 hours before and 24 hours after the surgical procedure. (6)

      Our hypothesis is that in the seven weeks after kidney transplantation, perioperative
      prophylaxis with FOS will show greater efficacy in comparison with standard prophylaxis
      (TMP/SMX). Considering that the mean number of UTI and BA episodes per patient in the first
      seven weeks is 0.8 episodes / patient, if we want to decrease it to 0.4 episodes per patient,
      using the means comparison formula will require 40 patients per arm per treatment, this
      considering a power of 80% and confidence intervals of 95%. The primary outcome will be to
      compare the mean number of episodes of urinary tract infection and asymptomatic bacteriuria
      per patient in each treatment arm. Secondary outcomes refer to the development of
      UTI-associated sepsis, pyelonephritis, recurrent UTI and asymptomatic bacteriuria. Safety
      outcomes included hematological and gastrointestinal side effects, the acute rejection rate,
      glomerular filtration rate, graft loss and patient death.

      Patients eligible for a kidney transplant will be invited to participate in the study, prior
      to renal transplant surgery. They are given an informed consent, which is reviewed and
      approved by the ethics and research committees of our institution. The arms of the study are
      discussed in detail below. The study followed the Declaration of Helsinki recommendations and
      was approved by the Institutional Review Board (Ref: 1649). Randomization was conducted
      centrally by stratifying according to gender, with specific software (www.randomization.com).
      Patients were assigned to one of two parallel groups in a 1:1 ratio and in blocks of 4.

      Subjects will be followed up for 7 weeks from renal transplant surgery. The outcome variables
      are defined as follows:

        -  Positive urine culture: The isolated germ will be defined depending on international
           standards. For enterobacteria and gram positive ≥100,000 colony-forming unit (CFU) / mL.

        -  Urinary tract infection: Positive urine culture plus presence of associated signs or
           symptoms.

        -  Significant Asymptomatic Bacteriuria: Will be identified from isolation ≥100,000 CFU/mL.
           In the case of women, the same insulation should be corroborated in a second urine
           culture sample.

        -  Asymptomatic Bacteriuria not significant: It will be identified from isolation of ≥1000
           CFU/mL and will not be given antibiotic treatment.

        -  Hospitalization due to UTI: It will be defined as any UTI event that warrants
           hospitalization or that, having another reason for hospitalization, develop IVU that
           requires intravenous antimicrobial treatment.

      The urine cultures will be taken from the first urine in the morning, obtaining the sample of
      medium jet with an approximate volume to collect of 25 to 50 mL. Urine samples were processed
      within the first hour after obtention.

      The sample was inoculated in human blood agar and McConkey agar with a 1 microliter
      calibrated loop, and incubated at 35ºC, overnight. The report included the number of CFU. All
      clinical isolates were identified with the gram-negative and gram-positive identification
      cards by Vitek 2 (BioMérieux, Lyon, France) following the manufacturer´s instructions.
      AST-285 Vitek2 cards were used for gram-negative bacilli and the AST-591 Vitek2 card for
      gram-positive cocci (BioMérieux, Lyon, France); they were incubated and then interpreted by
      an expert in the system (version 7.01) and according to the Clinical & Laboratory Standards
      Institute (CLSI) M100-S24 (2014) guideline (20). Susceptibility to fosfomycin was determined
      by disk diffusion on cation-supplemented Müeller Hinton agar plates (CLSI, M07-A9); a
      bacterial suspension was inoculated in 0.5 mL Mc Farland, and a fosfomycin disk (200
      micrograms [mcg]) supplemented with glucose-6-phosphate was used (50 mcg). Interpretation of
      inhibition halos in E. coli and Enterococcus faecalis isolates was based on CLSI M100-S24
      (2014) criteria. The following were used as controls: E. coli ATCC 25922, E. coli ATCC 35218,
      Staphylococcus aureus ATCC 29213 and S. aureus ATCC 43300. Antimicrobial sensitivity to
      fosfomycin was determined with the microdilution broth method in E. coli, Klebsiella
      pneumoniae and Enterococcus spp. isolates. Müeller Hinton broth supplemented with
      glucose-6-phosphate (25 mcg/ml) was used, E. coli ATCC 25922, S. aureus ATCC 29213 and
      Pseudomonas aeruginosa ATCC 27853 were included as controls and results were interpreted
      according to the CLSI (M07-A10) and European Committee on Antimicrobial Susceptibility
      Testing (EUCAST) 2015 criteria (20,21).

