Urinary tract infection (UTI) is one of the most common bacterial infections in children and infants and is a common cause of fever in infants [1]. Most patients have a good prognosis after appropriate antibiotic treatment; however, most UTIs require early diagnosis and appropriate treatment, as some types of renal injuries in infants can lead to long-term complications such as renal insufficiency, hypertension, or chronic renal failure as an adult [1,2]. Therefore, if UTI is clinically suspected in patients with fever who present to the hospital, empirical antibiotics should be started before urine culture results are finalized in order to decrease the possibility of sepsis or renal-associated complications [1,2].

Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumonia), Proteus spp, Citrobacter spp, and Enterococcus spp are common causes of UTI; E.coli is the most common pathogen, accounting for 65~90% of UTI children [1] . Although antibiotics such as ampicillin or amoxicillin are used as first-line treatment agents because of the high E. coli sensitivity to beta-lactam antibiotics, increasing resistance to these antibiotics has been reported in several studies [3,4]. In addition, cephalosporin and quinolone antibiotics seem to have emerged as the main problem of multi-drug resistance [3,4]. Quinolone-resistant strains have been found in spite of age restrictions on their use in Korea [5]. In addition, extended spectrum β-lactamase (ESBL) producing E. coli, which can hydrolyze antibiotics such as penicillin, has shown increasing resistance to third-generation cephalosporins and monobactams [6].

Urinary tract infection caused by antibiotic-resistant bacteria has led to problems such as inappropriate antibiotic treatment, increasing complications, and extended duration of treatment [2,3]. Therefore, we investigated trends in antibiotic resistance for gram-negative bacteria in children who have been diagnosed with urinary tract infection (UTI) over a 15-year period. We also explored trends in resistance rates of third-generation cephalosporins and quinolones and the frequency of ESBL-producing E. coli based on urine culture test results in pediatric patients younger than 24 months of age.

In this study, there was no difference in the pathogens isolated on urine culture (E. coli, 89.7% and K. pneumoniae, 10.3%) compared with a previous study [7]. When examined over three periods of 2000 to 2004, 2005 to 2009, and 2010 to 2014, the antibiotic resistance rates to third-generation cephalosporin and the ratio of ESBL-producing gram-negative bacteria significantly increased. In addition, the trend in antibiotic resistance to quinolones showed a steady distribution although it was not statistically significant. In a previous study with children older than 24 months, a trend of antibiotic resistance to third-generation cephalosporins and quinolones decreased over two periods, i.e., 2003-2005 and 2006-2008, different from our results with children younger than 24 months. We suggest that the results of this study reflect the impact of more frequent antibiotics use from 2000-2014. Recently, the increased use of third-generation cephalosporin antibiotics for the treatment of urinary tract, respiratory tract, or gastrointestinal tract infections have led to increased local antibiotic resistance rates in urinary tract infections [8]. According to another study, the rate of antibiotic prescriptions for respiratory infections in children decreased to 55.4% from 60.5% from 2009 to 2011; however, it has been reported that the third-generation cephalosporin antibiotic prescription rate increased from 4.2% to 6.0% [9].

In adults, fluoroquinolone-based or third-generation cephalosporin antibiotics have been recommended as the initial primary drug for treatment of urinary tract infections [10]. However, quinolone antibiotic-resistant strains are increasing in community-acquired infections, leading to a clinical problem. According to a recent study with adults, the ciprofloxacin resistance rate in E. coli was 28.4%, and it was found to be 20% in community-acquired acute pyelonephritis cases from 2010 to 2012 [11]. In the present study involving children younger than 24 months, the overall quinolone resistance rate was 11.4% (49/429) in E. coli; when analyzed according to time period, the rate was 7.9% in the A group (2000-2004), 9.7% in the B group (2005 to 2009), and 12.4% in the C group (from 2010 to 2014). Therefore, there was an approximately 10% antibiotic resistance rate in infants who did not have a history of quinolone exposure.

