Abstract
The global prevalence of infections caused by extended-spectrum beta-lactamase
(ESBL)-producing Escherichia coli has been increasing. In children,
ESBL-producing E. coli manifest mostly as febrile urinary tract
infections (fUTIs). This study aimed to elucidate the clinical features of fUTI resulting
from ESBL-producing E. coli in Japanese patients. The clinical features
of children with E. coli-related fUTI were retrospectively examined.
These children underwent treatment at the National Hospital Organization Saitama Hospital,
Japan, between May 2010 and April 2018. Urine specimens were obtained by either bladder
catheterization or the clean-catch method. All children having positive urine cultures
(≥104 colony-forming unit/mL for catheter specimens and ≥105
colony forming unit/mL for clean-catch specimens) and a fever of ≥38°C were considered to
have fUTI. During the study period, 171 patients were diagnosed with E.
coli-related fUTI. Among these, 17 (9.9%) fUTI cases were caused by
ESBL-producing E. coli. A significant difference was noted in the median
age of the populations having ESBL-producing E. coli and
non-ESBL-producing E. coli infections (2 and 5 months, respectively);
other characteristics were not significantly different between the two patient groups.
ESBL-producing E. coli infections markedly increased in our hospital
between 2013 and 2018. In the present study, young age was the only risk factor for fUTI
caused by ESBL-producing E. coli identified in Japanese children.
Introduction
The global prevalence of infections caused by extended-spectrum beta lactamase
(ESBL)-producing Enterobacteriaceae, which are resistant to a wide spectrum of newer
beta-lactam antibiotics, has increased.1,2 Moreover,
the number of infections in children related to these pathogens has also increased
worldwide. Escherichia coli and Klebsiella spp. are the
most common Enterobacteriaceae causing urinary tract infections (UTIs). However, in Japan,
most cases of febrile UTI (fUTI) are caused by E. coli; indeed,
Klebsiella is a rare pathogen in Japan.3,4
Therefore, this study focused only on E. coli.
Several reports have discussed the clinical significance and treatment of infections caused
by ESBL-producing Enterobacteriaceae.5,6,7,8 However, the
risk factors associated with fUTI caused by ESBL-producing pathogens, and their treatment,
remain unclear. Previous reports have suggested that the patient characteristics of
pediatric urinary tract infection in Japan are different from those in The United States and
European countries.3,4 However, no literature is available in English
on the comparison of clinical characteristics between pediatric fUTI caused by
ESBL-producing and non-ESBL-producing E. coli in Japan. The present study
therefore aimed to elucidate the clinical features of fUTI caused by ESBL-producing
E. coli in Japanese patients.
Patients and Methods
The clinical features of children having fUTI caused by E. coli were
retrospectively reviewed. We included patients aged <18 years who had undergone treatment
at the National Hospital Organization Saitama Hospital in Saitama, Japan, between May 2010
and April 2018. In the current study, we counted one patient per episode, even if the same
patient had more than one episode of fUTI. Urine specimens were obtained either by bladder
catheterization or by the midstream or clean-catch method. Patients were considered to have
fUTI if they had a fever of ≥38 °C and if a single pathogen (≥104 colony-forming
unit/mL for catheter specimens or ≥105 colony-forming unit/mL for clean-catch
specimens) was identified on urine culture. These diagnostic criteria were based on Japanese
guidelines. ESBL was identified using the BD Phoenix ESR test according to the 2010 Clinical
and Laboratory Standards Institute guidelines.9 The data collected from the medical records database included patients’
gender, age, history of urinary tract infections, results of blood culture, findings on
abdominal ultrasound and voiding cystourethrogram (VCUG), and recent antimicrobial use
(within 1 month). In addition, details about the initial antimicrobial therapy, definitive
therapy post-antimicrobial susceptibility testing, the duration of fever during treatment,
and medical history were recorded for patients with ESBL-producing E. coli
infection.
All statistical analyses were performed using the SPSS statistical software package
(version 24, SPSS Inc., Chicago, IL, USA and IBM, Armonk, NY, USA). Fisher’s exact test and
the Mann-Whitney test were used to compare patient characteristics and to determine P
values. P-values <0.05 were considered to be statistically significant. The study was
approved by the Institutional Medical Ethics Committee of the National Hospital Organization
Saitama Hospital. The approval number is R2018-31.
Results
During the observation period, 206 patients were diagnosed with fUTI; fUTI was caused by
E. coli in 171 patients and caused by ESBL-producing E.
coli in 17 (10%) patients. The median ages of the populations with fUTI caused by
ESBL-producing E. coli and by non-ESBL-producing E. coli
were significantly different, at 2 months and 5 months, respectively. Other characteristics,
including male gender, a medical history of fUTI, the presence of bacteremia, abnormal
ultrasound and VCUG findings, and recent antimicrobial use, were not significantly different
between the groups (Table 1).
