Can Probiotics be Used in the Prevention of Recurrent UTI in Paediatric Neurogenic Bladder

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.