Shorter courses of antimicrobial therapy for bacterial infections potentially reduce1 antimicrobial resistance (colonization and infection) at individual and population levels,2 adverse effects of therapy,3 costs of therapy, and4 possibly, long-term adverse impacts on the host microbiome.1–4 Current guidelines in the United States and Europe recommend 7 to 14 days of therapy for urinary tract infection (UTI) in children,5,6 but comparative data on treatment courses in children are limited, despite UTI being the most common bacterial infection in children and adults.7,8 Identifying effective shorter courses would be of great benefit, with caveats that undertreatment could have short- (eg, acute kidney injury, sepsis) and long-term consequences (eg, hypertension, renal scarring [ie, nephron loss]).8
In this issue of Pediatrics, Montini et al9 report results from a randomized trial comparing 5- versus 10-day courses of oral amoxicillin-clavulanate for the treatment of febrile UTI in children aged 3 months to 5 years (Short-Course Oral Antibiotic Therapy of Acute Pyelonephritis in Children [STOP] trial). The authors of STOP evaluated 172 children (66% female) from 8 pediatric emergency departments in Italy from May 2020 through September 2022. The treatment groups did not differ in primary endpoints or adverse events. The recurrence rate of any symptomatic UTI within 30 days of the end of therapy was 2.8% (2/72) with 5 days versus 14% (10/70) with 10 days, with a risk difference of –11.5% (95% confidence interval [CI] –20.5% to –2.5%). The recurrence of febrile UTI in this time frame was 1.4% (1/72) versus 5.7% (4/70), with a risk difference of 4.3% (95% CI –10% to 1.8%). All patients completed 30 days of follow-up. Five of 6 recurrent UTIs were caused by microbes resistant to amoxicillin-clavulanate (2 in the 5-day group and 3 in the 10-day group).9
The results of STOP contrast with those of the recently published Short-Course Therapy for UTI in Children (SCOUT) trial,10 the authors of which also compared 5 versus 10 days of therapy for UTI in children. The authors of this randomized, placebo-controlled trial evaluated 664 children aged 2 months to 10 years (62% afebrile, 96% female, 23% >6 years old) at 2 US hospitals from May 2012 through February 2023. Treatment failure by day 11 to 14 occurred in 4.2% (14/336) assigned to short-course therapy versus 0.6% (2/328) assigned to longer therapy. The risk difference was 3.6% (P < .01, upper bound of 95% CI, 5.5%). The groups did not differ in the secondary outcome of UTI recurrence after the 11- to 14-day visit, adverse events, or antimicrobial resistance in stool specimens at 24 to 30 days of follow-up.10
What are we to make of these disparate results? Variations in definitions, population, and procedures matter when trying to make such determinations. The authors of STOP defined febrile UTI as the presence of fever >38°C with a positive urine dipstick for nitrite or leukocyte esterase in a urine specimen collected by clean catch or urinary bag. The isolation of a single species in a culture of urine obtained by clean catch (≥100 000 colony-forming units [CFU]/mL) or bladder catheterization (≥10 000 CFU/mL) was required for confirmation.9
The STOP exclusion criteria included having complicated febrile UTI (defined as persistence of fever >48 hours after commencing treatment), the need to change the antibiotic regimen, dehydration, vomiting, adherence concerns, the presence of a urinary catheter, immunodeficiency, and neurogenic bladder. Randomization (on day 4 after enrollment after culture results were available) was stratified by the isolation of Escherichia coli versus non-E. coli microbes. The treatment duration was unblinded. Of the total number of study participants, 13 had grade III or higher vesicoureteral reflux (VUR).9
The authors of SCOUT defined UTI as (1) the presence of 1 or more of fever (at least 38°C), suprapubic, abdominal, or flank pain, urinary urgency, frequency, or hesitancy, dysuria, and poor feeding or vomiting, (2) pyuria (≥10 white blood cells/mL or 5 white blood cells/high power field) or positive leukocyte esterase of dipstick urinalysis, and (3) urine culture with the growth of a single uropathogen (≥50 000 CFU/mL, suprapubic or catheterized specimen, or ≥100 000 CFU/mL, clean voided specimen).10
Children were given 1 of 5 oral agents in SCOUT, with 89% receiving a β-lactam (1% amoxicillin-clavulanate); 62% were afebrile. Randomization was stratified by the presence or absence of fever and the initial antimicrobial agent. The exclusion criteria included genitourinary tract anomalies (except known grade I or II VUR), catheter-related UTI, and immunodeficiency. The authors of SCOUT recruited children from primary care sites, inpatient units, and emergency departments. The primary outcome of the recurrence of UTI between day 6 and days 11 to 14 after the initiation of therapy led to longer post-treatment follow-up for the 5-day group versus the 10-day group, potentially skewing outcome results.10
STOP and SCOUT have similarities but differ in multiple ways that were likely cumulatively important toward generating divergent results. It is difficult to disentangle factors in either study that identify subgroups for whom shorter courses would be appropriate or longer courses necessary. It can be challenging, clinically, to distinguish between cystitis and pyelonephritis in children8 in real-life or clinical trials. The authors of SCOUT did not address this issue well, but the criterion of febrile UTI in STOP may (or may not) have yielded predominately subjects with pyelonephritis.
Data from STOP provide some comfort that 5 days of oral therapy in young children with uncomplicated febrile UTI might be sufficient. Given the almost 4-fold greater sample size and slightly more rigorous study design of SCOUT, our thoughts generally align with Milstone and Tamma in their commentary7 on that study:
Currently available direct and indirect (adult) data support treating UTI in children that appears limited to cystitis with courses no longer than 5 days.
When there is clinical concern for pyelonephritis, it seems prudent, until we have more data, to maintain a modest preference for courses on the order of 10 days.
This “modest preference” when pyelonephritis is suspected is, however, fully compatible with engagement in shared decision-making with primary caretakers. Choosing shorter courses with close follow-up may be reasonable after a discussion of risks and benefits, especially when the child:
Is not ill enough to require hospitalization, and
Does not have genitourinary tract anomalies or severe VUR for which UTI recurrence due to undertreatment may increase the risk of nephron loss to a degree that could have long-term consequences.
Meanwhile, collectively we should not STOP SCOUT-ing out the likely nuanced answers to questions regarding the optimal duration of antibiotics for young children with febrile UTI.
Drs Woods and Atherton drafted the commentary and reviewed it critically for important intellectual content; and both authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2023-062598.
FUNDING: No external funding.
CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no potential conflicts of interest relevant to this article to disclose.
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