UTI treatment, prophylaxis remain controversial

Clinical practice guidelines were introduced in 1999 by the American Academy of Pediatrics for management of pediatric patients with urinary tract infections, but several studies have emerged in recent years that have muddied the waters about whether these guidelines are the best approach.

These studies have prompted AAP officials to re-examine the data and provide a revision to the 1999 guideline. However, none of the current studies offer definitive insights into best practices for children with urinary tract infections (UTIs).

In a meta-analysis published last year, Infectious Diseases in Children Editorial Board member Alejandro Hoberman, MD, and colleagues said there may be a general movement away from prophylaxis. However, the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) study, which is sponsored by the NIH and is currently being conducted by Hoberman and colleagues, may help end the debate on the effectiveness of prophylactic antibiotics in children with vesicoureteral reflux (VUR) to prevent recurrent UTIs and renal scarring. In addition, there are recently published data from Australia and Sweden that suggest that prophylaxis may be of value in some patients. Data also conflict on the best therapeutic approaches for children with recurrent infections.

Until more definitive answers are available, all of these articles recommend evaluating treatment options in each patient on an individual, case-by-case basis.

“The [AAP] guideline has been in the works for some time now, and it has been reviewed by a lot of people, and it is a rationale guideline,” said Infectious Diseases in Children Editorial Board member Ellen Wald, MD. Another Infectious Diseases in Children Editorial Board member, John S. Bradley, MD, who this month wrote an editorial on UTI management, agreed with Wald and said the problem is that there are simply not enough definitive data on which to base new guidelines.

Prophylaxis controversy

At the center of one of the UTI controversies is whether prophylaxis should be administered to prevent recurrent UTIs. The issue took center stage as investigators with the Prevention of Recurrent Urinary Tract Infection in Children with Vesicoureteric Reflux and Normal Renal Tracts (PRIVENT) trial published a study that concluded that long-term, low-dose trimethoprim-sulfamethoxazole moderately decreased UTIs in predisposed children.

In an interview with Infectious Diseases in Children, Hoberman said the results of the PRIVENT trial showed that a “one-size-fits-all approach” for children with this condition may not be appropriate.

The trial showed an overall reduction of about 6% in the absolute risk for symptomatic and febrile UTIs; time-to-event analysis showed that the benefit was not sustained and about 14 children would need to be treated to prevent one infection. However, there are probably subgroups of children (who are predisposed) who have a higher risk for recurrent UTIs and renal scarring; the reduction in absolute risk for symptomatic UTI was greatest among children with grade 3 to grade 5 VUR (6.8%) vs. children with grade 1 to grade 2 VUR (5.4%) or those with no reflux (1.8%), although the trend was not significant.

“None of us are ready to discount the efficacy of antimicrobial prophylaxis in those subgroups of children who are predisposed,” Hoberman said. “Perhaps, just earlier diagnosis and treatment of UTIs and management of the dysfunctional elimination frequently associated will make the biggest difference in preventing recurrent UTIs and renal scarring.”

Wald said another problem in managing UTIs in children centers on imaging. Specifically, she said earlier data published by Hoberman and colleagues showed that an ultrasound during acute illness is of limited value. However, that same study suggested that high degrees of VUR were associated with a higher incidence of renal scarring.

“The data suggest that prophylaxis does not appear to help the majority of children with infection, only those with higher degrees of reflux,” Wald said. “So the question is: Do you do a voiding cystourethrogram (VCUG) to detect the very few children with high degrees of reflux to determine whether prophylaxis is going to be necessary?”

Treatment controversies

Although a child with a febrile, symptomatic UTI requires therapy, results conflict as to the best treatment courses.

The most important factor in selecting antibiotics for treating patients is the knowledge of local antibiotic resistance in Escherichia coli, which is the most frequently isolated urinary tract pathogen, to help make an informed decision on the likelihood of success when selecting a particular antibiotic.

When treating symptomatic UTIs, “the choice of antibacterial agent will depend upon the clinical status of the patient, the site of infection, and the pharmacokinetics and pharmacodynamics of the agent,” John F. Fisher, MD, who works with the section of infectious diseases at the Medical College of Georgia in Augusta, said in an interview.

Wald said a third-generation cephalosporin administered for 10 days generally works well for children with UTIs.

