Urinary tract infections (UTIs) are among the most common bacterial infections requiring antimicrobial therapy in children. Diagnosis in non-toilet-trained children can be challenging because of nonspecific symptoms and difficulty in obtaining an appropriate urine sample. Accurate diagnosis and appropriate management are essential for preventing renal scarring and long-term sequelae. Escherichia coli is the most common uropathogen, accounting for approximately 80% to 90% of pediatric UTIs, followed by Klebsiella, Proteus, Enterococcus, and Enterobacter species [1]. Current clinical practice guidelines recommend the selection of initial empirical antibiotics based on local antimicrobial susceptibility patterns, with subsequent adjustments according to the antibiotic susceptibility profile of the isolated uropathogen [2-7]. In recent decades, the incidence of UTIs caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) has increased markedly worldwide; however, a consensus on the clinical implications and optimal management in children remains lacking. This review summarizes current literature on the prevalence, virulence factors, clinical impact, and management of UTIs caused by ESBL-PE.

The prevalence of ESBL-PE has increased worldwide in both hospital and community specimens. A meta-analysis by Flokas et al. [8], which included 7,374 cases of pediatric UTI between 1996 and 2014, reported that the prevalence of ESBL-PE was 14% (95% confidence interval [CI], 8%–21%). A recent multicenter survey of pediatric nephrologists from 232 centers in 77 countries also found that the prevalence of UTIs caused by ESBL-PE varies across continents, with relatively high prevalence rates in Asia, the Middle East, and Africa [9]. Since the early 2000s, UTI cases caused by ESBL-PE (ESBL(+) UTIs) in Asia have increased rapidly. In 2005, the SENTRY Asia-Pacific Surveillance Program from 1998 to 2002 reported high prevalence rates of ESBL-PE with significant differences between countries. High prevalence rates of ESBL-producing E. coli have been reported in mainland China (24.5%), Hong Kong (14.3%), and Singapore (11.3%) [10]. In Thailand, the incidence of ESBL(+) UTIs increased from 17% in 2005 to 32% in 2013 [11]. Although some studies were single-center studies and regional differences within countries should be considered, ESBL positivity rates of >20% have been reported in Asia. In Korea, in the 1990s, ESBL-PE, including E. coli and Klebsiella pneumoniae, was reported to be 4.5%–7.5% and 22.5%–22.8% of cases, respectively [12]. However, 20 years later, Yoo et al. [13] reported that 23.9% of pediatric UTIs were caused by ESBL-producing E. coli between 2012 and 2017, and that the prevalence increased rapidly from 4% in 2012 to 36.5% in 2017. Another domestic study of 265 children with UTIs between 2018 and 2019 found that 23.4% of cases were caused by ESBL-PE [14]. The prevalence of ESBL-PE in studies published over the past 10 years is summarized in Table 1 [8,11,13-23].

Uropathogenic E. coli (UPEC) is the most common subgroup of extraintestinal pathogenic E. coli and is a major cause of UTIs. These strains possess various virulence factors, including iron uptake systems, serum resistance factors, capsules, toxins, flagella, and adhesion elements, which are encoded by mobile genetic elements such as plasmids, transposons, and pathogenicity islands [24]. Genes conferring resistance to β-lactam antibiotics, such as TEM, SHV, and CTX-M, are well known. Among these, CTX-M is the most common, and genes that confer resistance to other antibiotics, including aminoglycosides, quinolones, and sulfonamides, may also be present [25,26]. Table 2 summarizes the genes conferring resistance to β-lactam antibiotics and the major virulence factors of ESBL-PE. In addition to virulence gene profiling, UPEC subtypes analyzed by multi-locus sequence typing have been reported to be associated with antibiotic resistance patterns. Globally, sequence type (ST) 131, a high-risk clone associated with ESBL production and multidrug resistance, has become the most prevalent ST type [27,28]. Although no large-scale studies of pediatric UTIs in Korea exist to date, several domestic studies on the virulence factors of ESBL-producing E. coli exist [28-30]. A single-hospital study of 114 UPEC isolates from community-acquired UTIs in children between 2011 and 2014 reported that 14% were ESBL producers, of which 50% were ST131 subtypes [30]. Another study analyzed 80 UPEC isolates from the blood and urine of 80 patients hospitalized with UTI and found that the ST131 clone was the most common (24%) and had significantly higher virulence scores and more virulence genes than other subtypes [29]. In a recent study of 120 ESBL-producing E. coli collected from urine and blood specimens in three regions of Korea, CTX-M and TEM were the major ESBL types detected in 71.7% and 61.7% of cases, respectively, and they co-occurred in 46.7% of cases. Regional multi-locus sequence typing analysis revealed consistent ST131 predominance across the region, although regional variations were observed (overall 38.3%, Gyeongnam 32.1%, Jeonbuk 17.8%, and Gyeongbuk 61.7%). These bacteria have a high prevalence of virulence factors such as iutA and kpsMII, and many show a combination of multiple virulence factors, suggesting a high potential to cause serious extraintestinal infections [28]. These studies support the rapid increase in ESBL-PE with high virulence factors, not only in hospitals but also in Korean communities. Understanding and monitoring the virulence profiles and distribution of ESBL-PE are important for the development of antibiotic treatment strategies and infection prevention.

