Discussion
The prevalence of pediatric UTI was 1% in males and 1–3% in females. Generally, males are diagnosed within the first year of life, while females are diagnosed at 3 years old. The male to female ratio of pediatric UTI patients varied according to age, from 2.8–5.4:1 within the first year of life and 1:10 between 1 and 2 years of age [
3]. In our study, the age at first diagnosis of UTI was higher in females than males, and the proportion of sex by age also showed a similar tendency. Because the proportion of children younger than 1 year who had a high prevalence rate in males was high, the overall ratio of male and female patients with UTI showed opposite results in this study.
It is known that 80–90% of pediatric UTIs are caused by
E. coli , and 10–15% are caused by
Klebsiella, Enterobacter, Proteus, and
Pseudomonas [
1,
3].
Enterococci, Pseudomonas, S. aureus, S. epidermidis, Haemophilus influenzae, Group B streptococci can be cultured in children who have urinary tract abnormalities or dysfunction and Lactobacillus species, Corynebacterium species, Coagulase-negative staphylococci, and α-hemolytic streptococci can be cultured when the urine is contaminated during collection [
4]. The percentage distribution of causative organisms in urine cultures was similar to previous studies;
E. coli (86.4%) was the commonest pathogen, followed by
Klebsiella (4.2%). In addition,
Enterococcus, Enterobacter, Proteus, Citrobacter, and
Staphylococcus were major causative
As the number of antibiotic-resistant strains has been rapidly increasing, it is more difficult to treat patients with UTI. Because pediatric patients are more likely to have high morbidity and mortality when infected by resistant bacteria and the use of non-susceptible antibiotic may confer a poor prognosis, it is essential to select appropriate empirical antibiotics after considering the antibiotic susceptibility patterns [
5].
Thus, we investigated the antibiotic susceptibility patterns of
E. coli that was the most common cause of UTI. Antimicrobial susceptibility to ampicillin was steadily low in both periods A and B.
E. coli has two strains, 29A and 29B, of which 29A was resistant to ampicillin but showed a higher level of resistance after receiving ampicillin, and 29B was previously susceptible to ampicillin but showed resistance after ampicillin administration. It is believed that susceptibility to ampicillin, one of the most common antibiotics that can be prescribed from the newborn period, was steadily low due to this mechanism [
6].
The susceptibility of
E. coli to trimethoprim/sulfamethoxazole (TMP/SMX) was moderate at 72.1% in period A, and 70.7% in period B, respectively. We concluded that TMP/SMX was not satisfactory as a primary antibiotic for the treatment of UTI. Lee et al. showed that the average resistance of
E. coli to TMP/SMX was 34.3% [
7]. It has also been reported that susceptibility to TMP/SMX was 52.38% (1995–2000), 50.00% (2001–2005) and 48.1% (2003–2005), 50.0% (2006–2008) in two other studies, respectively [
8,
9]. Overall, susceptibility of
E. coli to TMP/SMX was low in pediatric UTI patients, despite the variation of the results obtained in several studies. This is supported by the crossresistance mechanism, that is, resistance to trimethoprim also shows as resistance to TMP/SMX, ampicillin, ampicillin/clavulanate, and quinolone [
10].
Majority of study results showed that amikacin had a susceptibility higher than 90%. In this study, amikacin also showed susceptibilities as high as 99.4% and 99.3% in both periods A and B, respectively. Amikacin should be used with careful consideration of complications such as ototoxicity and nephrotoxicity in children with UTI, and their serum creatinine levels should be constantly monitored.
Third-generation cephalosporin, which has shown high susceptibility in many studies and has been most commonly used in the treatment of pediatric UTI, also showed significantly reduced susceptibility in this study. The susceptibility was as high as 91.7% in period A, but significantly decreased to 75.5% in period B. Other studies also showed similar results. Jang et al.’s five-year study (1993–1997) identified that resistance of
E. coli to ceftazidime increased from 3% to 14% [
11]. Lee et al. also determined that the resistance to third-generation cephalosporin increased to 2.1% in 2000–2004, 8.3% in 2005–2009, and 8.8% in 2010–2014. This may be due to the gradually increasing resistance due to extensive use of third-generation cephalosporins for urinary tract, upper respiratory, and gastrointestinal infections. Even if the diagnosis is uncertain, the tendency to use antibiotics with a wide range of antimicrobial activity is also considered one of the causes [
7,
12,
13]. Another study reported that the continuous increase in the use of third-generation cephalosporins has led to increased
E. coli resistance (from 14% to 50%) [
14]. The results of our study showed that patients with resistance to third-generation cephalosporins were more likely to have been hospitalized in the preceding 3 months, and were also more likely to have changed antibiotics after initial treatment failure. These two differences were statistically significant, and it is thought that the same factors would have affected the B group, since they showed a higher detection rate of third-generation cephalosporin-resistant bacteria in culture tests. Because we were unable to obtain medication histories for antibiotics prescribed outside our hospital, it was not possible to ascertain the precise frequency of previous antibiotic use. Thus, we postulated that the rate of antibiotic exposure would be higher among older patients, and investigated antibiotic susceptibility by age of diagnosis. We observed that patients showing third-generation cephalosporin susceptibility were 5 months younger, on average, than patients showing resistance, although this difference was not statistically significant. Thus, we expect that antibiotic medication history will also have an effect on susceptibility.
