Extended-spectrum β-lactamase-producing bacteria-induced urinary tract infections are increasing and require more potent antibiotics such as carbapenems. We evaluated the clinical significance of extended-spectrum β-lactamase urinary tract infection in children younger than 5 years to select proper antibiotics and determine prognostic factors. Differences were compared between age groups.
We retrospectively studied 288 patients with their first febrile urinary tract infection when they were younger than 5 years. Patients were divided into extended-spectrum β-lactamase-positive and extended-spectrum β-lactamase-negative urinary tract infection groups. Clinical characteristics and outcomes were compared between the groups; an infant group was separately analyzed (onset age younger than 3 months).
Extended-spectrum β-lactamase urinary tract infection occurred in 11 % patients who had more frequent previous hospitalization (
Extended-spectrum β-lactamase urinary tract infection requires more attention because of its higher recurrence rate. The antimicrobial susceptibility test demonstrated resistance to third-generation cephalosporins, but they can be used as first-line empirical antibiotics because of their high clinical response rate. Aminoglycosides can be second-line antibiotics before starting carbapenems when third-generation cephalosporins do not show bactericidal effects for extended- spectrum β-lactamase urinary tract infection.
Urinary tract infection (UTI) is one of the most common bacterial infections in children [
Extended-spectrum β-lactamase (ESBL)-producing bacteria are capable of degrading the β-lactam ring of most penicillins and cephalosporins [
ESBL-producing bacteria were first detected in Western Europe in the mid-1980s [
The aim of this study was to evaluate the clinical difference between ESBL-positive and ESBL-negative bacteria in febrile UTI in children younger than 5 years to evaluate risk factors for ESBL+ UTI and to suggest appropriate antibiotic treatment.
We retrospectively studied 288 patients who were diagnosed with their first febrile UTI when they were younger than 5 years at Severance Children's Hospital from September 2013 to December 2015. Data were collected from medical records. Patients who fulfilled the diagnostic criteria of the AAP guideline were included in this study. Patients without fever or presenting recurrent UTI were excluded. Flow diagram of 288 patients with first febrile UTI analyzed in this study is shown in
Urine specimens were obtained by transurethral bladder catheterization (n=186), urine bag collection methods (n= 100), and mid-stream sampling (n=2) for older children. UTI was diagnosed based on the guidelines defined by the American Academy of Pediatrics: findings of pyuria or bacteriuria on urine analysis (white blood cell [WBC] count >10-20/high-power field) and a positive urine culture result showing a single colony of bacteria with more than 50,000 colony-forming units (CFU)/mL with the clean catch and mid-stream collection method or more than 100,000 CFU/mL with the urine bag collection method.
The data collected by urine bag measurement could increase the possibility of contamination. However, with the 186 patients who underwent both bag analysis and bladder catheterization, we could compare the results of the urine culture. 168 of 186 (90%) showed same urine culture results between both specimens. 18 of 186 (10%) bag analyses did not show the same results as bladder catheterization; however, multiple organisms were detected, which were highly indicative of urinary tract infection. Also, urine bag collection was done with similar procedures with each patient, which makes the risk of contamination unlikely to be high.
The antimicrobial susceptibility test (AST) of the isolates was performed using the standard disc diffusion method, as recommended by the Clinical and Laboratory Standards Institute. The ESBL phenotypic confirmatory test with cefotaxime was performed for all isolates by using the disc diffusion method on Mueller Hinton agar plates.
For all patients, repeated urine analyses and urine cultures were performed 18-36 hours after the first administration of empirical antibiotics. Cefotaxime, third-generation cephalosporin, was used as empirical antibiotics for all patients intravenously. The clinical effects of antibiotics were evaluated by defervescence and negative culture results after administration of antibiotics. Antibiotics has not been modified according to the antibiogram if clinical improvement with negative urine culture was observed, and intravenous therapy has been followed by oral treatment for a total of 14 days.
We compared the clinical characteristics and outcomes of the ESBL+ UTI group and ESBL- UTI group to determine risk factors for ESBL+ UTI. Furthermore, causative organisms, AST, and antibiotic responses were analyzed in the ESBL+ UTI group. Infants younger than 3 months were studied separately. This study was approved by the Institutional Review Board of Severance Hospital, Yonsei University College of Medicine, Seoul, Korea (IRB number: 4-2017-0347).
SPSS 20 for Microsoft Windows was used for all statistical analyses. Results for continuous variables are presented as mean±standard deviation and categorical variables are reported as percentages. Fisher’s exact test was used to compare categorical variables. The Mann-Whitney U test was used for continuous variables.
