If you’re hoping to catch a clean episode covering a common childhood infection, urine luck! This special segment covers an evidence-based approach to urinary tract infection (UTI) featuring Dr. Ken Roberts, Professor Emeritus of Pediatrics at the University of North Carolina School of Medicine. He is an educator, clinician, and leader in pediatrics. He is also the lead author of both the 2011 AAP UTI guidelines and the upcoming AAP febrile infant guidelines. Listen as wee discuss cloudy diagnostic dilemmas and whiz through the appropriate management of UTI.
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Some factors as defined by the 2011 AAP Clinical Practice Guidelines that make the diagnosis of UTI more likely:
Everyone has different risk tolerances. Although the Guidelines provide pre-test probabilities, the authors intentionally did not provide specific definitions for “high-” and “low-” risk children to allow clinicians the independence to interpret diagnostic factors within their own specific clinical setting and context.
However, Dr. Roberts uses components of the Yale Observation Scale (YOS) to help stratify if a child may be “sick” or “not sick”. The scale utilizes a scoring system for specific physical exam findings to describe the risk of serious bacterial infection (SBI). Dr. Roberts believes that most of the time “no child who smiles has a serious illness, and no child who has a serious illness smiles”. Initial evaluations of the YOS indicated that the score produced a specificity of 88% and a sensitivity of 77%. A recent secondary analysis of a prospective cohort study of the YOS applied in several emergency departments revealed that many febrile infants ≤60 days of age with SBI had a normal YOS, so it is important to consider clinical history and laboratory values to calculate pre-test probability.
The authors also specified the Guidelines as written should be applied to children 2-24 months of age because this was the group in which the data was present at the time. Keep in mind other concomitant serious bacterial infections in younger infants.
Much of the emphasis on the association of uncircumcised status with an increased risk of UTI came from studies by Thomas Wiswell’s studies of infants of military recruits in the 1980s. The most recent AAP Policy Statement on circumcision from 2012 states that the current evidence indicates health benefits (e.g. prevention of UTI, penile cancer, and transmission of some sexually transmitted infections, including HIV) of newborn male circumcision outweigh the risks of the procedure. However, the evidence of those health benefits is not great enough to recommend routine circumcision for all male newborns.
Several studies have reported a significantly higher prevalence of UTI in white infants compared to black infants. Based on that data, the Guidelines include race as a factor that can be used to assess the likelihood of UTI in febrile infants. No clear epigenetic, immunologic, or anatomic cause for increased risk of UTI in white females or non-black males has yet been determined. Some authors have expressed concern that using race as a risk-stratifier in diagnosing UTI may lead to disparate care of children and have recently urged the AAP to consider removing race as an included factor in the Guidelines. Dr. Roberts and other groups have reiterated that it is important to eliminate implicit biases in medicine and to recognize the fact that race is a social and not biologic construct. However, it is argued that additional high-quality research is required to elucidate reasons for the well observed disproportionate prevalence of UTI between races before key Guidelines can be definitively revised.
Producer Note: Be sure to check out our companion episode on Race and UTI release on 10/16/20.
The UTI Calculator is a fantastic resource created using the Guidelines applied to a specific population at the University of Pittsburgh. An advantage (or possible disadvantage) of the UTI Calculator is its interpretation of “high-” and “low-” pre-test probability provided for the user.
Dr. Roberts recommends obtaining a catheterized urine sample if time is of the essence especially if the child appears ill. However, if time permits, he is a believer in the The Quick-Wee method. The method was initially developed when there were not small enough catheters available on hand to obtain a urine sample. While a proven effective method, contamination rates are as high as 35% and not much different from a clean catch sample. Another limitation is the number of “hands” required to allow for successful collection. Dr. Roberts reminds us to not send a voided specimen for urine bacterial culture.
The two-step method is another possible option for obtaining a urine sample to diagnose UTI. It is a practical algorithm that has limited catheterizations to children with positive urine bag specimen screens (i.e. moderate or large leukocyte esterase or presence of nitrites on urine dipstick) without missing cases of UTI.
