The use of prophylactic antibiotics to prevent urinary tract infections (UTIs) associated with vesicoureteral reflux (VUR) has been controversial, and a multisite clinical trial in which The Children’s Hospital of Philadelphia participated in is adding to the debate. Results from the trial published in The New England Journal of Medicine were “pretty dramatic,” according to co-investigator Ron Keren, MD, MPH, vice president of quality and chief quality officer for CHOP.
About 5 percent of children will experience a UTI by the time they reach age 6, and approximately one-third of these patients have VUR. When a child with VUR urinates, some urine backs up in the ureters toward the kidneys and so the bladder does not empty completely. This increases the chance of a UTI occurring, and if it reaches the kidneys, it is often accompanied by a fever and is called pyelonephritis.
“The problem with pyelonephritis is that it sometimes results in kidney scarring, and there is a concern that this could lead to high blood pressure and renal failure when you get older,” Dr. Keren explained.
Clinicians currently use a long-term course of daily antibiotics or antireflux surgery to treat children with VUR. However, an international clinical study conducted in the 1980s that compared the two approaches showed no difference in the rates of recurrent UTIs or renal scarring. More recent trials that looked at antibiotics’ effectiveness had conflicting results and methodological weaknesses, so researchers launched the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial to obtain more evidence to guide clinical practice.
The study included 607 children, mostly girls, between the ages of 2 and 6 who had VUR. They were recruited from 19 clinical sites across the U.S and followed for two years. Researchers analyzed the data to determine if children who received daily doses of trimethoprim-sulfamethoxazole had fewer recurrences of UTIs than children who received the placebo and if there were any differences in the occurrence of renal scarring.
“The rate of recurrent UTIs was cut in half for those in the antimicrobial prophylaxis group,” Dr. Keren said. “I was surprised that the prophylactic antibiotics worked as well as they did.”
The percentage of children getting UTIs continued to increase over time in the placebo group but not in the treatment group, Dr. Keren pointed out, which demonstrates the sustained effectiveness of antibiotic prophylaxis. Also, certain subgroups of children — those with bowel and bladder dysfunction and those who had febrile UTIs — seemed to benefit the most from the long-term antibiotics.
The occurrence of renal scarring did not differ significantly between the treatment and placebo groups. This finding likely will add fuel to an ongoing debate, Dr. Keren said. Some physicians will say it is not worth using daily antibiotics in children with VUR if they do not prevent kidney damage. Others will say it is important to continue to treat these children with antibiotics because a UTI recurrence could land them in the emergency room or hospital.
Another contentious issue among clinicians is the use of urinary tract imaging, known as a voiding cystourethrogram (VCUG), to screen for VUR. While VCUG can be a helpful diagnostic tool, it involves radiation exposure, is invasive and uncomfortable, and can be traumatic for young children. Current guidelines recommend that physicians take a watchful waiting approach until a second febrile UTI happens before suggesting that a child go through the procedure. Part of the rationale for the watchful waiting approach was the lack of strong evidence for the effectiveness of prophylaxis in children found to have VUR.
“Now that we know that prophylaxis works, this changes our calculus about the risks and benefits of getting a VCUG on every child who has a first UTI,” Dr. Keren said.
But even without prophylaxis, only one-quarter of children with VUR will experience a repeat UTI, so Dr. Keren emphasized that it is important to explain to families what the research shows and to help parents to make informed decisions about whether to proceed with VCUG imaging.
With so many ongoing discussions about the best ways to approach UTIs, the issue is ripe for further research. Dr. Keren is involved with another NIH supported study that follows a design similar to RIVUR, known as the Careful Urinary Tract Infection Evaluation (CUTIE) trial, but it is focusing on the rate of recurrent UTIs and kidney scarring in children who do not have VUR.
The RIVUR study was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases and the National Center for Advancing Translational Science. In addition to CHOP, the primary clinical trial sites included Children’s Hospital of Pittsburgh; Women and Children’s Hospital of Buffalo; Wayne State University School of Medicine, Detroit; and Johns Hopkins School of Medicine, Baltimore.