Narrowing the Focus: What We Now Know (and Still Don’t Know) About Antibiotic Prophylaxis for Children With Vesicoureteral Reflux

Abstract

Commentary on RIVUR Trial Investigators, Hoberman A, Greenfield SP, Mattoo TK, et al. Antimicrobial prophylaxis for children with vesicoureteral reflux. N Engl J Med. 2014;370(25):2367-2376. Commentary on RIVUR Trial Investigators, Hoberman A, Greenfield SP, Mattoo TK, et al. Antimicrobial prophylaxis for children with vesicoureteral reflux. N Engl J Med. 2014;370(25):2367-2376. The role of antimicrobial prophylaxis in children with vesicoureteral reflux, the retrograde flow of urine from the bladder to the kidneys, has been the subject of ongoing debate among pediatricians, pediatric nephrologists, and urologists. Vesicoureteral reflux is found in ∼30% of children presenting with a febrile urinary tract infection (UTI), but resolves spontaneously in many. When present, vesicoureteral reflux increases the risk of febrile UTI in children, which has been associated with renal scarring.1Hoberman A. Charron M. Hickey R.W. Baskin M. Kearney D.H. Wald E.R. Imaging studies after a first febrile urinary tract infection in young children.N Engl J Med. 2003; 348: 195-202Crossref PubMed Scopus (568) Google Scholar The mainstays of therapy for vesicoureteral reflux have been active surveillance with or without antibiotic prophylaxis or surgical intervention, including endoscopic subureteric injections and ureteral reimplantation, to correct the reflux. Until completion of the Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR) trial, the efficacy and associated harms of antibiotic prophylaxis in preventing recurrent febrile UTI among children with vesicoureteral reflux were uncertain. RIVUR was a randomized, double-blind, placebo-controlled trial of daily trimethoprim-sulfamethoxazole in children aged 2 to 71 months with grades I to IV vesicoureteral reflux diagnosed after 1 or 2 febrile or symptomatic UTIs.2Hoberman A. Greenfield S.P. Mattoo T.K. et al.RIVUR Trial InvestigatorsAntimicrobial prophylaxis for children with vesicoureteral reflux.N Engl J Med. 2014; 370: 2367-2376Crossref PubMed Scopus (361) Google Scholar The children, of whom 92% were girls, were recruited from 19 study sites across the United States and followed up for 2 years. The primary outcome was febrile or symptomatic recurrent UTI. Catheterized urine cultures were obtained for non–toilet-trained children and clean voided specimens were obtained from toilet-trained children. The investigators also assessed several secondary outcomes, including new renal scarring by kidney dimercaptosuccinic acid (DMSA) scan, antibiotic resistance, and treatment failure. Treatment failure was defined as 2 febrile recurrences, 1 febrile and 3 symptomatic recurrences, 4 symptomatic recurrences, or new or worsening kidney scarring. Importantly, the investigators systematically assessed bowel-bladder dysfunction, which increases the risk of recurrent UTI in children with vesicoureteral reflux.3Leslie B. Moore K. Salle J.L. et al.Outcome of antibiotic prophylaxis discontinuation in patients with persistent vesicoureteral reflux initially presenting with febrile urinary tract infection: time to event analysis.J Urol. 2010; 184: 1093-1098Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar Antibiotic prophylaxis reduced the risk of recurrent UTI by 50% (hazard ratio [HR] 0.50; 95% confidence interval [CI], 0.34-0.74). Significant effect modification by type of index infection (febrile vs nonfebrile) and bowel-bladder dysfunction (present vs absent) was found. Antibiotic prophylaxis reduced the absolute risk of recurrent UTI by 12%. Accordingly, 8 children with vesicoureteral reflux would need to be treated to prevent one UTI over a 2-year period. In children with bowel-bladder dysfunction, prophylaxis reduced the risk by 79% (HR, 0.21; 95% CI, 0.08-0.58), and in children in whom the index infection was febrile, prophylaxis reduced the risk by 39% (HR, 0.41; 95% CI, 0.26-0.64). Of the children who developed a recurrent UTI, 63% of bacteria causing the infection were resistant to trimethoprim-sulfamethoxazole in the prophylaxis group, whereas 19% were resistant in the placebo arm. The proportion of children with baseline “scars” was low (∼4%), and there were no differences in new kidney scars on 1- or 2-year DMSA scans between groups. Well powered to detect a clinically important outcome, RIVUR represents one of the most definitive studies conducted to date to address the question of whether antibiotic prophylaxis reduces recurrent UTIs in children with vesicoureteral reflux. The distribution of age, sex, and reflux grade in the patients enrolled in the study is representative of the population seen clinically. One of the most intriguing and important findings of RIVUR is the identification of patients who are at high risk of recurrent UTI and for whom antibiotic prophylaxis is particularly effective (children with bowel-bladder dysfunction and a first UTI associated with fever). As in all randomized trials, it is uncertain whether results will translate to real-life clinical practice. In RIVUR, 77% of children were given either