Dr. Roberts defines pyuria as the presence of any level of leukocyte esterase in the urine indicating a white blood cell mediated inflammatory response. Pyuria on urinalysis is used to help distinguish between asymptomatic bacteriuria (i.e. positive urine culture without pyuria on urinalysis as defined by the Guidelines) or contamination from a true UTI.
Can a true UTI be diagnosed without pyuria on urinalysis? The Guidelines state that the diagnosis of UTI requires a urinalysis that suggests infection, specifically pyuria, nitrites, and/or presence of bacteria, and growth of a uropathogen cultured from an appropriately collected specimen. Furthermore, the Guidelines emphasize a negative urinalysis result does not rule out a UTI with complete certainty. Keep in mind that Enterococcus, Klebsiella, and Pseudomonas (common in children receiving clean intermittent catheterization) have been noted to occasionally present without pyuria.
However, Dr. Roberts puts a lot of stock in pyuria in making the right diagnosis.
According to many large prospective studies, about 5-7% of febrile infants will have a UTI. The Guidelines report leukocyte esterase sensitivity of ~90-95% (other studies have supported that sensitivity) about 5-10% of that 5-7% (i.e. ~0.3-0.7%) of febrile infants will have a positive urine culture without pyuria on urinalysis. The importance of that proportion depends on if that result is considered asymptomatic bacteriuria or a true UTI. Will 3-7/1000 febrile infants with asymptomatic bacteriuria be over treated or will 3-7/1000 cases of true UTI who present with a positive urine culture without pyuria be missed? Dr. Roberts supports the former. Some authors believe the latter.
Dr. Roberts reiterates that animal studies have revealed pyuria represents an inflammatory response that can potentially lead to renal fibrosis or scarring. If no pyuria is present, are those 3-7/1000 missed cases of “true UTI” clinically significant in the long-run? Post-hoc analysis of the RIVUR and CUTIE studies found that the incidence of renal scarring was 3% after the 1st febrile UTI, 26% after a 2nd UTI, and 29% after the 3rd UTI. Note that the percentages reported for scarring after the 2nd and 3rd UTI are percentages of percentages so the absolute numbers are actually very small.
Furthermore, there may be harm in presuming that a positive urine culture without pyuria is a true UTI as treatment of asymptomatic bacteriuria increases the likelihood of the development of a symptomatic UTI according to a meta-analysis cited by Dr. Roberts. Inappropriate diagnosis of UTI may also result in discomfort from catheterization, unwarranted imaging (discussed later) and radiation exposure, increased costs, and unnecessary parental concern. It is also important to consider contamination as a source for a positive urine culture without pyuria.
The bottom line is: the significance of asymptomatic bacteriuria is still actively debated, and clinicians are encouraged to learn about all current positions on the topic.
What about other components of the urinalysis such as nitrites? Nitrites indicate the presence of bacteria. But, Dr. Roberts wonders, is that bacteria metabolically active or does it represent asymptomatic bacteriuria or contamination? Furthermore, seeing evidence of bacteria on urinalysis is significantly different from a gram stain which actually allows for an estimate of the amount of bacteria present.
Cystitis and pyelonephritis is difficult to differentiate in children up to 2 years of age. However, fever usually means pyelonephritis. Distinction between the two may be more relevant in older children when determining class of antibiotic and duration of treatment (e.g. choosing nitrofurantoin for a case of cystitis). Dr. Roberts will treat presumptively with positive leukocyte esterase either way.
There is evidence to support that starting with a 1st generation cephalosporin can successfully treat UTI while reducing overuse of 3rd generation cephalosporins and potential microbial resistance through antibiotic selective pressure. The advent of the electronic medical record has been useful in discerning historical compliance and show rates to guide antibiotic choice. Of course, narrow antibiotics based on sensitivities and susceptibilities. Remember nitrofurantoin should not be used to treat febrile infants with UTI because parenchymal and serum antimicrobial concentrations may not be sufficient.