      Urine culture will be performed in the following situations: 1.- 48 hrs after the removal of
      the urinary catheter. 2.- Prior to removal of the ureteral catheter. 3.- At 4 weeks after
      renal transplantation. 4.- At 6 weeks after renal transplantation. 5.-In case of urinary
      storage symptoms suggestive of UTI or elevated creatinine (If the emergency department
      approach requires it). 6.- After antibiotic treatment of urinary tract infection or
      significant asymptomatic bacteriuria. In the case of women who have an episode of significant
      asymptomatic bacteriuria, this should be corroborated in two consecutive urine cultures.

      Subjects will have the following follow-up visits: before ureteral catheter removal (first
      visit), 4 weeks of renal transplantation (second visit), 6 weeks (third visit) and one final
      visit at week 7.

      Both follow-up visits and reports of urine cultures are recorded in the CRFs for each
      patient. In the follow-up consultations, adverse events will also be registered, if they are
      reported, are notified to the institutional committees and to the regulatory institutions of
      the health system of Mexico. An intermediate analysis will be carried out to determine both
      the effectiveness and safety of the interventions.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: This is a randomized, parallel-group, controlled clinical trial conducted in a single center that will include renal transplant recipients over the age of 18 to assess the efficacy and safety of disodium fosfomycin in the perioperative period of renal transplantation. The intervention group will receive intravenous fosfomycin 4 g disodium three hours prior to: renal transplant surgery, removal of the urinary catheter and withdrawal of the ureteral catheter. The control group will receive placebo at the same time. Both groups will receive standard prophylaxis consisting of trimethoprim / sulfamethoxazole (160/800 mg) orally every 24 hours when the GFR is greater than 30 mL / min / 1.73m2.
primary purpose: Prevention
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: To compare the efficacy of Fosfomycin-disodium/Trimethoprim-sulfamethoxazole with Placebo/Trimetoprim-sulfamexazol in the prophylaxis of urinary tract infection or significant asymptomatic bacteriuria among kidney transplantation recipients.
time frame: 7-weeks after transplantation
description: The primary outcome in this clinical trial is the comparison of the mean number of episodes of urinary tract infection or significant asymptomatic bacteriuria, per patient in both arms of treatment among kidney transplantation recipients during the first seven weeks after surgery.
measure: The elapsed time period until the first urinary tract infection or asymptomatic bacteriuria developed
time frame: 7-weeks after transplantation
description: Refers to the elapsed time period until the first urinary tract infection or asymptomatic bacteriuria developed during the first 7 weeks post-KT
measure: Incidence of urinary tract infection
time frame: 7-weeks after transplantation
description: The number of patients that develope tract urinary infection in the first seven weeks after transplantation in each group, divided by the number of patients allocated in each group at randomization.
measure: Incidence of asymptomatic bacteriuria
time frame: 7-weeks after transplantation
description: The number of patients that develope asymptomatic bacteriuria in the first seven weeks after transplantation in each group, divided by the number of patients allocated in each group at randomization.
measure: Incidence of bacteremia
time frame: 7-weeks after transplantation
description: The number of patients that develope bacteremia in the first seven weeks after transplantation in each group, divided by the number of patients allocated in each group at randomization.
measure: Incidence of hospitalization for urinary tract infection
time frame: 7-weeks after transplantation
description: The number of patients that develope hospitalization for urinary tract infection in the first seven weeks after transplantation in each group, divided by the number of patients allocated in each group at randomization.
measure: Incidence of Clostridium difficile infection
time frame: 7-weeks after transplantation
description: The number of patients that develope Clostridium difficile infection in the first seven weeks after transplantation in each group, divided by the number of patients allocated in each group at randomization.
measure: Incidence of multidrug resistant bacteria colonization