Several domestic and international studies have compared the clinical features of ESBL(+) UTIs and ESBL(–) UTIs [8,14,16,17,19,21,22,31,32]. Most studies did not find differences in demographic factors, such as age or sex, between the two groups. Some studies have reported longer hospitalization periods [8,16,22], longer duration of fever [17], and higher C-reactive protein levels [24] in patients with ESBL(+) UTIs than in those with ESBL(–) UTIs. However, most studies reported no significant differences in clinical manifestations, such as time to defervescence, laboratory findings, presence of urosepsis, and renal scarring, between the two groups [11,20,21]. ESBL(+) UTI in children has been reported to have favorable treatment outcomes, regardless of the type of empirical or therapeutic antibiotics used [14,19,20,22,23]. Studies on whether ESBL(+) UTIs have a higher recurrence rate than ESBL(–) UTIs have shown varying results depending on the patient population and definition of recurrence. To date, no large-scale cohort study or meta-analysis has investigated this issue. In a domestic study of 288 children with first febrile UTI, the UTI recurrence rate in the ESBL(+) UTI group was significantly higher than that in the ESBL(–) UTI group (34.4% [11/32] vs. 19.1% [49/256]) [16]. However, in another study of 845 children with febrile UTI, the recurrence rate in the ESBL(+) UTI group was 2.7%, while that in the ESBL(–) UTI group was 1.1%, showing no significant difference [19]. Recent antibiotic administration, previous hospitalization history, and congenital anomalies of the kidney and urinary tract have been commonly reported as risk factors for ESBL(+) UTI [8,14,16,17,19,23]. A meta-analysis by Flokas et al. [8] identified vesicoureteral reflux (odds ratio [OR], 2.79; 95% CI, 1.39–5.58), a history of UTI (OR, 2.89; 95% CI, 1.78–4.68), and recent antibiotic use (OR, 3.92; 95% CI, 1.76–8.70) as risk factors for ESBL(+) UTI. However, the risk factors for ESBL(+) UTI remain controversial. Studies on the clinical manifestations and risk factors of ESBL(+) UTI over the past 10 years are summarized in Table 1.

In the aforementioned multicenter survey, the initial empirical antibiotic use for UTI was 41.6% for third-generation cephalosporins, 22.6% for second-generation cephalosporins, and 19.9% for ampicillin with a β-lactamase inhibitor [9]. Third-generation cephalosporins, such as cefotaxime and ceftriaxone, are the most commonly used empirical antibiotics for UTI in Korea. Many clinicians have experienced favorable outcomes with empirical cephalosporin treatment in children with ESBL(+) UTIs, despite antibiotic susceptibility testing indicating resistance to these antibiotics. Even when ESBL-PE isolates and in vitro antibiotic susceptibility testing predict resistance to β-lactam antibiotics, treatment failure is rare for the following reasons: First, third-generation cephalosporins (particularly cefotaxime and ceftriaxone) achieve significantly higher drug concentrations in urine than in plasma and have a longer duration of action, enabling effective bactericidal activity exceeding the minimum inhibitory concentration [33,34]. Second, many febrile UTIs in children are uncomplicated ascending infections without bacteremia or anatomical obstruction. Furthermore, fluid administration and increased urinary flow promote bacterial clearance, rapidly reducing the bacterial load and contributing to favorable treatment outcomes [1,2].

In a single-center study in Korea, third-generation cephalosporins were used as the initial antibiotics in 90% of 845 UTI cases in children aged <2 years. In the ESBL(+) UTI group, 33.6% of the patients were switched to antibiotics based on culture-confirmed susceptibility. Notably, 11% of the patients experienced fever lasting more than 48 hours after antibiotic administration, leading to a change in antibiotics before susceptibility testing. In 41.1% of patients, the initial antibiotics remained unchanged even after susceptibility testing. No difference was observed in the recurrence rates according to the antibiotic treatment strategy [19]. In another single-center study in Korea involving 687 infants with UTI, none of the infants with ESBL(+) UTI was switched to carbapenem antibiotics based on antibiotic susceptibility test results. Both the ESBL(+) and ESBL(–) groups were treated with non-carbapenems, and both groups showed good treatment outcomes [21]. However, the ESBL(+) group was more susceptible to cefoxitin (86.7%) and amoxicillin/clavulanate (63.8%) than to other antibiotics. Another domestic study of 43 infants with ESBL(+) UTI treated with non-carbapenems showed good treatment outcomes, with a clinical success rate of 90.7% and a microbiological success rate of 97.7%. The use of non-susceptible antibiotics did not affect the time to fever resolution or recurrence rate [20].