Some evidence suggests no significant differences in efficacy between IV antibiotic therapy given for 3 days followed by oral therapy for another 2 weeks. Published data have led to the recommendation that children with a febrile UTI should receive oral treatment with a second- or third-generation cephalosporin, amoxicillin-clavulanate or TMP-SMX.

TMP-SMX is also commonly used for treatment, but because it is frequently used for prophylaxis, strains of E. coli that are colonizing the colon may become resistant to TMP-SMX and subsequently cause infection. Besides TMP-SMX, nitrofurantoin has been used for prophylaxis based on adequate concentrations of antibiotic in the urine after oral administration. Data suggest that resistance emerges less quickly with nitrofurantoin compared with TMP-SMX, but resistance will ultimately develop to nitrofurantoin as well. Nitrofurantoin or sulfa drugs, however, should not be used in infants aged younger than 6 weeks. In cases such as these, reduced doses of a first-generation cephalosporin should be used.

The RIVUR trial focuses on TMP-SMX vs. placebo. Both are provided to children with VUR (grades 1-4) in a randomized, double blind trial design whose primary endpoint is recurrent UTIs within 2 years of prophylaxis. Secondary endpoints include the occurrence of renal scarring and the development of TMP-SMX resistance among uropathogens. The trial has met its enrollment goals of 600 children, but results are not expected for several years.

Diagnosis

Despite the controversies, there are some areas of agreement, specifically UTI epidemiology and diagnosis. UTI is one of the most common reasons for hospitalization, with 45,000 children per year affected, according to published data. Long-term complications of pyelonephritis, or upper UTI, can include end-stage renal disease, pregnancy complications or hypertension. Cystitis, or a lower UTI, is not typically associated with kidney damage. The voiding symptoms associated with lower UTIs usually clear within 24 to 48 hours of effective treatment. Wald said systematic reviews of treatments for cystitis showed no difference in the efficacy with a 1- to 2-week course of therapy compared with 2 to 4 days of treatment.

UTI incidence typically varies based on age and gender, affecting about 7% of girls and 2% of boys aged younger than 6 years. Data suggest that uncircumcised boys have a higher incidence of UTI in the first 3 months of life and females younger than 12 months of age have the highest baseline rate.

Other risk factors may include:

• Urinary tract structural abnormalities;
• Dysfunctional voiding;
• Indwelling urinary catheters;
• Constipation;
• Anatomic or congenital abnormalities. (VUR is the most common pathologic finding after UTI); and
• In older children, sexual activity.

UTI symptoms

Symptoms of UTI illness typically include fever, failure to thrive, irritability, lethargy, fever and abdominal pain, dysuria, urinary frequency, urgency and pain.

If a UTI is suspected, physicians are urged to obtain a catheterized urine specimen on any young infant or child aged younger than 2 years. Other diagnostics can include procalcitonin (PCT), a polypeptide marker for biologic disease for pyelonephritis in children with febrile UTI, urinalysis, C-reactive protein and erythrocyte sedimentation rate (not always reliable), ultrasonography and Doppler ultrasound, although Hoberman said some of these tests may not be widely available and may take days for results.

Preventing UTIs

Physicians are urged to avoid unnecessary use of antibiotics because they may compromise natural defenses against colonization by pathogenic agents. Some studies have suggested that circumcision of boys may reduce UTIs, and one study has suggested that drinking cranberry juice reduced UTI recurrence in girls. Also, some authorities continue to recommend good hygiene practices, such as frequent diaper changes, encouraging children to urinate often and to wipe from front to back after bowel movements, and taking showers instead of baths, as a way to prevent UTIs. However, according to Bradley, no high-quality, prospective, comparative data currently exist that document that any of these measures are truly effective.

More data, continued controversies

All of the clinicians interviewed said patients’ medical histories should be examined to look for predisposing factors, and patients should be managed on an individual basis, letting sound judgment guide clinical decisions. The researchers also all agree that the guidelines, once issued by the AAP, will hopefully shed further insights into best treatment practices. However, many said the best treatment will continue to be debated.