The use of quinolone antibiotics has been limited in pediatric patients because of the risk of joint cartilage damage shown in animal studies and the increasing risk of antibiotic resistance. However, according to accumulated research results, the United States FDA (Food and Drug Administration) and the EMA (European Medicines Agency) approved quinolones for some infectious diseases (pneumonia caused by Pseudomonas aeruginosa in patients with cystic fibrosis, chronic suppurative otitis media, complicated urinary tract infections, etc.) [5]. For local use, quinolone antibiotics are still restricted. The quinolone antibiotics prescription rate has been reported to have significantly decreased to 0.26% from 4.81% in children since the Korea Pharmaceutical Management Service contraindicated the extensive use of quinolone antibiotics in children younger than 18 years through the DUR (Drug Utilization Review) Notice in December 2009 [12]. Therefore, other factors must be considered to explain antibiotic resistance in infants who do not have a history of antibiotic exposure and the steady increase in resistance over time. Patients were excluded from this study if they had risks associated with increasing antibiotic resistance (previous quinolone antibiotic use, hospitalization history, frequent urinary tract infections, invasive procedure prior to catheter placement, and chronic diseases such as neurological disorders) [11]. Some studies on antibiotic resistance rates in pediatric patients without antibiotic exposure have suggested that quinolone antibiotic resistance in children is associated with a gene derived from a non-pathogenic ‘qnr’ bonded to the E. coli pathogen or K. pneumoniae (conjugation). These researchers posited that the source of these genes is horizontal transmission from a different reservoir such as adults, animals, or water [13,14]. This could lead to resistance through multiple propagation factors even if there was no exposure to quinolone antibiotics. Epidemiological research is also needed to demonstrate other community risk factors. In addition, efforts evaluating the proper use of quinolone antibiotics in adults are necessary as increasing antibiotic consumption in adult patients can lead to childhood antibiotic resistance.

The incidence of ESBL-producing gram-negative bacteria has increased rapidly over the past 10 years; it has been reported in 17.9% of UTIs in children with underlying diseases and in 10.8% of community-acquired UTIs [15,16]. In this study, ESBL-producing bacteria was found in 1.4%, 7.6%, and 8.2% of bacteria cultured in the periods 2000-2004, 2005-2009, and 2010-2014, respectively, showing a statistically significant increasing trend. All 28 patients had community-acquired UTIs without associated underlying disease, and 96.4% of these occurred in patients younger than 12 months. According to a previous study, the ratio of ESBL-producing Gram-negative bacteria decreased from 39.8% to 22.8% after extensive cephalosporin antibiotic use was limited in 2002 [17]. It supported the more frequent use of extensive cephalosporins as an important factor in the increase in ESBL-producing gram -negative bacteria. In addition, decreased immunity, history of long-term hospitalization, and history of infection within the hospital such as a urinary tract infection are also risk factors [18]. It has been reported that quinolone resistance has an association with ESBL-producing UTI pathogens. However, the exact mechanism is not yet well known, although the ‘qnr’ gene in the plasmid encoding for ESBL in K. pneumoniae has been found in a large number of ‘qnr’-positive strains expressing ESBL [11]. In other words, there has not yet been a clear epidemiological investigation, despite other suspected risk factors. In patients with UTIs caused by ESBL-producing gram-negative bacteria, the use of carbapenem and quinolones is recommended. This treatment requires constant monitoring and research because increasing use of such antibiotics could increase the incidence of antibioticresistant strains [19].

This study has several limitations. There were only 478 cases over 15 years; it was also limited in the ability to verify previous oral antibiotics as it was only a retrospective study. These results are also specific to university hospital and might vary in local clinics or other community situations. In our study, the resistance rates to ampicillin-sulbactam significantly decreased, but this change was not correlated with the change of the resistance rate to ampicillin or piperacillin-tazobactam. There was a possibility of the change in cut-off value for antibiotic sensitivity, and further evaluation is necessary.

In conclusion, third-generation cephalosporins, which have been suggested as alternative empiric antibiotics, show a statistically significant increasing trend in resistance rates. The antibiotic resistance rates of quinolones and the ratio of ESBL-producing gram-negative bacteria also increased. Therefore, before the empiric use of these antibiotics, we suggest proper follow-up and monitoring of antibiotic resistance rates for UTI in children.