Table 1.
Characteristics of fUTI patients
|
Non-ESBL |
ESBL |
P |
| No. of patients (%) |
154 (90.0) |
17 (9.9) |
|
| Sex male, % |
63.0 |
76.5 |
0.271* |
| Age in months, median (IQR) |
5 (2, 9) |
2 (2, 4) |
0.014** |
| Recurrent UTI (%) |
16 (10.3) |
1 (5.9) |
1.000* |
| Bacteremia (%) |
6/153 (3.9) |
1 (5.9) |
0.700* |
| Abnormal ultrasound (%) |
48/148 (32.4) |
6 (35.3) |
0.791* |
| Abnormal VCUG (%) |
41/141 (29.0) |
4/14 (28.6) |
1.000* |
| Recent Antimicrobial use (%) |
7/74 (9.5) |
1 (5.9) |
1.000* |
*Fisher's exact test, ** Mann-Whitney test.
fUTI: febrile urinary tract infection, IQR: interquartile rage, VCUG: voiding
cystourethrogram.
The percentage of ESBL-producing pathogens among total E. coli in the
periods between May and April 2010–2011, 2011–2012, 2012–2013, 2013–2014, 2014–2015,
2015–2016, 2016–2017, and 2017–2018 were 0%, 15%, 6%, 0%, 4%, 11%, 16%, and 18%,
respectively (Fig. 1). The proportion of
infections caused by ESBL-producing E. coli decreased from 2011 to 2013.
However, this proportion increased between 2013 and 2018.
A total of 16 of 17 patients with ESBL-producing E. coli were initially
treated with cephalosporin antimicrobials, which are ineffective against ESBL-producing
E. coli (Table 2). Treatment
was switched to antimicrobials effective against ESBL in 14 of 16 patients after
antimicrobial susceptibility was identified. The other patients continued receiving the same
antimicrobials as before. All patients, including one with bacteremia, were afebrile within
48 h, which was before switching antimicrobials.
Table 2.
fUTI patients with ESBL-producing
E. coli
| No. |
Age in months |
Sex |
Initial
antimicrobials |
Time to afebrile (h) |
Definitive therapy |
Blood culture |
Ultrasound |
Voiding
cystourethrogram |
Recent antimicrobials use |
Medical history |
| 1 |
9 |
F |
Cefotaxime |
<12 |
Trimethoprim-sulfamethoxazole |
neg |
normal |
normal |
none |
n.p. |
| 2* |
1 |
M |
Ampicillin+
Cefotaxime |
<12 |
Cefmetazole |
neg |
normal |
VUR grade 2 |
none |
n.p. |
| 3* |
2 |
M |
Piperacillin/
Tazobactam |
<12 |
Piperacillin/ Tazobactam |
neg |
normal |
VUR grade 2 |
Ampicillin+
Cefotaxime |
fUTI |
| 4 |
2 |
M |
Ceftriaxone |
<24 |
Cefmetazole |
neg |
Hydronephrosis
SFU grade1 |
normal |
none |
n.p. |
| 5 |
7 |
F |
Cefotaxime |
<48 |
Cefmetazole |
neg |
normal |
normal |
none |
n.p. |
| 6 |
4 |
M |
Cefotaxime |
<48 |
Meropenem |
neg |
normal |
normal |
none |
n.p. |
| 7 |
3 |
M |
Ceftriaxone |
<12 |
Trimethoprim-sulfamethoxazole |
neg |
Hydronephrosis
SFU grade1 |
normal |
none |
n.p. |
| 8 |
1 |
M |
Cefotaxime |
<24 |
Cefmetazole |
neg |
Hydronephrosis
SFU grade1 |
normal |
none |
n.p. |
| 9 |
3 |
M |
Cefazolin |
<12 |
Cefazolin |
neg |
normal |
normal |
none |
n.p. |
| 10 |
2 |
M |
Cefotaxime |
<12 |
Cefmetazole |
neg |
Hydronephrosis
SFU grade1 |
not performed |
none |
n.p. |
| 11 |
2 |
M |
Cefotaxime |
<12 |
Cefmetazole |
neg |
Hydronephrosis
SFU grade1 |
normal |
none |
n.p. |
| 12 |
1 |
M |
Cefotaxime |
<12 |
Cefmetazole |
neg |
Hydronephrosis
SFU grade1 |
normal |
none |
n.p. |
| 13 |
2 |
F |
Cefotaxime |
<48 |
Meropenem |
neg |
normal |
VUR grade 4 |
none |
n.p. |
| 14 |
3 |
M |
Cefotaxime |
<12 |
Cefotaxime |
neg |
normal |
not performed |
none |
n.p. |
| 15 |
4 |
M |
Cefotaxime |
<12 |
Trimethoprim-sulfamethoxazole |
neg |
normal |
not performed |
none |
n.p. |
| 16 |
1 |
M |
Cefotaxime |
<24 |
Cefmetazole |
pos |
normal |
normal |
none |
n.p. |
| 17 |
18 |
F |
Cefotaxime |
<48 |
Cefmetazole |
neg |
normal |
VUR grade 2 |
none |
n.p. |
*Cases 2 and 3 involve the same patient.