Currently, no recent clinical guidelines exist for antibiotic treatment of children with ESBL(+) UTI in Korea. A single-center domestic study that analyzed the initial empirical intravenous (IV) antibiotics divided into cefotaxime and piperacillin-tazobactam (TZP) in 220 patients with febrile UTI suggested that TZP could be used as an alternative to cefotaxime in infants with UTI who were >3 months of age and required hospitalization [23]. Other domestic studies have suggested the continued use of third-generation cephalosporins or non-carbapenems if clinical features improve [19-21]. In a multinational multicenter study, when ESBL-PE was isolated from urine cultures and the patient showed a good clinical response, 19.8% of the respondents continued the initial antibiotic, 39.7% switched to non-carbapenems, and 31.9% switched to carbapenems [9].

Given the high prevalence of ampicillin-resistant bacteria in Korea and the generally favorable treatment outcomes for ESBL(+) pediatric UTIs, regardless of the type of empirical antibiotic used, third-generation cephalosporins remain the first-line empirical antibiotic treatment for most pediatric UTIs. However, given the high prevalence of ESBL-PE and the increasing prevalence of high-risk clones such as ST131, early assessment of patients’ clinical response and a rapid “escalation strategy” to TZP or carbapenems if the response is poor may be important antibiotic treatment strategies to prevent treatment failure. Furthermore, a “de-escalation strategy” after initial TZP or carbapenem use should be considered in patients with severe clinical symptoms, a history of recurrent UTI, risk factors for frequent prior antibiotic use, or a history of ESBL-PE infection. Using broad-spectrum antibiotics, such as carbapenems, as initial empirical antibiotics may also pose problems such as the emergence of carbapenem-resistant Enterobacteriaceae. Short-term concomitant use of aminoglycosides, such as amikacin, may also be considered an alternative to non-carbapenems. The 2024 Infectious Disease Society of America guidelines on antimicrobial-resistant Gram-negative bacterial infections and several studies have suggested that short-term concomitant use of aminoglycosides may be considered an alternative to non-carbapenem use [7,35,36]. The 2025 European Society for Pediatric Infectious Disease guidelines suggest the empirical use of aminoglycosides or broad-spectrum β-lactam antibiotics in complicated UTIs in children (especially those with high-grade vesicoureteral reflux), neonates, or infants with bacteremia [6]. The risk of nephrotoxicity associated with the duration of aminoglycoside therapy should be considered in all patients receiving any type of aminoglycoside, especially young infants [37].

If a patient’s clinical symptoms improve after empirical intravenous antibiotic therapy, a “step-down” to oral antibiotics based on antibiotic susceptibility testing is recommended. If an isolated uropathogen is susceptible to trimethoprim-sulfamethoxazole (TMP/SMX), it can be used as an oral antibiotic, as recommended by various guidelines [3,4,7]. However, 26.2% to 77.8% of uropathogens identified in Korea are resistant to TMP/SMX, regardless of ESBL production [21,29,38]. Park et al. [38] reported that the susceptibility rates to fosfomycin and nitrofurantoin in ESBL(+) E. coli isolated from urine were as high as 97.2% (105/108) and 96.3% (104/108), respectively, suggesting that fosfomycin and nitrofurantoin are effective oral antibiotics. However, only 33% (3/9) of the ESBL(+) K. pneumoniae strains were susceptible to nitrofurantoin, suggesting the need for further research. These two drugs require further study, especially in cases of pediatric febrile UTI, as pediatric data are limited.

In summary, based on the patient’s condition and risk factors, the initial empirical antibiotic should be a third-generation cephalosporin, TZP, or carbapenem. If necessary, the antibiotics should be changed promptly based on the initial clinical or laboratory response. In most cases, urine culture results are available after 3 to 5 days. Therefore, based on clinical improvement and antibiotic susceptibility results, switching to an oral antibiotic, such as a third-generation cephalosporin, TMP/SMX, fosfomycin, or nitrofurantoin, should be considered (Fig. 1).

Currently, more than one in five pediatric UTIs in Korea are caused by ESBL-PE. Although third-generation cephalosporins remain effective antibiotics for pediatric UTIs, their widespread use contributes to the spread of ESBL-producing strains. Clinical management should balance empirical efficacy with antimicrobial stewardship. Several clinical practice guidelines exist for antibiotic treatment of pediatric UTIs [2,3,6,7]. However, the Korean guidelines for pediatric UTIs have not been updated since the second revision in 2015 [5]. Because the prevalence, strain subtypes, and virulence factor distribution of ESBL-PE vary significantly across continents and countries, guidelines tailored to the Korean context are required. Appropriate antibiotic treatment strategies are crucial not only for treating UTIs and preventing renal scarring but also for establishing preventive strategies to limit the prevalence and spread of resistant strains in both community and hospital settings.