Is Antibiotic Prophylaxis in Children With Vesicoureteral Reflux Effective in Preventing Pyelonephritis and Renal Scars? A Randomized, Controlled Trial

To the Editor.—The study by Pennesi et al1 was impressive in scope—spanning 7 centers and nearly 8 years—but had several limitations that threaten the validity of its findings and the certainty with which we can dismiss the role of antibiotic prophylaxis outright. First, the study sample was very small and had power to show only large differences in recurrent pyelonephritis rates. Given their sample size and observed 30% rate of recurrent pyelonephritis in the “no-prophylaxis” group, the recurrent pyelonephritis rate in children receiving antibiotic prophylaxis would had to have been <6.6% for the study to detect a statistically significant effect with 80% power. The study was not powered to detect smaller clinically significant reductions in recurrent pyelonephritis or to perform subgroup analyses to identify groups of children for whom prophylactic antibiotics might have been effective.Second, we have serious concerns about the validity of the urine cultures obtained in the study, the majority of which were bag specimens. Requiring pyuria and ≥107 colony-forming units per mL of the same bacterium in 2 different samples likely improved the specificity of the urine cultures, but bag specimens are fraught with false-positive results caused by contamination,2 and so any potential effect of antibiotic prophylaxis might have been diluted by (presumably) nondifferential misclassification of the primary outcome, recurrent pyelonephritis.Finally, the study, like its recent predecessors,3,4 was unblinded (no placebo control). If some urinary tract infections (UTIs) get better without antibiotics, and parents of children not receiving prophylaxis were more likely to seek medical care and their providers more likely to attempt to diagnose a UTI, then this “workup” bias could have inflated the number of UTIs diagnosed in children not receiving prophylaxis, biasing the results against showing a benefit of prophylaxis.The RIVUR (Randomized Intervention for Children With Vesicoureteral Reflux) Study, a National Institutes of Health–funded multicenter, randomized, placebo-controlled trial of prophylactic trimethoprim-sulfamethoxazole for children aged 2 to 72 months diagnosed with grades I through IV vesicoureteral reflux after a first or second UTI, will address these limitations. [See supplement with this issue of Pediatrics.] With a larger sample size (N = 600), double-blinding, and requirement of catheterized urine samples from children unable to provide clean-catch samples, we seek to validate the results of similar recent small trials and possibly identify subgroups of patients who may benefit from antimicrobial prophylaxis.