trimethoprim-sulfamethoxazole or placebo at least 75% of the time, and 85% were given the medication at least 50% of the time. However, in clinical practice, Copp et al4Copp H.L. Nelson C.P. Shortliffe L.D. et al.Compliance with antibiotic prophylaxis in children with vesicoureteral reflux: results from a national pharmacy claims database.J Urol. 2010; 183: 1994-1999Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar estimated that only 40% of children with vesicoureteral reflux were adherent to treatment, defined as taking antibiotics 80% of the prescribed time. This calls into question whether the effectiveness of antibiotic prophylaxis will be maintained when administered less consistently, as may occur in clinical practice. Furthermore, the risk of development of antimicrobial resistance in recurrent febrile or systematic UTI was substantially higher in children receiving prophylaxis. In the New England Journal of Medicine in 2009, Craig et al5Craig J.C. Simpson J.M. Williams G.J. et al.Antibiotic prophylaxis and recurrent urinary tract infection in children.N Engl J Med. 2009; 361: 1748-1759Crossref PubMed Scopus (330) Google Scholar reported results of a randomized placebo-controlled trial of the efficacy of daily trimethoprim-sulfamethoxazole in preventing recurrent symptomatic UTI in children with a history of UTI, with and without vesicoureteral reflux. Antibiotic prophylaxis reduced the risk of recurrent infection by 39% (HR, 0.61; 95% CI, 0.40-0.93). Although the reduction in the relative hazard of UTI was substantial, the absolute risk reduction conferred by antibiotic prophylaxis was 6%. This means that 17 patients would need to be treated to prevent one recurrent UTI over 1 year. The absolute risk reduction also was 6% when only febrile recurrences were considered. Similar to RIVUR, no differences in renal scarring were observed between the antibiotic group and the placebo group. From these results, the authors concluded that it would be reasonable to recommend prophylaxis in children who are at high risk for recurrent infection or in whom the index infection was severe. However, given there were no significant interactions between age, sex, reflux status, number of UTIs, or antibiotic susceptibility of the organism causing the index infection, the population in whom antibiotic prophylaxis could be used most effectively remained uncertain. In 2010, Swedish investigators reported in The Journal of Urology the results of a multi-institutional trial in which children with a history of UTI were randomly assigned to antibiotic prophylaxis, endoscopic injection, or observation without antibiotics. The results, which were presented in 5 separate articles,6Brandstrom P. Neveus T. Sixt R. Stokland E. Jodal U. Hansson S. The Swedish reflux trial in children: IV. Renal damage.J Urol. 2010; 184: 292-297Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar, 7Brandstrom P. Esbjorner E. Herthelius M. Swerkersson S. Jodal U. Hansson S. The Swedish reflux trial in children: III. Urinary tract infection pattern.J Urol. 2010; 184: 286-291Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar, 8Sillen U. Brandstrom P. Jodal U. et al.The Swedish reflux trial in children: V. Bladder dysfunction.J Urol. 2010; 184: 298-304Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 9Holmdahl G. Brandstrom P. Lackgren G. et al.The Swedish reflux trial in children: II. Vesicoureteral reflux outcome.J Urol. 2010; 184: 280-285Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar, 10Brandstrom P. Esbjorner E. Herthelius M. et al.The Swedish reflux trial in children: I. Study design and study population characteristics.J Urol. 2010; 184: 274-279Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar generally showed that girls were at higher risk for adverse outcomes including recurrent infection and scarring, and that treatment (either endoscopic injection or antibiotic prophylaxis) reduced the proportion of children with UTI recurrence and new kidney abnormalities on DMSA scan. However, relative or absolute risks associated with either intervention or outcomes were not specifically reported. Additionally, 18 of 49 (37%) patients with the event of recurrent UTI had urine obtained by bagged collection, with <5% of urine cultures obtained by catheter or suprapubic aspiration. The use of urine specimens obtained by bagged collection further confounded the potential interpretation because children in the surveillance arm had a disproportionate proportion of urine specimens obtained by bag collection and 7 of 24 girls randomly assigned to surveillance who developed “recurrent febrile UTI” had culture results that did not meet a priori–defined criteria. These methodological differences in reporting limit the ability to directly compare RIVUR results with the Swedish Reflux Trial. A systematic Cochrane review published in 2011 evaluating 20 randomized controlled trials including the Swedish Reflux Trial and the trial of Craig et al5Craig J.C. Simpson J.M. Williams G.J. et al.Antibiotic prophylaxis and recurrent urinary tract infection in children.N Engl J Med. 2009; 361: 1748-1759Crossref PubMed Scopus (330) Google Scholar suggested