Abstract & Commentary

Antimicrobial Prophylaxis for Children with Vesicoureteral Reflux

By Philip R. Fischer, MD, DTM&H, Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN.

Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN.

Dr. Fischer reports no financial relationships relevant to this field of study.

SYNOPSIS: Antimicrobial prophylaxis reduces the rate of recurrent urinary tract infection in children with vesicoureteral reflux, but it does not alter the rate of renal scarring. Intestinal flora develop antimicrobial resistance in children receiving prophylaxis.

SOURCE: RIVUR Trial Investigators. Antimicrobial prophylaxis for children with vesicoureteral reflux. New Engl J Med 2014;370:2367-2376.

The value of antimicrobial prophylaxis for children with vesicoureteral reflux is controversial. A collaborative effort included investigators at 19 sites in the United States. Otherwise healthy children aged 2 to 72 months without structural urologic abnormalities were enrolled after either a first or a second urinary tract infection if they had vesicoureteral reflux (grade I to grade IV). Subjects were randomized to receive either placebo or trimethoprim-sulfamethoxazole and were followed for evidence of recurrent urinary tract infections. Technetium-based renal scans were done at baseline and after one and two years of treatment. Rectal swabs at the end of the two-year study period were used to evaluate for E. coli resistance to trimethoprim-sulfamethoxazole.

A total of 607 children (92% female, median age 12 months) were enrolled in the study between June 2007 and May 2011. Most (91%) were enrolled after a first urinary tract infection, and 86% had been febrile with the initial urinary tract infection. Vesicoureteral reflux was graded II or III in 80% (and grade IV in just 8%) of subjects and was bilateral in 48%. Approximately one-fourth of parents discontinued use of the study medication.

There were 171 recurrent infections among 111 children; children treated with trimethoprim-sulfamethoxazole had only half the risk of recurrent infection as those treated with placebo. The risk of renal scarring was similar between groups (11.9% with prophylaxis, 10.2% with placebo, a statistically non-significant difference). Of children with a first recurrent urinary tract infection due to E. coli, rectal isolates showed trimethoprim-sulfamethoxazole resistance in 63% of those receiving prophylaxis and in 19% of those receiving placebo. Reflux had resolved in 51% of children by two years of study.

Thus, antimicrobial prophylaxis reduced the risk of recurrent urinary tract infection in children with reflux, but it did not alter the risk of developing renal scarring. The authors suggest that their findings might rightly prompt reevaluation of the "watchful waiting" approach to first urinary tract infections whereby imaging to identify reflux (and potentially give preventive antibiotics) is not recommended.

COMMENTARY

There is significant controversy regarding the evaluation and management of children following initial urinary tract infections. In 2011, the American Academy of Pediatrics (AAP) published a practice guideline suggesting that children aged 2 to 24 months with an initial febrile urinary tract infection not undergo testing for reflux (voiding cystourethrogram) since antimicrobial prophylaxis in children with reflux was not effective in reducing the risk of subsequent recurrent infection.¹ The AAP’s Section on Urology challenged the data underlying the AAP recommendation and countered with support of imaging following initial urinary tract infections; ² the original AAP group remained convinced of its recommendation.³

This new study provides data in support of the challenge to the AAP clinical practice guideline. This multi-centered study included only children with rigorously diagnosed urinary tract infection (allowing only cathetherized or suprapubically aspirated urine for culture) and shows conclusive evidence that prophylaxis is associated with a decreased risk of subsequent infection. Logically, since the evidence underlying the AAP clinical practice guideline is now supplemented with good contradictory evidence, there is reason to reconsider the AAP recommendation.

However, "reason to reconsider" is not the same as "reason to replace" the AAP recommendation. There are several "costs" associated with imaging and prophylaxis, including:

• the physical discomfort, potential psychological sense of being violated, and financial expense associated with voiding cystourethrograms in infants and young children

• the hassle of daily preventive medication (perhaps a reason that one-fourth of study subjects failed to continue the daily treatment)

• the risk to individuals and contacts of spreading organisms with enhanced antimicrobial resistance.

And, while these new data are clear about a reduced risk of subsequent infection with urinary prophylaxis, the extent of "benefit" of prophylaxis is not clear. Yes, preventive treatment will reduce infection (and, thus, discomfort, medical visits, and antimicrobial costs), but these new data show no change in renal scarring. If the benefit of prophylaxis is only on infection rates and not associated with any change in later outcomes or changed renal function, then the "benefit" of prophylaxis is somewhat limited.

Thus, further studies and further cost-benefit analyses are needed. As mentioned in an editorial accompanying the RIVUR paper, a move to recommend prophylactic antibiotics "awaits more evidence before universal adoption."⁴ Despite remaining questions,⁵ it is anticipated that ongoing study will provide answers to guide future practice.

References

1. Subcommittee on Urinary Tract Infection, American Academy of Pediatrics. Urinary 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;128:595-610.
2. Wan J, Skoog SJ, Hulbert WC, et al. Section on Urology response to the new guidelines for the diagnosis and management of UTI. Pediatrics 2012;129.
3. Roberts KB, et al. Response to the AAP Section on Urology concerns about the AAP Urinary Tract Infection Guideline. Pediatrics 2012:129:e124-126.
4. Ingelfinger JR, Stapleton FB. Antibiotic prophylaxis for vesicoureteral reflux – answers, yet questions. New Engl J Med 2014;370:2550-2441.
5. Clyne M. Paediatrics: antimicrobial prophylaxis for vesicoureteral reflux – where will the RIVUR study lead us? Nat Rev Urol 2014;11:301.