PERIFOS: Perioperative Fosfomycin in the Prophylaxis of Urinary Tract Infection in Kidney Transplant Recipients

Sponsor

Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran (Other)

Overall Status

Completed

CT.gov ID

NCT03235947

Collaborator

Laboratorios Senosiain, S.A. de C.V. (Industry)

Enrollment

Location

Arms

Actual Duration (Months)

5.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Urinary Tract Infection Asymptomatic Bacteriuria	Drug: Fosfomycin disodium Drug: Trimethoprim / Sulfamethoxazole Drug: Intravenous placebo	Phase 4

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

82 participants

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.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.

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Prevention

Official Title:

Perioperative Disodium Fosfomycin in the Prophylaxis of Urinary Tract Infection in Kidney Transplant Recipients. Controlled Clinical Trial (PERIFOS Trial)

Actual Study Start Date :

Sep 7, 2016

Actual Primary Completion Date :

Nov 6, 2017

Actual Study Completion Date :

Nov 6, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Fosfomycin disodium 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.	Drug: Fosfomycin disodium Fosfomycin disodium 4 g intravenously dissolved in 100 mL of normal saline 0.9% three times in the perioperative period of renal transplant surgery. Drug: Trimethoprim / Sulfamethoxazole Trimethoprim / Sulfamethoxazole (160/800 mg) orally every 24 hours during the study follow-up (7 weeks)
Active Comparator: Trimethoprim / Sulfamethoxazole 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.	Drug: Trimethoprim / Sulfamethoxazole Trimethoprim / Sulfamethoxazole (160/800 mg) orally every 24 hours during the study follow-up (7 weeks) Drug: Intravenous placebo 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

Intervention/Treatment

Experimental: Fosfomycin disodium

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.

Drug: Fosfomycin disodium

Fosfomycin disodium 4 g intravenously dissolved in 100 mL of normal saline 0.9% three times in the perioperative period of renal transplant surgery.

Drug: Trimethoprim / Sulfamethoxazole

Trimethoprim / Sulfamethoxazole (160/800 mg) orally every 24 hours during the study follow-up (7 weeks)

Active Comparator: Trimethoprim / Sulfamethoxazole

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.

Drug: Trimethoprim / Sulfamethoxazole

Trimethoprim / Sulfamethoxazole (160/800 mg) orally every 24 hours during the study follow-up (7 weeks)

Drug: Intravenous placebo

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

Outcome Measures

Primary Outcome Measures

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. [7-weeks after transplantation]
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.

Secondary Outcome Measures

The elapsed time period until the first urinary tract infection or asymptomatic bacteriuria developed [7-weeks after transplantation]
Refers to the elapsed time period until the first urinary tract infection or asymptomatic bacteriuria developed during the first 7 weeks post-KT

Other Outcome Measures

Incidence of urinary tract infection [7-weeks after transplantation]
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.
Incidence of asymptomatic bacteriuria [7-weeks after transplantation]
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.
Incidence of bacteremia [7-weeks after transplantation]
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.
Incidence of hospitalization for urinary tract infection [7-weeks after transplantation]
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.
Incidence of Clostridium difficile infection [7-weeks after transplantation]
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.
Incidence of multidrug resistant bacteria colonization [7-weeks after transplantation]
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.
Incidence of acute rejection [3-months after transplantation]
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.