Effects of Antibiotic Prophylaxis on Recurrent UTI in Children
Condition: Urinary Tract Infection; Recurrent Urinary Tract Infection
MeSH terms: Infections; Communicable Diseases; Urinary Tract Infections; Recurrence
Study type: Interventional
Phase: Phase 4

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.
    

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.
    

Intervention name(s): Antibiotic Prophylaxis
Intervention type(s): Drug
Intervention description(s): Approved clinical dosage or antibiotics
Intervention MeSH terms: Anti-Bacterial Agents
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Antibiotic Prophylaxis; Urinary Microbiota