that there was no compelling evidence for routine antibiotics in primary vesicoureteric reflux grades I to V.11Nagler E.V. Williams G. Hodson E.M. Craig J.C. Interventions for primary vesicoureteric reflux.Cochrane Database Syst Rev. 2011; 6: CD001532PubMed Google Scholar Due to heterogeneity of the predictor variables and outcomes assessed by studies included in the Cochrane review, analyses of effect modification by bowel-bladder dysfunction and febrile index UTI on UTI recurrence were not performed. RIVUR seems to provide substantially more evidence for intervention in these groups. After years of uncertainty about the efficacy of antibiotic prophylaxis in vesicoureteral reflux, RIVUR has provided new information, specifically demonstrating that antibiotic prophylaxis using trimethoprim-sulfamethoxazole safely decreases the risk of recurrent febrile UTI in children with vesicoureteral reflux. Although there was no evidence of a decrease in the incidence of new renal scarring, the study was not powered to assess this secondary end point. It may be reasonable to prescribe prophylaxis for children with known vesicoureteral reflux and a history of febrile UTI and/or bowel-bladder dysfunction, although it is worth considering that 8 children would have to take 2 years of daily antibiotics to prevent one recurrent UTI. Use of antimicrobial prophylaxis should not preclude treating other modifiable risk factors for recurrent UTI. Specifically, coincident with administering prophylaxis in these patients, clinicians should aggressively treat bowel-bladder dysfunction through timed voiding, treating constipation, and hydration. In order to identify bowel-bladder dysfunction, providers should carefully assess elimination habits and elicit commonly associated symptoms, such as frequency of voiding, urinary holding, and, in potty-trained children, daytime and night-time wetting. Additionally, it needs to be recognized that prophylaxis also increases the risk for the development of resistant organisms. The benefits of reducing risk for recurrent UTI along with the risk for developing antibiotic resistance should be discussed with patients and families in deciding treatment plans. The conclusions of this study also raise a number of questions. In current pediatric practice, first febrile UTIs are evaluated with sonography, but not necessarily a voiding cystourethrogram, to assess for the presence of reflux. In 2003, Hoberman et al1Hoberman A. Charron M. Hickey R.W. Baskin M. Kearney D.H. Wald E.R. Imaging studies after a first febrile urinary tract infection in young children.N Engl J Med. 2003; 348: 195-202Crossref PubMed Scopus (568) Google Scholar noted that “A voiding cystourethrogram to identify children with vesicoureteral reflux is recommended under the so far unproven assumption that continuous antimicrobial therapy is effective in reducing the incidence of reinfection and renal scarring.”1Hoberman A. Charron M. Hickey R.W. Baskin M. Kearney D.H. Wald E.R. Imaging studies after a first febrile urinary tract infection in young children.N Engl J Med. 2003; 348: 195-202Crossref PubMed Scopus (568) Google Scholar Although the authors of RIVUR suggest that the efficacy of prophylaxis in reducing recurrent UTI supports “reconsideration” of the 2011 American Academy of Pediatrics guidelines to not routinely obtain a voiding cystourethrogram after the first UTI,12Subcommittee on Urinary Tract Infection Steering Committee on Quality Improvement and ManagementUrinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months.Pediatrics. 2011; 128: 595-610Crossref PubMed Scopus (1175) Google Scholar the objective of RIVUR was not to determine when a child with a UTI should be screened for vesicoureteral reflux. We must be careful not to conflate the decision to screen a child for vesicoureteral reflux with the decision to treat a child with vesicoureteral reflux. The waters are still muddy here, particularly when one takes into account the results of Craig et al,5Craig J.C. Simpson J.M. Williams G.J. et al.Antibiotic prophylaxis and recurrent urinary tract infection in children.N Engl J Med. 2009; 361: 1748-1759Crossref PubMed Scopus (330) Google Scholar who found that antibiotic prophylaxis reduces the risk of recurrent UTI among children regardless of the presence of reflux. Should all children with an initial UTI receive prophylaxis? Probably not. RIVUR results provide some guidance here because those with febrile UTIs and those with bowel and bladder dysfunction appear to receive the most benefit. Should all children with an initial UTI receive a voiding cystourethrogram? Probably not, but RIVUR does not directly address this question. Further light may be shed on this subject by the ongoing Careful Urinary Tract Infection Evaluation (CUTIE) Study of Risk Factors for Renal Scarring in Children After Urinary Tract Infection. RIVUR shows us who the highest risk groups are that may benefit from antibiotic prophylaxis, but how long they should be treated and whether a voiding cystourethrogram should be obtained in the evaluation of a first febrile UTI remain unanswered questions. Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.