time frame: 7-weeks after transplantation
description: The number of patients that develope multidrug resistant bacteria colonization infection in the first seven weeks after transplantation in each group, divided by the number of patients allocated in each group at randomization.
measure: Incidence of acute rejection
time frame: 3-months after transplantation
description: The number of patients that develope acute rejection in the first seven weeks after transplantation in each group, divided by the number of patients allocated in each group at randomization.
arm group label: Fosfomycin disodium
arm group type: Experimental
description: Fosfomycin disodium 4 g intravenously: 3 hours before kidney transplant surgery, 3 hours before urinary catheter removal and 3 hours prior to ureteral catheter removal.
Trimethoprim / Sulfamethoxazole (160/800 mg) 1 tablet orally every 24 hours.
arm group label: Trimethoprim / Sulfamethoxazole
arm group type: Active Comparator
description: Trimethoprim / Sulfamethoxazole (160/800 mg) 1 tablet orally every 24 hours.
Intravenous placebo solution at the same time of application of fosfomycin disodium in the experimental arm.
intervention type: Drug
intervention name: Fosfomycin disodium
description: Fosfomycin disodium 4 g intravenously dissolved in 100 mL of normal saline 0.9% three times in the perioperative period of renal transplant surgery.
arm group label: Fosfomycin disodium
intervention type: Drug
intervention name: Trimethoprim / Sulfamethoxazole
description: Trimethoprim / Sulfamethoxazole (160/800 mg) orally every 24 hours during the study follow-up (7 weeks)
arm group label: Fosfomycin disodium
arm group label: Trimethoprim / Sulfamethoxazole
intervention type: Drug
intervention name: Intravenous placebo
description: Normal saline 0.9% 100 mL intravenous administered three times in the perioperative period of the renal transplant, at the same times corresponding to disodium fosfomycin
arm group label: Trimethoprim / Sulfamethoxazole
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: José Sifuentes-Osornio, MD
role: Principal Investigator
affiliation: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
facility: 
country: Mexico
citation: Linares L, Cervera C, Cofan F, Ricart MJ, Esforzado N, Torregrosa V, Oppenheimer F, Campistol JM, Marco F, Moreno A. Epidemiology and outcomes of multiple antibiotic-resistant bacterial infection in renal transplantation. Transplant Proc. 2007 Sep;39(7):2222-4. doi: 10.1016/j.transproceed.2007.06.061.
PMID: 17889144
citation: Kawecki D, Kwiatkowski A, Sawicka-Grzelak A, Durlik M, Paczek L, Chmura A, Mlynarczyk G, Rowinski W, Luczak M. Urinary tract infections in the early posttransplant period after kidney transplantation: etiologic agents and their susceptibility. Transplant Proc. 2011 Oct;43(8):2991-3. doi: 10.1016/j.transproceed.2011.09.002.
PMID: 21996207
citation: Senger SS, Arslan H, Azap OK, Timurkaynak F, Cagir U, Haberal M. Urinary tract infections in renal transplant recipients. Transplant Proc. 2007 May;39(4):1016-7. doi: 10.1016/j.transproceed.2007.02.060.
PMID: 17524879
citation: Figueroa-Sánchez G, Arreola-Guerra JM, Morales-Buenrostro LE. Time of presentation and antimicrobial resistance pattern of urinary tract infection in the early period after kidney transplantation. Rev Mex Traspl 2016; 5: 20-26.
citation: Falagas ME, Kastoris AC, Karageorgopoulos DE, Rafailidis PI. Fosfomycin for the treatment of infections caused by multidrug-resistant non-fermenting Gram-negative bacilli: a systematic review of microbiological, animal and clinical studies. Int J Antimicrob Agents. 2009 Aug;34(2):111-20. doi: 10.1016/j.ijantimicag.2009.03.009. Epub 2009 Apr 28.
PMID: 19403273
citation: Wagenlehner FM, Thomas PM, Naber KG. Fosfomycin trometamol (3,000 mg) in perioperative antibiotic prophylaxis of healthcare-associated infections after endourological interventions: a narrative review. Urol Int. 2014;92(2):125-30. doi: 10.1159/000355103. Epub 2013 Sep 13.
PMID: 24051657
citation: Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing; twenty-fourth informational supplement. Document M100-S24. Wayne, PA: CLSI; 2014.
citation: The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 6.0, 2016. http://www.eucast.org
responsible party type: Sponsor
mesh term: Infections
mesh term: Communicable Diseases
mesh term: Urinary Tract Infections
mesh term: Bacteriuria
mesh term: Trimethoprim
mesh term: Sulfamethoxazole
mesh term: Fosfomycin
sharing ipd: Undecided
ipd description: The data would be available for future analysis for possible additional multicentered studies or metaanalysis.