Antimicrobial prophylaxis for children with vesicoureteral reflux

Abstract

Background: Children with febrile urinary tract infection commonly have vesicoureteral reflux. Because trial results have been limited and inconsistent, the use of antimicrobial prophylaxis to prevent recurrences in children with reflux remains controversial.

Methods: In this 2-year, multisite, randomized, placebo-controlled trial involving 607 children with vesicoureteral reflux that was diagnosed after a first or second febrile or symptomatic urinary tract infection, we evaluated the efficacy of trimethoprim-sulfamethoxazole prophylaxis in preventing recurrences (primary outcome). Secondary outcomes were renal scarring, treatment failure (a composite of recurrences and scarring), and antimicrobial resistance.

Results: Recurrent urinary tract infection developed in 39 of 302 children who received prophylaxis as compared with 72 of 305 children who received placebo (relative risk, 0.55; 95% confidence interval [CI], 0.38 to 0.78). Prophylaxis reduced the risk of recurrences by 50% (hazard ratio, 0.50; 95% CI, 0.34 to 0.74) and was particularly effective in children whose index infection was febrile (hazard ratio, 0.41; 95% CI, 0.26 to 0.64) and in those with baseline bladder and bowel dysfunction (hazard ratio, 0.21; 95% CI, 0.08 to 0.58). The occurrence of renal scarring did not differ significantly between the prophylaxis and placebo groups (11.9% and 10.2%, respectively). Among 87 children with a first recurrence caused by Escherichia coli, the proportion of isolates that were resistant to trimethoprim-sulfamethoxazole was 63% in the prophylaxis group and 19% in the placebo group.

Conclusions: Among children with vesicoureteral reflux after urinary tract infection, antimicrobial prophylaxis was associated with a substantially reduced risk of recurrence but not of renal scarring. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; RIVUR ClinicalTrials.gov number, NCT00405704.).

Figure 1. Enrollment, Randomization, and Follow-up of Children in the Trial

Capture of screening data commenced in November 2007; children were enrolled at various clinical sites (emergency departments, radiology departments, and primary care, urology, and nephrology offices), resulting in diverse criteria for screening (abnormal urinalysis results, positive urine culture, and abnormal result of voiding cystourethrography [VCUG]). Enrollment of children commenced in June 2007; 115 eligible children were enrolled throughout the study without corresponding screening data for those not enrolled. Children who were withdrawn from the study by a parent include some children who discontinued the intervention because they met criteria for treatment failure or had a parent who preferred prophylaxis to be prescribed. TMP-SMX denotes trimethoprim–sulfamethoxazole, UTI urinary tract infection, and VUR vesicoureteral reflux.

Figure 2. Time to First Recurrent Febrile or Symptomatic UTI

Shown are Kaplan–Meier estimates of the cumulative percentage of children who had a recurrent febrile or symptomatic UTI according to study group. Fewer children assigned to TMP-SMX prophylaxis had a UTI than children assigned to placebo (P<0.001 by log-rank test). I bars indicate 95% confidence intervals.

Figure 3. Effect of Antimicrobial Prophylaxis on the Risk of Febrile or Symptomatic UTI

Depicted are hazard ratios (rectangles) and 95% confidence intervals (horizontal lines) for a first recurrent febrile or symptomatic UTI overall and for subgroups. P values are based on Wald tests for the interaction of subgroup with study-group assignment. Hazard ratios of less than 1.00 indicate that the risk of a recurrent febrile or symptomatic UTI was lower among the children randomly assigned to antimicrobial prophylaxis than among those assigned to placebo. BBD denotes bladder and bowel dysfunction.