SFU: Society for Fetal Urology, VUR: vesicoureteral reflux, n.p: nothing
particular.
Discussion
Knowledge of the risk factors for ESBL-producing organism-related infections in children
could help to identify high-risk patients and enable initiation of the appropriate empirical
therapy. This is the first report discussing the risk of pediatric fUTI caused by
ESBL-producing E. coli during treatment in the Japanese municipal hospital.
Younger age was the only risk factor identified in this study. Previous studies from other
countries have reported that the occurrence of previous UTI, current exposure to
antimicrobials, and underlying diseases such as renal abnormalities and bacteremia are risk
factors for ESBL-producing organism-related infections.6,10 However,
in our study, gender, a medical history of fUTI, rates of bacteremia, and abnormal
ultrasound and VCUG findings did not significantly differ between patients with ESBL and
non-ESBL fUTI. A total of 16 of 17 patients did not have a history of previous episodes of
fUTI and antibiotic use.
A majority of UTIs are ascending infections caused by bacteria from the fecal
flora.11 Although stool cultures were
not performed in the present study, we speculate that ESBL-producing E.
coli were present in the fecal flora of patients. The infective strains
colonizing infants usually originate from the mother’s vaginal and perineal microbiota, the
skin flora of parents and siblings, breast milk, or other foods.12 It is probable that ESBL-producing E. coli
are transmitted soon after birth. In the present study, the pathogens were possibly
transmitted from family members, particularly the mother.
The incidence of fUTI caused by ESBL-producing Enterobacteriaceae has increased
worldwide.1 Based on the findings of
previous reports and the known strong association between ESBL-producing E.
coli infections and antibiotic use, certain conditions need to be fulfilled for
clinicians to suspect an infection to be related to ESBL-producing E. coli.
First, the patient must have acquired the ESBL-producing E. coli through
contact with a colonized health care worker or a contaminated fomite. Second, the isolate
must emerge as a result of the selective effect of antibiotic use.13 In Japan, the Shimane Prefectural Central Hospital reported in
2018 a dramatic increase in the incidence of upper UTI caused by ESBL-producing E.
coli in children.2 This was
reflected in the findings of our study; the incidence of ESBL-producing E.
coli significantly increased between 2013 and 2018.
Third-generation cephalosporins are the most commonly used antimicrobials for treating
fUTI, but susceptibility tests show that ESBL-producing E. coli strains are
resistant to drugs in this class. Despite carbapenems being the standard treatment for
infections with ESBL-producing pathogens, third-generation cephalosporins, because of their
high urinary concentrations, have been successfully used to treat fUTI caused by these
organisms.14 In the current study,
most children with fUTI but without bacteremia received third-generation cephalosporins as
empirical therapy and did well during the treatment period.15 In our study, 16 of 17 patients treated with first- or
third-generation cephalosporins became afebrile within 48 h, even though one child had
bacteremia. However, treatment based on an ineffective antimicrobial might have deleterious
effects on patients with serious complications, such as bacteremia.13 The use of third-generation cephalosporins may
be continued as empirical therapy for fUTI; however, antimicrobials should be selected
carefully in seriously ill patients with suspected bacteremia. Furthermore, renal outcomes,
including scarring, are still unclear in patients who are empirically treated with
third-generation cephalosporins for ESBL-producing pathogens.
The current study has some limitations. First, according to the study design, the study
population was drawn entirely from a single community hospital in Japan, and the sample size
was small. Second, ultrasound and VCUG were not performed in all patients with fUTI.
In conclusion, to our knowledge, this is the first study discussing the risk of pediatric
fUTI caused by ESBL-producing E. coli discovered during treatment in the
Japanese municipal hospital. Younger patient age was the only risk factor for developing
ESBL-producing E. coli infections identified in this study. In contrast to
previous reports, other characteristics were not significantly different between the ESBL
and non-ESBL groups. Further multicentric prospective studies are essential to elucidate the
clinical characteristics of ESBL-producing E. coli infections and their
most appropriate treatment.
Acknowledgments
All authors have seen and agreed to the submitted version of this article. The authors
would like to thank Editage (www.editage.jp) for English language editing.
Conflict of interest
The authors declare that no conflict of interest exists.
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