Can Probiotics be Used in the Prevention of Recurrent UTI in Paediatric Neurogenic Bladder
Can Probiotics be Used in the Prevention of Recurrent UTI in Paediatric Neurogenic Bladder
Although clean intermittent catheterization (CIC) remains the mainstay to ensure complete
 low-pressure bladder emptying in neurogenic bladder (NB) patients, this forms a vehicle for
 bacterial entry and colonization of the urinary tract, which can lead to recurrent urinary
 tract infection (RUTI) and renal damage. Up to 25% of NB patients on CIC suffer from RUTI and
 daily, low-dose antibiotic prophylaxis is widely prescribed to prevent these infections.
 Unfortunately, this therapeutic option is not evidence-based and can be associated with a
 higher risk of RUTI secondary to development of antibiotic resistance. In addition, many
 children suffer from a range of adverse reactions and emergence of drug resistant organisms.
 Moreover, recent studies have shown that antibiotics cause a major disruption in the human
 microbiome, potentially leading to long term major problems.

 Probiotics are live microorganisms, which when administered in adequate amounts confer a
 health benefit on the host. There is evidence that probiotics restore microbial homeostasis
 in the vagina, reduce the risk of pathogen ascension into the bladder, and modulate immunity
 to better protect the host. Probiotic strains, including Lactobacillus rhamnosus GR-1,
 Lactobacillus reuteri B-54 and RC-14, have been shown to be safe and efficacious in an oral
 formulation or as a vaginal suppository in improving the microbiota profile of the vagina and
 decreasing the risk of RUTI. Various mechanisms appear to be involved, including modulating
 antimicrobial and inflammatory defenses, up-regulating protective mucin production and
 reducing the pressure on pathogens to acquire antibiotic resistance genes. A randomized trial
 comparing probiotics to antibiotic prophylaxis in children with vesicoureteric reflux showed
 equivalent reduction in the incidence of RUTI and development of new renal scarring. In
 addition, down regulation of inflammatory cytokines can potentially favorably alter bladder
 function and prevent bladder fibrosis.

 Investigators at London Health Sciences Centre (LHSC) have the opportunity to acquire
 clinical data that would strengthen the case for probiotics to be integrated into pediatric
 urology practice for managing CIC and RUTI. This would be the first such study in pediatric
 NB patients.

 The main objective of this study is to determine whether the use of probiotics (lactobacilli)
 can decrease the impact of adverse side effects and the antibiotic resistance that is seen
 with the prolonged use of antibiotics for patients with neurogenic bladder conditions.
From Dr. Dave's practice 53 suitable patients who are using CIC to manage NB disease, and are
 receiving long term, low-dose antibiotic prophylaxis designed to prevent RUTI have been
 identified.

 On average, another 5 eligible patients would be expected within a six- month window. From
 this pool, the study will enroll 36 adolescents ≥ 12 years of age. They will have had a
 history of RUTI over the past 12 months and will have been receiving chemoprophylaxis for at
 least one month. The study design and reporting will conform to the CONSORT guidelines.

 Patients will be enrolled after informed consent and the baseline evaluation will include a
 history and physical examination, and verification of previous culture proven UTI. A urine
 sample will be obtained using clean catheterization and subjected to: urinalysis, microbiome,
 metabolome, bacteriological culture and antibiotic resistance assessment, and assayed for
 markers for inflammation. A stool sample will also be collected to analyse the gut microbiota
 and drug resistance profiles of E. coli. Each patient will receive counselling at baseline
 and at 3 months follow up on ensuring adequate fluid intake, proper clean intermittent
 catheterization technique and frequency, and over the- counter treatment for constipation.
 Post catheterization bladder scans will be performed to ensure completeness of bladder
 emptying. Baseline bladder and renal function will be assessed.

 Investigators expect interest from the patients/parents in their practice as at the very
 least the study will entail a check-up of how their condition is being managed, and for us to
 be able to provide them with additional information on their microbiota in urine and stool.
 Thus, patients who do not wish to be randomized to receive probiotics or change to a
 probiotic regimen, can still be included as a control group remaining on prophylaxis (12
 subjects). Investigators would expect their bacterial drug resistance profiles and intestinal
 side effects to remain unchanged for the next six months. For 24 subjects interested in being
 considered for a different approach to their care, they will be randomized using a computer
 generated randomization sequence with balanced block randomization (block size= 4), pre
 generated, and allocation performed using sealed envelopes and a third party to preserve
 allocation concealment from the recruiting physician. A 1: 1 allotment will be performed to
 the 2 study groups: 12 patients will continue antibiotic prophylaxis but also receive daily
 probiotic capsules, and the other 12 will be randomized to receive probiotics and a drug
 placebo for six months after a washout period of 1 week. Patient and parent blinding will be
 partially achieved by each patient taking two pills each day, with the placebo pill or
 capsule resembling the active product. The placebo drug used will be a similar appearance
 sugar based pill with no active ingredient. The probiotic capsule will contain only food
 grade excipients present in the probiotic capsule. Patients will be supplied with their pills
 and capsules for 3- month duration.

 In addition, the laboratory technician and outcome assessor (data entry and analysis) will be
 blinded to patient allotment. Antibiotic prophylaxis will consist of Septra (trimethoprim 2
 mg/kg; sulfamethoxazole) (for the 12 controls or 12 randomized to antibiotic and probiotic
 arm). Probiotic therapy will comprise of two capsules of RePhResh Pro-B (approved by Health
 Canada and sold at Shoppers Drug Mart in Canada), which consists of 5 billion total organisms
 of L. rhamnosus GR-1 and L. reuteri RC-14 per capsule. The capsule can be added to milk or
 orange juice if the patient is unable to swallow it. All 36 patients/parents will be asked to
 keep a diary to record use of medications (OTC medications for colds, flu, others) and will
 be asked not to take any probiotic products (including probiotic yogurt) during the study
 duration. In addition, patients will fill out a questionnaire each week (study duration is 6
 months after the first baseline visit is conducted) to assess a range of potential adverse
 events (such as constipation, diarrhea, bloating, nausea, pain, fever) on a scale of 1-10. At
 the three month follow-up compliance will be assessed by return of the empty product
 containers, and review of the diary. A second course of three month treatment will then be
 provided. At three and six month's clinical assessment, urine and stool samples will be
 provided.

 At 6 month follow-up, patients will receive a renal ultrasound to assess the health of the
 upper renal tract, as well as a post-catheterization bladder scan an cystometry. During the
 study, any patient with two or more episodes of UTI will be treated with an alternative
 antibiotic prophylactic regimen.
Inclusion Criteria:

 -  - Patients will have had a history of recurrent urinary tract infections over the past
 12 months.

 -  Patients will have been receiving chemoprophylaxis for at least one month.

 -  Patients who are using clean intermittent catheterization to manage a neurogenic
 bladder condition.

 -  PATIENTS WILL BE BETWEEN THE AGES OF 6-20.

 Exclusion Criteria:

 -  Patient has a known allergy to Septra

 -  Patients pregnant or nursing will be excluded.