“With all guidelines, there will likely be people who disagree with it,” Wald said. “You will see that if and when new data emerge, the guidelines will continue to be revisited.” – by Colleen Zacharyczuk

For more information:

• Craig JC. N Engl J Med. 2009;361:1748-1759.
• Doganis D. Pediatrics. 2007;120:e922-e928.
• Hellerstein S. Curr Opin Pediatr. 2006;18:134-138.
• Hoberman A. New Engl J Med. 2003;348:195-202.
• Hoberman A. N Engl J Med. 2009;361:1804-1806.
• Hoberman A. Pediatrics. 1999;104(1 Pt1):79-86.
• Ishimine P. Emerg Med Clin North Am. 2007;25:1087-1115.
• Pennesi M. Pediatrics. 2008;121:e1489-1494.
• Pong AL. Pediatr Clin North Am. 2005;52:869-894.
• RIVUR Study Online Posting. Available at: clinicaltrials.gov/ct2/show/NCT00405704?term=rivur&rank=1.
• Roussey-Kesler G. J Urol. 2008;179:674-679.
• Silva JM. Pediatr Nephrol. 2006;21:981-988.
• Venhola M. Scand J Urol Nephrol. 2006;40:98-102.
• Williams G. Cochrane Database Syst Rev.2011;3:CD001534.

Disclosures: Drs. Bradley, Fisher, Hoberman and Wald report no relevant financial disclosures.

Does your practice advocate VCUG as a means to detect children with high degrees of reflux?

UTI management is controversial at the present time. I work in a pediatric ICU with a background in primary care. In the hospital, when you have the tools at your fingertips, you tend to use them. More times than not, we do image, especially in young infants and children who present with sepsis. Generally, we start with the ultrasound, which can also identify some anatomical abnormalities. In terms of the VCUG, if a child has an acute UTI, our critical care team follows the AAP guidelines and has the child come back or follow up with their primary care provider after acute symptoms have subsided. However, if there is any question that the family will not follow up or other underlying concerns, we may try the VCUG during ho spital stay.

We tend to image more than in general community practices because the children we see are acutely or critically ill, and we have the imaging equipment available to us. In a young infant with fever and no source, an initial ultrasound may help in diagnosis and support treatment options, As far as the DMSA, the 1999 AAP guidelines have no recommendations, but this study has been found to be effective in identifying pyelonephritis and renal scarring in the acute care setting, so at this point, we’re using our best judgment with the patient’s best interest in mind.

Cathy Haut, DNP, CPNP, is from The Children’s Hospital at Sinai, Baltimore. Disclosure: Haut reports no relevant financial disclosures.

I work in a private pediatric practice with 21 independent providers. I’d love to say that we follow the 1999 AAP guidelines all the time, but honestly, the guidelines are so dated, and with more recently published research conflicting what the guidelines recommend, many practitioners are not doing what is considered the “recommended standard of practice.”

The general rule is that at a minimum we will get a renal ultrasound and VCUG for any child aged younger than 1 year who presents with a UTI.

Where it gets gray is those children who are 2 to 5 years of age who are newly potty trained. Due to irregular voiding patterns and wiping habits, these children have many other contributing factors that need to be considered, besides just worrying about VUR.

Furthermore, the collection process that occurs with a clean catch urine in a newly potty-trained child can lead to false positive cultures. For these reasons, the usefulness of imaging is questionable and decisions are made on a case-by-case basis.

If imaging studies would change our management of the patient, then the decision to proceed with imaging is made. In this age group, with more than two UTIs, they are often referred to the urologist to assist us in making the decision.

As far as the DMSA, I just had one of the pediatricians in my office tell me he ordered his first DMSA scan in 9 years! This is likely because most of the patients who require DMSA scans are the more acutely ill ones who present with pyelonephritis who receive follow-up from the specialists. I think the lack of a clear-cut recommendation on the DMSA makes it difficult to know exactly when these are indicated.

It is very interesting because there is a lot of good research out there recommending conflicting follow-up. I recently gave a talk on this issue at the annual National Association of Pediatric Nurse Practitioners conference, where there was a room full of about 300 people. We gave the attendees different scenarios regarding UTI management based on the 1999 AAP guidelines and asked if they were doing this. Only three people raised their hands. That is very telling.

Gwyn Reece, MSN, is from Annapolis Pediatrics. Disclosure: Reese reports no relevant financial disclosures.

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