Dosing intervals occasionally vary in treatment of UTI, specifically with cephalexin. The Guidelines recommend prescribing cephalexin 50-100 mg/kg/day divided into four doses (i.e. qid). Such frequent dosing can result in excess medication burden and non-compliance. Several studies have concluded that bid or tid dosing is equally as effective as the recommended qid dosing in treatment of Staphylococcus aureus bone and joint infections or Group A streptococcal pharyngitis. No dosing comparison studies in UTI treatment were found. In children over 1 year of age, the FDA recommends dosing cephalexin 25-50 mg/kg day divided in equal doses. In children at least 15 years of age, the FDA states that cephalexin can be given at doses of 500 mg q12h.
Since some evidence at the time showed that 1- to 3-day courses are inferior to 7-day courses, the Guidelines settled on a recommended range of 7- to 10-days for duration of antibiotic treatment. Many choose a duration that is a “football score.” Dr. Roberts reports that a clinical trial comparing 5-day and 10-day courses is underway!
Dr. Roberts is a big proponent of IM ceftriaxone since it is dosed daily and less likely to fail. However, this regimen requires daily follow-up which may be difficult for families. Therefore, PO antibiotics are his normal go-to. He also does not believe IV antibiotics are really indicated unless IV hydration is required.
The likelihood of a real penicillin allergy and the likelihood of cross reactivity is very, very low. Dr. Roberts thinks sulfa allergies may actually be more of a concern in this day and age.
Among children with vesicoureteral reflux (VUR), several studies have shown that antibiotic prophylaxis can decrease rates of recurrence of UTI but does not have any effect on rates of scarring (discussed above and later). However, the Guidelines do not recommend antibiotic prophylaxis as the benefits may not outweigh the well established increased risk of microbial resistance.
Keep in mind bowel and bladder dysfunction as possibly the most common cause of recurrent UTI. Make sure to obtain a good and thorough history. A bowel regimen such as Miralax might be the best prophylaxis!
The guidelines recommend all febrile infants with UTI undergo renal and bladder ultrasonography (RBUS). However, RBUS will only detect high grade IV-V VUR. The timing of the necessary imaging is critical. RBUS obtained too early might result in misinterpretation due to detected edema related to the initial infection. Dr. Roberts recommends waiting for a few days after the episode before obtaining imaging to allow the inflammation to subside.
It has been long thought that higher grades of VUR reflux increases the likelihood of recurrence of UTI (regardless of antibiotic prophylaxis). But many children actually do not have recurrent infections. The post-hoc analysis mentioned earlier found that 86% of children who have a febrile UTI do not have a second UTI. Furthermore, the incidence of renal scarring was 26% after a 2nd UTI and 29% after the 3rd UTI. Note that the percentages reported for scarring after the 2nd and 3rd UTI are percentages of percentages so the absolute numbers are actually very small.
Dr. Roberts encourages others to think about it in a different way. Maybe recurrence of UTI is a marker of higher grade VUR, not necessarily a consequence. With that in mind, a cost-effective strategy endorsed by the Guidelines is to obtain voiding cystourethrogram (VCUG) in children with abnormal RBUS findings or with recurrence of UTI. Typically, grade III-IV VUR found on VCUG requires follow-up with a pediatric urologist. Dr. Roberts utilizes any prenatal ultrasounds that may have been obtained to help eliminate the need for acute imaging.
Listeners will confidently diagnose and appropriately manage urinary tract infections.
After listening to this episode listeners will…
Dr. Roberts reports no relevant financial disclosures. The Cribsiders report no relevant financial disclosures.
Roberts K, Karim TJ, Chiu C, Berk J. “Liquid Gold with Dr. Roberts”. The Cribsiders Pediatric Podcast. https:/www.thecribsiders.com/ Original Air Date: October, 2020.
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