Shorter treatments for (febrile) urinary tract infections: are we there?

Urinary tract infections (UTIs) are the second most common reason for prescribing antibiotics in children, following respiratory tract infections (RTIs) (1). Antibiotic use for these conditions is widespread, even though many RTIs in children under five are viral in origin. For uncomplicated, community-acquired lower RTIs, studies have shown that 5 days of antibiotic treatment is as effective as 10 days, provided antibiotics are necessary (2). This approach is now commonly practiced (3).

In contrast, UTIs are inherently bacterial in origin. Febrile UTIs, or pyelonephritis, carry a risk of renal scarring, potentially leading to long-term consequences. Additionally, young children with febrile UTI may develop bacteremia or sepsis. Those shorter and longer-term consequences could explain the lack of studies exploring optimal treatment duration for pediatric UTI. Antibiotic stewardship aims to optimize antimicrobial use to improve patient outcomes, reduce resistance, and minimize adverse effects. In pediatric care, this often involves selecting the appropriate antibiotic spectrum and transitioning to oral therapy when safe.

The duration of antibiotic treatment for many infectious indications stems from a statement by Alexander Fleming during his Nobel Prize speech: “If you use penicillin, use enough.” He warned against both underuse and overuse, because both could contribute to the risk of resistance. However, the standard treatment durations (e.g., 3, 7, 10, or 14 days) are more rooted in traditional practices than in scientific evidence (4).

Recently, more studies have begun investigating shorter courses of antibiotic therapy, including for pediatric UTI. For uncomplicated lower UTI (cystitis), a 3–5-day course is now widely accepted (1,5). However, for febrile UTIs, where the risk of renal scarring is higher, this remains a subject of debate.

In the Italian STOP trial, published in Pediatrics in 2024, researchers studied whether children aged 3 months to 5 years with febrile UTIs could be treated with a 5-day course of amoxicillin/clavulanic acid, compared to the traditional 10-day course (6). Children with complicated UTIs or resistant pathogens were excluded, as randomization occurred after 4 days of treatment once response and pathogen data were available. The trial initially aimed to demonstrate non-inferiority (5%) in 520 patients with respect to UTI recurrence within 30 days. However, a prespecified interim analysis after 2 years revealed non-inferiority at 2.8% UTI recurrence for the short course versus 14.3% for the longer course in 142 participants, leading to early termination of the trial. Febrile UTI recurrences were 1.4% for the short course versus 5.7% for the long course.

While these results are promising, they may not apply to children with underlying anatomical abnormalities, as only a small subset of such children was included in the study. Only 10 of the 142 participants had known risk factors for UTI, such as vesicoureteral reflux. Furthermore, with the increasing overall resistance rates of E. coli to amoxicillin/clavulanic acid, careful monitoring and follow-up are essential (7). The authors suggest that more data is needed to confirm their findings.

Meanwhile, the SCOUT trial, conducted in the U.S., studied 664 children aged 2 months to 10 years with UTIs. Results were published in JAMA Pediatrics in 2023 (8). This trial did not distinguish between febrile and non-febrile UTIs, with only 38% of participants having febrile UTIs. Children were randomized to receive either 5 or 10 days of active treatment, comprising of different antibiotics, with a placebo given to the 5-day group for the remaining 5 days. The primary outcome, symptomatic UTI recurrence, was assessed between days 11–14 for all participants. The non-inferiority margin of 5% was not met (5.5%), but this was unrelated to fever in children in the interventional group. The rate of UTI recurrence was low (0.6% in the 10-day group vs. 4.2% in the 5-day group). When considering recurrences within 9 days of treatment cessation, no significant difference was observed between the groups (2.7% vs. 4.2%). While the trial did not distinguish between initial febrile and non-febrile UTI, a subgroup analysis (although not powered for this) did not find a difference in treatment failure between those children with and without fever.

It should be noted that most SCOUT participants received oral cephalosporins, which are known for their low bioavailability, potentially affecting clinical outcomes. Additionally, while both the STOP and SCOUT trial reported febrile recurrence rates in the first month after treatment below 5%, with non-inferiority regarding the shorter treatment regimen, the follow-up periods differed slightly. In the context of antibiotic stewardship, the SCOUT investigators estimated that treating 67 children with the longer regimen would prevent one febrile UTI. When applying the shorter treatment regimen, this could potentially save over 300 days of antibiotic use, reducing side effects, resistance, and microbiome disturbances (4).

However, this could not be applied to infants <2 months of age as they were excluded in both studies.

Both studies represent significant advances in understanding UTI treatment duration in children. Even so, we need to take into account several concerns about the study designs, especially with respect to the heterogeneity of the study groups, blinding, antibiotics used and the end points. There are also differences between the studies regarding the inclusion criteria (age and presence of fever) and diagnosis of UTI. The STOP study used single germ culture confirmation of a positive stick test by clean catch (≥100 k CFU/mL) or catheterized specimen (≥10 k CFU/mL), while SCOUT used ≥50 k for a catheterized specimen or ≥100 k CFU/mL for a clean void specimen. Whether this had led to an overestimation of febrile UTI diagnosis in the STOP trial is unknown.

Would further research be needed before guidelines can be changed, particularly for children with febrile UTIs? Ongoing studies, such as the Danish NCT05301023 and Polish NCT03221504 trial, are investigating individualized and shorter treatment regimens compared to the traditional 10-day course and might shed further light on this question (9).

In the meantime, the presented STOP and SCOUT trials, although very different in design, both point towards a shorter course of antibiotics may be a reasonable option for children showing improvement within a few days of therapy, especially those without anatomical abnormalities and having susceptible pathogens. The risk and benefits should be carefully weighted. In this case, when prescribing a shorter course, close follow-up with a ‘safety net’ construction is essential. More data are needed before shorter regimens can be broadly adopted in clinical practice.

Acknowledgments

Funding: None.

Footnote

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