Quinolone is commonly used to treat cystitis in adults, but is rarely prescribed in children due to several side effects. In children, the use of quinolone has been approved only for cystic fibrosis, immunosuppression, severe typhoid fever, paratyphoid, and complicated urinary tract infection. However, studies using young animals showed that cartilage lesions were found in joints as a result of quinolone administration. Moreover, other reported side effects were increased QT interval on electrocardiogram, gastrointestinal damage, central nervous system damage, and photosensitivity, thereby requiring careful administration [
15]. In this study,
E. coli ’s susceptibility to quinolone was significantly reduced from 88.4% to 78.2%. Lee et al. reported that the resistance to quinolone increased to 7.9% in 2000–2004, 9.7% in 2005–2009, and 12.4% in 2010–2014 [
7]. A study found that drug resistance occurred through mechanisms that cannot be understood by similar drugs or other irrelevant drugs even without exposure. Another study argued that the conjugation of qnr (a plasmid-mediated quinolone gene, derived from other avirulent bacteria) into
E. coli or
K. pneumoniae (virulent bacteria) was an important mechanism of pediatric quinolone drug resistance development [
16]. Therefore, quinolone abuse should be prevented in adults because it can cause resistance in children.
In recent years, the incidence of ESBL-producing gramnegative bacteria has increased, making it difficult to choose antibiotics. ESBLs are β-lactamases that hydrolyze cephalosporin and monobactams with an oxyimino side chain via a plasmid-mediated mechanism. Therefore, they have multi-resistance to antibiotics related to oxyimino- β-lactams [
17]. This resistance is mainly observed in
E. coli and Klebsiella as well as other intestinal bacteria. It has been increasingly observed in bacteria, such as
K. pneumoniae,
Pseudomonas species, and
E. coli worldwide. In Korea, ESBL-producing bacteria have been reported since the 1990s and have increased rapidly over the past decade. The incidence of ESBL in Korea was 4.8–7.5% in Pai et al., study from 1994 to 1998, 10.8% in Lee et al.’s study from 2001 to 2003, 11.03% in Park et al., study from 2008 to 2010, and 13.6% in Ahn et al.’s study from 2011 to 2013, indicating a continuous increase [
18-
21]. In this study, a total of 45 ESBL-producing strains were found, all of which were
E. coli . The percentage of ESBL-producing strains was 6.1% in period A and 17.1% in period B, thus showing a statistically significant increase in the incidence rate. In a study by Lee et al., the percentage of ESBL-producing strains continuously increased to 1.4%, 7.6%, and 8.2% over the three periods [
7]. Risk factors for increased ESBL-producing Gram-negative bacteria are decreased immunity, long-term hospitalization, and frequent use of cephalosporins due to the infection history, such as UTI. In addition, studies have shown that there were a significant number of infections caused by ESBL+ strains in male infants younger than 1-year-old and female infants older than 1-year-old. A study showed that risk factors included history of anatomical/functional urinary anomalies, recurrent urinary tract infections and sepsis, as well as hospital admission in the last 3 months [
22]. In the results of our study, there were no significant differences between the ESBL-producing
E. coli infection group and the non-ESBL-producing
E. coli infection group regarding age, fever duration, or blood tests. However, the ESBL-producing group showed significantly higher rates of hospitalization in the preceding 3 months and change of antibiotics during treatment due to persistent fever. Also, the ESBL-producing
E. coli group tended to show higher recurrence rates for vesicoureteral reflux and UTI, although this difference was not statistically significant. The recurrence rate and failure rate of UTI treatment due to ESBL-producing
E. coli are high; therefore, the necessity of guidelines for antimicrobial therapy has developed. In this study, all of the children infected by ESBL+ strains were susceptible to carbapenem and 82% were susceptible to quinolone. Other studies also recommended carbapenem and quinolone. Therefore, these antibiotics should be used while carefully monitoring changes in antibiotic susceptibility.
This study has limitations because of the small sample size (589 for >8 years) with an uneven age distribution and was conducted in a limited local community. In addition, there was a large gap in the number of patients during the two comparative periods. Therefore, further studies should be conducted to overcome these limitations.
In conclusion, ampicillin and TMP/SMX, which are widely used as conventional antibiotics for treating pediatric UTI, may no longer be appropriate. Due to the decreased susceptibility to third-generation cephalosporin and quinolone depending on the period and continuously increasing ESBL strains, the discovery and use of appropriate antibiotics are required.