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Effects of Antibiotic Prophylaxis on Recurrent UTI in Children

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ClinicalTrials.gov Identifier: NCT02357758
Recruitment Status : Unknown
Verified February 2015 by Sumit Dave, Lawson Health Research Institute.
Recruitment status was:  Recruiting
First Posted : February 6, 2015
Last Update Posted : February 6, 2015
Sponsor:
Collaborator:
University of Western Ontario, Canada
Information provided by (Responsible Party):
Sumit Dave, Lawson Health Research Institute

Brief Summary:

Approximately, 3% of males and 8% of females will develop a urinary tract infection (UTI) during childhood, and most of these will be effectively treated by short-term antibiotic therapy. A subset of these children (20-48%), will develop recurrent UTI (RUTI), which may have long-term effects in the form of hypertension or renal damage.

In an effort to prevent RUTIs physicians prescribe sulfamethoxazole-trimethoprim (Septra) or nitrofurantoin as low dose antibiotic prophylaxis. However, recent evidence suggests that during prophylactic therapy the body is exposed to antibiotic levels capable of increasing antibiotic resistance and bacterial virulence. This has been shown to be true in the uropathogens E. coli and Staphylococcus saprophyticus, yet it is not known if Enterococcus sp. demonstrate similar mechanisms. Additionally, antibiotics have been shown to disrupt the natural balance of the human microbiome, potentially leading to major long term problems.

As a uropathogen, enterococci consistently rank in the top 3 causes of RUTI, especially in children under 3 years of age. Additionally, Enterococcus is notorious for developing antibiotic resistance and studies have shown that children with enterococcal UTIs exhibit a higher rate of recurrence than those with non-enterococcal UTIs.

The investigators hypothesize the current practice of antibiotic prophylaxis in children with RUTI is detrimental and can change the bacterial and sensitivity profiles of these patients.


Condition or disease Intervention/treatment Phase
Urinary Tract Infection Recurrent Urinary Tract Infection Drug: Antibiotic Prophylaxis Phase 4

Detailed Description:

Patients meeting the inclusion criteria will be recruited to the study at Dr. Dave's discretion through the urology clinic. As clinically indicated patients will then fall into one of two groups, patients receiving antibiotic prophylaxis or those undergoing clinical observation. This reflects the standard of care these children receive and no additional procedures are mandated.

At the initial appointment information sheets and consent forms will be given to the parent/caregiver to consider; due to the nature of the study, the parent or legal guardian will be required to give informed consent. Following the receipt of informed consent, patients will be asked to provide a mid stream urine sample given they are infection free and not currently on antibiotics. Patients will be assessed simultaneously for dysfunctional elimination syndrome (DES) through review of their 48-hour bowel bladder diary, the completed Dysfunctional Voiding Scoring System (DVSS) questionnaire and performing uroflowmetry. Patients may withdraw from the study at any stage without repercussion.

Patients in the antibiotic prophylaxis group will receive a 3-month script for antibiotic prophylaxis, if clinically indicated according to the standard of care. Septra (Trimethoprim dose 2 mg/kg) or nitrofurantoin (dose 2 mg/kg) will be the antibiotics used for prophylaxis based on past cultures or allergy history. Antibiotic prescription will be renewed at 3 months and an informal assessment on compliance will be performed through review of the number of doses left. Patients not tolerating one of these antibiotics will be offered the alternate. From months 6-12, prophylaxis will cease (washout period) unless a symptomatic UTI is suspected at which point appropriate treatment will be implemented. Lifestyle changes, behavioural modification and management of constipation will be instituted in both groups. Patients will return for follow up visits at 3, 6, 9 and 12 months. In addition, patients can return to the urology clinic at any time if UTI is suspected.

