Ignite Creation Date:
2024-05-06 @ 10:21 AM
Last Modification Date:
2024-10-26 @ 12:28 PM
Study NCT ID:
NCT03235947
Status:
COMPLETED
Last Update Posted:
2017-11-13
First Post:
2017-06-06
Brief Title:
Perioperative Fosfomycin in the Prophylaxis of Urinary Tract Infection in Kidney Transplant Recipients
Sponsor:
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Organization:
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Study Overview
Official Title:
Perioperative Disodium Fosfomycin in the Prophylaxis of Urinary Tract Infection in Kidney Transplant Recipients Controlled Clinical Trial PERIFOS Trial
Status:
COMPLETED
Status Verified Date:
2017-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
PERIFOS
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 trimethoprimsulfamethoxazole 160800 mg per day This prophylaxis will be administered once the estimated glomerular filtration rate is greater than 30 mLmin173m2
The primary objective is to compare the average number of episodes of UTIs 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
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 trimethoprimsulfamethoxazole 160800 mg per day This prophylaxis will be administered once the estimated glomerular filtration rate is greater than 30 mLmin173m2
The primary objective is to compare the average number of episodes of UTIs 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
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 TMPSMX 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 TMPSMX 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 UTIs 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 UTIs 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 TMPSMX Considering that the mean number of UTI and BA episodes per patient in the first seven weeks is 08 episodes patient if we want to decrease it to 04 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 wwwrandomizationcom Patients were assigned to one of two parallel groups in a 11 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 100000 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 100000 CFUmL 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 CFUmL 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 manufacturers 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 701 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 05 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 mcgml 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 2021
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
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 UTIs 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 UTIs 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 TMPSMX Considering that the mean number of UTI and BA episodes per patient in the first seven weeks is 08 episodes patient if we want to decrease it to 04 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 wwwrandomizationcom Patients were assigned to one of two parallel groups in a 11 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 100000 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 100000 CFUmL 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 CFUmL 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 manufacturers 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 701 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 05 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 mcgml 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 2021
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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None