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Prophylactic antibiotics halve UTI risk in VUR.


VANCOUVER, B.C. -- 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.

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). Prophylaxis was particularly effective in children whose index UTI was febrile (HR, 0.41) and in those with baseline bladder and bowel dysfunction (HR, 0.21). 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 = .55), severe renal scars (4.0% vs. 2.6%; P = .37), or new renal scars since baseline (8.2% vs. 8.4%; P = .94) (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.

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.

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.

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.

Dr. Hoberman had no disclosures. The work was funded by the National Institute of Diabetes and Digestive and Kidney Diseases.

The jury is still out

"As in most studies of complex conditions, unresolved questions remain. Only one form of antibiotic prophylaxis was used [in the study]; therefore, the effectiveness of other prophylactic antibiotic strategies remains untested. The evaluation of scarring was determined after only 2 years, leaving the long-term degree of renal injury unknown.

"Sadly, the decision to use antibiotic prophylaxis in children with reflux remains a clinical dilemma, despite this well-done study. In the face of the emergence of antibiotic resistance, the lack of a significant between-group difference in renal parenchymal scarring, and questions about generalizability, the RIVUR study results would imply that the general recommendation of prophylactic antibiotics for vesicoureteral reflux in young children awaits more evidence before universal adoption."

Dr. Julie Ingelfinger is the senior consultant in pediatric nephrology at the Massachusetts General Hospital in Boston. Dr. F. Bruder Stapleton is a professor and chair of pediatrics at the University of Washington in Seattle. They made their comments in an editorial that accompanied the study (N. Eng. J. Med. 2014 May 4 [doi: 10.1056/NEJMe1404774]), and they had no relevant disclosures.


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Author:Otto, M. Alexander
Publication:Pediatric News
Date:May 1, 2014
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