Enterococcus faecalis persistence in paediatric patients treated with continuous antibiotic prophylaxis for recurrent urinary tract infections
Samantha Whiteside, PhD1, Shannon Seney, BSc2, Peter Wang, Doctor of Medicine3, Gregor Reid, PhD2, Jeremy Burton, PhD2, Sumit Dave, Doctor of Medicine3.
1University of Western Ontario, Department of Microbiology and Immunology, London, ON, Canada, 2Lawson Health Research Institute, London, ON, Canada, 3London Health Sciences Centre, London, ON, Canada.
The use of continuous antibiotic prophylaxis (CAP) is controversial in children with recurrent urinary tract infections (RUTI). Enterococcus faecalis, is one of the common causes of RUTI, yet enterococcal urinary pathogenesis is poorly understood. Given the inherent resistance of E. faecalis to antimicrobials we hypothesized that E. faecalis would be prevalent in the urine of paediatric patients with RUTI, and short-term CAP would not eradicate these bacteria.
We conducted a prospective cohort study in pediatric patients with a history of RUTI (>2 febrile culture proven UTI’s in the 6 months prior to enrolment), with no anatomical anomalies (negative US and VCUG) between 2014-2016. Patients were divided into two groups at the discretion of parents, who were given the option of choosing CAP (either trimethoprim-sulfamethoxazole or nitrofurantoin for 6-months) or observation according to standard clinical practice. Both groups received standard management of associated bladder bowel dysfunction. First-void and midstream urine samples were collected at baseline and at 3-month intervals for one year. Age-matched, healthy controls provided urine samples at a single time-point. Bacterial culture of urine samples was completed and urinary cytokines were quantified. In vitro, the attachment of clinical strains of E. faecalis and E. coli to a human urinary bladder epithelial cell line was determined in the presence and absence of TMP/SMX or nitrofurantoin. The transcriptional response of E. faecalis to nitrofurantoin was assessed by quantitative RT-PCR.
Although none of the patients were symptomatic at the time of sample collection, 19% of urine samples met the diagnostic cut-off for UTI (105 bacteria of one species), suggesting asymptomatic bacteriuria. Viable counts of E. faecalis were not significantly different between RUTI and healthy controls, while E. coli load was significantly higher in RUTI patients (p < 0.0001). Enterococci were significantly more likely to be isolated from RUTI patients (p= 0.04), compared to controls. Antibiotic prophylaxis mediated a slight decrease in uropathogen load; however, bacterial counts returned to pre-CAP levels during the 6-month period after cessation of CAP. Urinary cytokine assessment showed that IL-6 levels was significantly higher in controls compared to the RUTI group at baseline (p = 0.03). We noted a significant increase in the attachment of E. faecalis to urothelial cells in the presence of nitrofurantoin (P = 0.0001), which did not correlate with increased expression of genes involved in enterococcal attachment.
This study demonstrates the presence of enterococci in the urine of asymptomatic healthy and RUTI paediatric patients, suggesting that these bacteria may be part of the normal urinary microbiome. CAP causes a transient decrease in urinary bacterial load, but counts return to pre-CAP levels at the culmination of therapy. Our data also indicate that bacteria may be interfering with the innate immune system as IL-6 was lower in the urine of RUTI patients. Additionally, CAP using nitrofurantoin increases Enterococcal bacterial attachment, which may lead to enterococcal UTI recurrence after CAP cessation. These findings raise questions about the use of nitrofurantoin prophylaxis for enterococcal RUTI in children.
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