Urinary Tract InfectionPhase 4NCT02357758
Effects of Antibiotic Prophylaxis on Recurrent UTI in Children
A Phase 4 study testing Antibiotic Prophylaxis in people with Urinary Tract Infection and Recurrent Urinary Tract Infection, run by London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's at 1 site in Canada.
Trial 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. Read more about this study
- Who is it for?
- Ages 3 to 15 yearsHealthy volunteers can take part
- Conditions the study is for
- Urinary Tract Infection, Recurrent Urinary Tract Infection
- What is being tested?
- Antibiotic Prophylaxis
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 59 participants
- Where
- 1 siteCanada
- Study dates
- Sep 2012to Mar 2016
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 3 to 15 years
- All sexes
- Healthy volunteers accepted
- Child
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
Canada1 site
Children's Hospital - London Health Sciences Centre
London, Ontario, N6A 5W9
About this study
Official title: Recurrent Urinary Tract Infections in Children: Bacterial Identification, Antibiotic Susceptibility Profiling and Cytokine Levels Associated With Antibiotic Prophylaxis
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.
Read more
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.
Read the 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.
- Being tested
- Antibiotic Prophylaxis
- Keywords
- Antibiotic Prophylaxis, Urinary Microbiota
- Medical subject headings
- Urinary Tract Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Antibiotic ProphylaxisDrug
Approved clinical dosage or antibiotics
| Study group | Role | What they receive |
|---|---|---|
| Antibiotic Prophylaxis | Active comparator | Patients with RUTI receiving Septra (Trimethoprim dose 2mg/kg) or nitrofurantoin (dose 2 mg/kg) as determined by clinician. Receives: Drug: Antibiotic Prophylaxis |
| Healthy Population | No intervention | Healthy population |
| Clinical Observation | No intervention | Patients experiencing RUTI that do not require antibiotic prophylaxis as determined by clinician. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Changes to the Urinary Microbiota
Changes to the urinary microbiota were measured as changes in the colony forming units (CFUs) of Enterococcus sp., Escherichia coli, Klebsiella sp./Enterobacter sp., Staphylococcus saprophyticus, or Pseudomonas sp./Staphylococcus aureus when the participant urine was cultured on CHROMagar Orientation. The data was analyzed in terms of bacterial counts, presence/absence, and presence at or above the diagnostic threshold for UTI (10^5 CFU/mL of one species). Here we present participant midstream urine samples that met the diagnostic threshold for UTI at baseline.
Measured: Baseline, 3-, 6-, 9-, 12-months
Secondary outcomes (3)
Changes to Metabolic Profiles of Urine
Changes to metabolic profiles of urine as determined using gas chromatography mass spectrometry (GC-MS).
Measured: Baseline, 3-, 6-, 9- 12-months
Changes to Antibiotic Susceptibility
Changes to antibiotic susceptibility of cultured bacteria as determined by the Kirby Bauer disc diffusion method.
Measured: Baseline, 3-, 6-, 9-, 12-months
Changes in Pro-inflammatory Cytokines
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.
Measured: Baseline, 3-, 6-, 9-, 12-months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Feb 2015 (estimated)
- Study startSep 2012
- Primary completionJan 2016
- Study completionMar 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Urinary Tract InfectionStudies of the same condition, open and under way.
- More trials run by London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph'sThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 59 participants (actual)
Sponsor and investigators
- Lead sponsor
- London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's
- Sponsor type
- University, hospital or other
- Collaborators
- University of Western Ontario, Canada
- Responsible party
- Sponsor
- Investigators
- Sumit Dave, MD, MCh, Principal investigator, Assistant Professor, Pediatric Urologist, London Health Sciences Centre
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02357758
- Sponsor's protocol ID
- R-12-387
- Status last verified
- Sep 2015
- First submitted
- 3 Feb 2015
- Last updated
- 21 Sep 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
Whiteside SA, Dave S, Seney SL, Wang P, Reid G, Burton JP. Enterococcus faecalis persistence in pediatric patients treated with antibiotic prophylaxis for recurrent urinary tract infections. Future Microbiol. 2018 Aug;13:1095-1115. doi: 10.2217/fmb-2018-0048. Epub 2018 Aug 22.
PubMed 30132694
Study at a glance
From the registry record, last updated by the sponsor on 21 Sep 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Recurrent Urinary Tract Infections in Children: Bacterial Identification, Antibiotic Susceptibility Profiling and Cytokine Levels Associated With Antibiotic Prophylaxis
- ClinicalTrials.gov ID
- NCT02357758
- Acronym / sponsor ID
- R-12-387
- Keywords
- Antibiotic Prophylaxis, Urinary Microbiota
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 59 participants (actual)
- Lead sponsor
- London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph'sUniversity, hospital or other
- Collaborators
- University of Western Ontario, Canada
- Study start
- Sep 2012
- Primary completion
- Jan 2016 (actual)
- Study completion
- Mar 2016 (actual)
- First posted
- 6 Feb 2015 (estimated)
- Results
- Posted 14 Oct 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Antibiotic Prophylaxis | Active comparator | Drug: Antibiotic ProphylaxisPatients with RUTI receiving Septra (Trimethoprim dose 2mg/kg) or nitrofurantoin (dose 2 mg/kg) as determined by clinician. |
| Healthy Population | No intervention | –Healthy population |
| Clinical Observation | No intervention | –Patients experiencing RUTI that do not require antibiotic prophylaxis as determined by clinician. |
Who may qualify
- Ages
- 3 to 15 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child
Key inclusion criteria (3 listed)
- 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.
Key exclusion criteria (1 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Antibiotic ProphylaxisApproved clinical dosage or antibiotics | Drug | Antibiotic Prophylaxis |
Primary outcome
Changes to the Urinary Microbiota
Time frame: Baseline, 3-, 6-, 9-, 12-months
Changes to the urinary microbiota were measured as changes in the colony forming units (CFUs) of Enterococcus sp., Escherichia coli, Klebsiella sp./Enterobacter sp., Staphylococcus saprophyticus, or Pseudomonas sp./Staphylococcus aureus when the participant urine was cultured on CHROMagar Orientation. The data was analyzed in terms of bacterial counts, presence/absence, and presence at or above the diagnostic threshold for UTI (10^5 CFU/mL of one species). Here we present participant midstream urine samples that met the diagnostic threshold for UTI at baseline.
3 secondary outcomes
Changes to Metabolic Profiles of Urine
Time frame: Baseline, 3-, 6-, 9- 12-months
Changes to Antibiotic Susceptibility
Time frame: Baseline, 3-, 6-, 9-, 12-months
Changes in Pro-inflammatory Cytokines
Time frame: Baseline, 3-, 6-, 9-, 12-months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Sep 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 30132694Whiteside SA, Dave S, Seney SL, Wang P, Reid G, Burton JP. Enterococcus faecalis persistence in pediatric patients treated with antibiotic prophylaxis for recurrent urinary tract infections. Future Microbiol. 2018 Aug;13:1095-1115. doi: 10.2217/fmb-2018-0048. Epub 2018 Aug 22.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sumit Dave, MD, MCh principal investigator
Assistant Professor, Pediatric Urologist, London Health Sciences Centre
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Antibiotic Prophylaxis in people with Urinary Tract Infection and Recurrent Urinary Tract Infection, run by London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 21 Sep 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 14 Oct 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Changes to the Urinary Microbiota (time frame: Baseline, 3-, 6-, 9-, 12-months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02357758, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Sep 2021.