Probiotics [LGG-BB12 or RC14-GR1] versus placebo as prophylaxis for urinary tract infection in persons with spinal cord injury [ProSCIUTTU]: a randomised controlled trial

© 2019, The Author(s). Study design: Randomised double-blind factorial-design placebo-controlled trial. Objective: Urinary tract infections (UTIs) are common in people with spinal cord injury (SCI). UTIs are increasingly difficult to treat due to emergence of multi-resistant organisms. Probiotics are efficacious in preventing UTIs in post-menopausal women. We aimed to determine whether probiotic therapy with Lactobacillus reuteri RC-14+Lactobacillus GR-1 (RC14-GR1) and/or Lactobacillus rhamnosus GG+Bifidobacterium BB-12 (LGG-BB12) are effective in preventing UTI in people with SCI. Setting: Spinal units in New South Wales, Australia with their rural affiliations. Methods: We recruited 207 eligible participants with SCI and stable neurogenic bladder management. They were randomised to one of four arms: RC14-GR1+LGG-BB12, RC14-GR1+placebo, LGG-BB12+ placebo or double placebos for 6 months. Randomisation was stratified by bladder management type and inpatient or outpatient status. The primary outcome was time to occurrence of symptomatic UTI. Results: Analysis was based on intention to treat. Participants randomised to RC14-GR1 had a similar risk of UTI as those not on RC14-GR1 (HR 0.67; 95% CI: 0.39–1.18; P = 0.17) after allowing for pre-specified covariates. Participants randomised to LGG-BB12 also had a similar risk of UTI as those not on LGG-BB12 (HR 1.29; 95% CI: 0.74–2.25; P = 0.37). Multivariable post hoc survival analysis for RC14-GR1 only vs. the other three groups showed a potential protective effect (HR 0.46; 95% CI: 0.21–0.99; P = 0.03), but this result would need to be confirmed before clinical application. Conclusion: In this RCT, there was no effect of RC14-GR1 or LGG-BB12 in preventing UTI in people with SCI

Methods for tracking the microbiome of neurogenic bladders and the effect of probiotic treatment and urinary tract infection on microbial community composition

Long-term catheterisation, such as in spinal cord injured patients, increases the risk of urinary tract infection (UTI). Urine culture, the standard UTI diagnostic test, limits the scope of detectable microorganisms, whereas molecular methods allow for the identification of culturable and unculturable microorganisms. This study followed a cohort of patients enrolled in a probiotic clinical trial to determine how the urinary tract microflora changed as a function of probiotic treatment and UTI status. Terminal Restriction Fragment Length Polymorphism (T-RFLP) and next-generation sequencing revealed that urinary catheter biofilms were diverse and differed significantly between individuals. For a given subject, the types and relative abundances of taxa within the microbiome were altered as a result of ingesting probiotics, with significant changes in community composition pre and post probiotic therapy. The onset of symptomatic UTI was also associated with significant fluctuations in the microbial community. Disturbances in the flora associated with probiotic therapy and infection were evident when examining a single individual across time, but less clear in a cohort of individuals. Likewise, grouping patients by UTI history did not reveal distinctions between those with recurrent symptomatic infection as opposed to the asymptomatic. High inter-patient variability may make patterns in the flora difficult to detect when examining multiple subjects. For a given patient, T-RFLP and sequencing generated similar patterns in community composition. However, dominant organisms isolated by urine culture did not match those identified by sequencing urinary catheter flora. Urine cultures revealed a narrower range of organisms, and at times no bacterial growth compared to corresponding sequence data from catheters. This suggests that T-RFLP and sequencing of biofilm dwelling bacteria should be incorporated into methods of investigating urinary tract infection. Longitudinal examination of the individual over time may be the best way to monitor changes in urinary tract flora. T-RFLP is a relatively cheap and rapid technique that can be used to examine changes to the patient's urinary tract flora, which may predict infection and can be used as a diagnostic tool for UTI management

Shannon diversity indices of the three patients at the genus level from meta-sequencing data.

<p>Shannon diversity indices of the three patients at the genus level from meta-sequencing data.</p

MDS plot showing inter-patient differences in microbial communities of the three patients at time points of probiotic treatment and post-treatment.

<p>Data are shown for T-RFLP analysis (A) and metacommunity sequence analysis (B). The microbial flora for Patient 1 (Blue triangles), Patient 2 (Red circles) and Patient 3 (Grey squares) were plotted for each time point collected. The red arrow indicates the pre-UTI sample for patient 2. The contours group samples with a given percentage of similarity (20%, 40% and 60%) based on composition and relative abundances of taxa present.</p

The microbial community composition from Patient 3 during and after probiotic treatment.

<p>(A) Samples and time line for Patient 3. MDS plot of the microbial flora from Patient 2 during and after probiotic treatment based on T-RFLP (B) and Illumina sequencing data (C). The four green triangles represent the samples collected during the probiotic interventional period between November 2012 and April 2013, with November being the baseline time point examined. All other samples were collected at five post-treatment time points between May and October 2013. D. Microbial flora composition at the genus level for Patient 3 during and after probiotic treatment based on Illumina sequencing data. The samples collected from November 2012 to April 2013 correspond to Month 0 (Pre-treatment), and Months 3, 5 and 6 of probiotic intervention. The post-treatment samples were collected at five time points between May 2013 and October 2013. Only OTUs representing at least 1% of the total community are shown. OTUs that were not resolved at the genus level are referred to by their lowest identified phylogenetic classification.</p

Patient characteristics.

<p>Patient characteristics.</p

Taxonomic distribution of microorganisms in catheterized patients.

<p><b>(</b>A) Phyla as a percentage of taxonomic assignment in urinary catheter microbiota of the three patients across probiotic treatment and post-treatment time points based on meta-community sequence analysis. (B) Genera as a percentage of taxonomic assignment for the three patients across probiotic treatment and post-treatment time points based on meta-community sequence analysis. Only genera with an average representation of 1% or greater are shown. Error bars show standard deviations. OTUs that were not resolved at the genus level are referred to by their lowest identified phylogenetic classification and OTU number. Only phyla with a representation of at least 1% in a single individual’s catheter microbiome are shown.</p

The microbial community composition from Patient 2 during and after probiotic treatment.

<p>(A) Samples and time line for Patient 2. MDS plot of the microbial flora from Patient 2 during and after probiotic treatment based on T-RFLP (B) and Illumina sequencing data (C). The green triangle represents the sample collected in November 2011 at Month 6 of probiotic treatment. All other samples were collected post-treatment between September 2013 and February 2014. The plot also shows time points prior to and after UTI occurrence and antibiotic treatment between September and October 2013. D. Microbial community composition at the genus level for Patient 2 during and after probiotic treatment, and prior to and after UTI occurrence based on Illumina sequencing data. The sample on the left was collected in November 2011 corresponding to Month 6 of probiotic treatment. The other samples were collected at six time points in the post-treatment period, between September 2013 and February 2014. The September 2013 sample was at a time point prior to UTI. Only OTUs representing at least 1% of the total community are shown. OTUs that were not resolved at the genus level are referred to by their lowest identified phylogenetic classification.</p

Additional file 1: of Probiotics [LGG-BB12 or RC14-GR1] versus placebo as prophylaxis for urinary tract infection in persons with spinal cord injury [ProSCIUTTU]: a study protocol for a randomised controlled trial

Guidelines for MRO change and clearance. (DOC 27 kb