VANCOUVER – Two years of low-dose trimethoprim-sulfamethoxazole prophylaxis halved the risk of recurrent urinary tract infections, but did not prevent renal scarring in a trial of 607 children with vesicoureteral reflux that was published online May 4 in the New England Journal of Medicine, and presented concurrently at the annual meeting of the Pediatric Academic Societies.
Within 112 days of their first or second febrile or symptomatic urinary tract infection (UTI), 302 young children diagnosed with vesicoureteral reflux (VUR) by voiding cystourethrogram were randomized to 3 mg of trimethoprim plus 15 mg of sulfamethoxazole per kilogram; and 305 other VUR children were randomized to placebo.
Alexander Otto/Frontline Medical News
Dr. Alejandro Hoberman
Thirty-nine (13%) children who received antimicrobial prophylaxis developed a recurrent febrile or symptomatic UTI, compared with 72 (24%) who received a placebo (hazard ratio for risk of recurrence, 0.50; 95% confidence interval, 0.34-0.74). Prophylaxis was particularly effective in children whose index UTI was febrile (HR, 0.41; 95% CI, 0.26-0.64) and in those with baseline bladder and bowel dysfunction (HR, 0.21; 95% CI, 0.08-0.58).
Nuclear imaging showed no significant between-group differences in the incidence of renal scarring (11.9% in the treated group vs. 10.2% in the placebo group; P = 0.55), severe renal scars (4.0% vs. 2.6%; P = 0.37), or new renal scars since baseline (8.2% vs. 8.4%; P = 0.94) at trial completion (N. Eng. J. Med. 2014 May 4 [doi: 10.1056/NEJMoa1401811]).
"This study showed unequivocal evidence that antimicrobial prophylaxis reduced at least in half the likelihood of children having recurrent UTIs. Rates of renal scarring ... were low and not reduced by prophylaxis, perhaps because most children were enrolled after their first infection and because parents, instructed to be vigilant, sought early medical attention," said Dr. Alejandro Hoberman, a professor of pediatrics at the University of Pittsburgh and lead investigator in the multicenter study, dubbed the RIVUR (Randomized Intervention for Children with Vesicoureteral Reflux) trial.
"As long as evidence supporting the benefit of prophylaxis was dubious, the recommendation of a watchful-waiting approach, without performance of a voiding cystourethrographic study, seemed reasonable, because the imaging findings would not affect the nature of treatment. However, our finding that antimicrobial prophylaxis was associated with a reduced risk of recurrence may warrant reconsideration of that recommendation," the investigators said.
Eight children would have had to be treated for 2 years to prevent one case of febrile or symptomatic UTI. Several audience members, after hearing the results, wondered if the benefits of prophylaxis outweighed the costs, given that there was no effect on the incidence of renal scarring in the short term, and the difficulty and expense of performing voiding cystourethrographic studies, among other concerns.
Dr. Hoberman plans to investigate the cost-effectiveness implications of the findings, and, in the meantime, he noted that the study offers proof that prophylaxis helps prevent recurrent UTIs, something that was uncertain in the past. Also, he noted, the study was not powered to detect a difference in renal scarring as a primary outcome.
The children were aged 2-71 months (median age, 12 months), and 92% were girls. Eighty percent had grade II or III vesicoureteral reflux, and 48% had bilateral reflux.
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. "Not unexpectedly, recurrences that did occur in children who received prophylaxis were more likely to have been caused by a resistant pathogen," the investigators said.
Parents of 77% of the children reported that they had given the study medication at least 75% of the time, and parents of 85% reported administering it at least 50% of the time. There was no significant difference in reported adherence between the study groups.
Dr. Hoberman had no disclosures. The work was funded by the National Institute of Diabetes and Digestive and Kidney Diseases.