A Phase Ia Clinical Trial of Intravesical Probiotic Instillation in Children and Adults Demonstrates Safety and Tolerability, and Suggests the Urine Microbiome Varies with Age
Michael Hsieh, MD/PhD1, Suzanne Groah, MD2, Marcos Perez-Losada, PhD3, Ljubica Caldovic, PhD1, Tanya Davis, MD1, Inger Ljungberg, BS2, Amanda Rounds, BS2, Bruce Sprague, MS1, Hans Pohl, MD1.
1Children's National Medical Center, Washington, DC, USA, 2National Rehabilitation Hospital, Washington, DC, USA, 3George Washington University, Washington, DC, USA.
Introduction: Manipulation of the microbiome is an emerging approach to promote health. We conducted a Phase Ia safety study of a single bladder instillation of probiotics in asymptomatic children and adults with neuropathic bladder. We sought to determine the tolerability and safety of a single instillation, whether the instilled Lactobacillus persists in the urine, and if children differ from adults with regards to these endpoints.
Methods: IRB and FDA approval was obtained for this study. Target enrollment was five children with spina bifida(SB), and five adults with spinal cord injury(SCI) or SB. Inclusion criteria were: 1) if SCI, at least 1-year duration; 2) neuropathic bladder; 3) utilizing intermittent catheterization; and 4) community dwelling. We excluded patients with: 1) genitourinary pathology beyond neuropathic bladder; 2) instillation of other intravesical agents; 3) psychological or psychiatric conditions influencing the ability to follow instructions; 4) participation in a confounding study; 5) pregnant or breastfeeding women; 6) individuals with immunodeficiencies; active or chronic serious infections; 7) individuals with cancer/autoimmune disorders; 8) allergy to any component in the probiotic product; 9) a change in neurologic status in the previous 2 weeks; 10) taken antibiotic in the previous 2 weeks; 11) sensitivity to ampicillin or tetracycline; and 12) UTI within the previous 2 weeks(as defined by Infectious Diseases Society of America CAUTI Guidelines, 2010).
At baseline, subjects completed the validated Urinary Symptoms Questionnaire for People With Neuropathic Bladder(USQ-NB). Urine was collected for urinalysis, urine culture, and 16S bacterial rRNA-based microbiome analyses. Patients underwent one Lactobacillus(Culturelle GG, 20 Billion live organisms) instillation by study personnel at the study site. Participants were observed in the clinic for 30 minutes after instillation to assure that no adverse reactions occurred.
Afterwards, participants self-monitored symptoms using the USQ-NB daily for one week. They were instructed to contact study personnel for any urinary symptoms. They returned to the clinic 7-10 days after instillation for repeat urinalysis, urine culture, and microbiome analyses.
Results: Five children with spina bifida (4 boys and 1 girl aged 6-12 years) and five adults with spina cord injury or spina bifida were recruited at Children's National Medical Center and the Medstar National Rehabilitation Hospital. Probiotic instillation was well-tolerated. One child had upper respiratory tract symptoms during the trial, whereas two had transient malodorous and/or cloudy urine. Three out of 5 of the children had E. coli on culture both pre- and post-probiotic instillation, and a fourth child acquired E. coli following probiotic instillation. Lactobacillus did not grow on culture post-instillation. There were differences in beta diversity of the urine microbiome in children vs. adults with neuropathic bladder (p<0.0156). There was a trend toward variation in the mean proportion of Neisseria comparing children vs. adults (p=0.058). Streptococcus was associated with pyuria and younger age (p=.00314).
Conclusions: Our trial suggests that intravesical instillation of Culturelle may be well-tolerated by and safe for children. Microbiome analyses confirm that children and adults may have differing urine microbiomes, which has important implications for future probiotic interventions.
Back to 2017 Program