Urine samples will be collected at baseline and at 3, 6, 9 and 12 months from both groups (prophylaxis versus observation) by registered nurses at Children's Hospital, London Health Sciences Centre. Healthy patients, those with no recent history of UTI or antibiotic use or known urinary tract abnormalities, will be included to give an indication of the healthy urinary microbiota in the paediatric population. These participants will be asked to provide urine at two time points a minimum of three months apart. Samples will be assessed for bacterial identification via both culture dependent and independent methods. Antibiotic susceptibility profiles will be determined for viable organisms using the Kirby Bauer disk method and bacterial virulence analyzed via bladder and kidney cell line adherence and internalization assays, as well as PCR to determine the presence of virulence genes associated with the pathogen (adhesins, fimbriae, toxins). Urinary cytokine analysis via Luminex will also be conducted as a measure of host bladder state, immune response and disease severity.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Recurrent Urinary Tract Infections in Children: Bacterial Identification, Antibiotic Susceptibility Profiling and Cytokine Levels Associated With Antibiotic Prophylaxis
Study Start Date : September 2012
Estimated Primary Completion Date : October 2015

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Antibiotic Prophylaxis
Patients with RUTI receiving Septra (Trimethoprim dose 2mg/kg) or nitrofurantoin (dose 2 mg/kg) as determined by clinician.
Drug: Antibiotic Prophylaxis
No Intervention: Healthy Population
No Intervention: Clinical Observation
Patients experiencing RUTI that do not require antibiotic prophylaxis as determined by clinician.



Primary Outcome Measures :
  1. Changes to the urinary microbiota [ Time Frame: Baseline, 3-, 6-, 9-, 12-months ]
    Changes to the urinary microbiota as determined by high-throughput 16S rRNA sequencing.


Secondary Outcome Measures :
  1. Changes to metabolic profiles of urine [ Time Frame: Baseline, 3-, 6-, 9- 12-months ]
    Changes to metabolic profiles of urine as determined using gas chromatography mass spectrometry (GC-MS).

  2. Changes to antibiotic susceptibility [ Time Frame: Baseline, 3-, 6-, 9-, 12-months ]
    Changes to antibiotic susceptibility of cultured bacteria as determined by the Kirby Bauer disc diffusion method.

  3. Changes in pro-inflammatory cytokines [ Time Frame: Baseline, 3-, 6-, 9-, 12-months ]
    Changes in pro-inflammatory cytokines associated with inflammation and immune cell recruitment will be measured using multiplexed immunoassay kits employing Luminex® xMAP fluorescent beadbased technology.



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Ages Eligible for Study:   3 Years to 15 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Patient has experienced a minimum of 2 UTIs within the last year, as well as a culture proven UTI for inclusion into either of the RUTI groups.
  • Patients must be deemed to require antibiotic prophylaxis, at the discretion of Dr. Dave and following the standard of care, for inclusion in the antibiotic prophylaxis group.
  • Patients with no known urological abnormalities, recent history of UTI or antibiotic use are eligible for inclusion in the healthy patient group.

Exclusion Criteria:

  • Patients with an abnormal urinary tract as determined through the use of ultrasound and, given an abnormal ultrasound, or greater than two febrile UTIs, a voiding cystourethrogram (VCUG). The use of both ultrasound and VCUG given these indications is standard of care.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02357758


Contacts
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Contact: Sumit Dave, MD, MCh 519.685.8439 sumit.dave@lhsc.on.ca

Locations
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Canada, Ontario
Children's Hospital - London Health Sciences Centre Recruiting
London, Ontario, Canada, N6A 5W9
Contact: Sumit Dave, MD, MCh         
Sponsors and Collaborators
Lawson Health Research Institute
University of Western Ontario, Canada
Investigators
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Principal Investigator: Sumit Dave, MD, MCh Assistant Professor, Pediatric Urologist, London Health Sciences Centre

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Sumit Dave, Principal Investigator, Lawson Health Research Institute
ClinicalTrials.gov Identifier: NCT02357758     History of Changes
Other Study ID Numbers: R-12-387
First Posted: February 6, 2015    Key Record Dates
Last Update Posted: February 6, 2015
Last Verified: February 2015

Keywords provided by Sumit Dave, Lawson Health Research Institute:
Antibiotic Prophylaxis
Urinary Microbiota

Additional relevant MeSH terms:
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Infection
Communicable Diseases
Urinary Tract Infections
Urologic Diseases
Anti-Bacterial Agents
Antibiotics, Antitubercular
Anti-Infective Agents
Antitubercular Agents