Patients were predominantly male (73%) and had a mean age of 6 months. Previous hospitalization was reported for 17% of all patients. The incidence of UTI with ESBL-producing bacteria was 11% (
A comparison of ESBL+ UTI and ESBL-UTI groups is shown in
Causative organisms of UTI and antibiotic responses are shown in
We also compared the ESBL+ UTI group and ESBL- UTI group comprising patients younger than 3 months. During early infancy, the ESBL+ UTI group had a more frequent previous hospitalization (54%;
ESBL-producing organisms were typically limited to healthcare facilities, but they have begun to appear in communities as well, and their prevalence is consistently increasing, as is the severity of infection [
There have been different results regarding severity, prognostic factors, and treatment of ESBL+ UTI for children [
In our study, the ESBL+ UTI group did not show differences in clinical microbiologic response rate, renal scarring on DMSA scan, or vesicoureteral reflux on VCUG compared to ESBL- UTI group. However, our study demonstrated that ESBL+ UTI was associated with a significantly higher recurrence rate of UTI. Children with ESBL+ UTI require more attention during follow-up because of UTI recurrence. Also, further study is needed if patients with ESBL+ UTI are likely to repeatedly encounter the same ESBL+ bacteria, because 73% of recurred patients in ESBL+ UTI group infected with the same ESBL+ bacteria.
Studies have indicated that previous antibiotic usage is a risk factor for ESBL+ UTI [
In our study, the influence of ESBL on UTI in infants(younger than 3 months) was analyzed separately. Infants younger than 3 months might have weaker immune systems than older children and might show different clinical features in ESBL+ UTI. Even though the analysis regarding CRP showed meaningful differences in the infant group with age younger than 3 months (
ESBL-producing bacteria were infrequent pathogens of UTI in children, but their prevalence is consistently increasing [
In our study, 31 of 32 (97%) patients with ESBL-producing bacterial infection responded to third-generation cephalosporin. Therefore, patients who responded to treatment were maintained with the same antibiotics for 14 days. This indicated that the
Generally, carbapenems are recommended for treating infections with ESBL-producing strains [
According to
Our study has several limitations. Data analyses were performed retrospectively using patient medical records. Also, the urine culture method included urine bag measurement, which could increase the possibility of contamination. In the future, a prospective, large-scale, longitudinal study is necessary to investigate clinical characteristics of ESBL+ UTI according to patient age, disease course, and treatment response. Results from such a study might lead to an appropriate therapeutic guideline for the clinical management of ESBL+ UTI.
In conclusion, ESBL+ UTI requires more attention because of its high recurrence rate. Infants younger than 3 months with a previous hospitalization had more severe infections and higher recurrence rates; therefore, we should select antibiotics carefully. Third-generation cephalosporins showed resistance in the AST, but can be used as first-line empirical antibiotics because of their high clinical response rate. For ESBL+ UTI resistant to third-generation cephalosporin, we can also consider aminoglycoside as a second-line antibiotic before starting carbapenem.
No potential conflict of interest relevant to this article was reported.
Flow diagram summarizing the patient selection process.
Demographics of the Patients
Total number of patients | 288 |
Sex ratio (male/female) | 2.64 |
Age (months) | 6.0±10.0 |
Weight (kg) | 7.5±1.8 |
Previous hospitalization | 49 (17%) |
Duration of hospitalization (days) | 4.3±1.3 |
Sepsis |
15 (5%) |
Urine culture | ESBL+ 256 (89%), ESBL- 32 (11%) |
Data are presented as mean±standard deviation or number (%).
Patients with bacteria in the blood culture and the same bacteria in the urine culture.
Comparison of ESBL- and ESBL+ UTI Groups
ESBL- (n=256) | ESBL+ (n=32) | ||
---|---|---|---|
Patient characteristics | |||
Sex (male/female) | 2.77 | 1.91 | 0.35 |
Age (months) | 6.26±10.62 | 4.31±1.94 | 0.30 |
Previous hospitalization |
39/256 (15%) | 10/32 (31%) | 0.02 |
Hydronephrosis on antenatal sonography | 6/256 (2%) | 2/32 (6%) | 0.22 |
Duration of hospitalization (days) | 4.27±1.14 | 5.00±2.05 | 0.06 |
Duration of fever (days) | 3.24±1.79 | 3.22±1.74 | 0.95 |
Duration of fever after antibiotics (days) | 1.15±0.91 | 1.09±0.82 | 0.76 |
Gastrointestinal symptom | 44/256 (17%) | 4/32 (12%) | 0.50 |
Laboratory findings | |||
Hemoglobin (g/dL) | 14.6 | 13.2 | 0.40 |
Platelet count (×103/µL) | 428±110 | 442±107 | 0.48 |
WBC (×103/µL) | 15450±5790 | 14660±5450 | 0.47 |
MPV (fL) | 7.6±0.6 | 7.6±0.5 | 0.97 |
ESR (mm/hr) | 33.6±24.9 | 39.4±22.1 | 0.23 |
CRP (mg/L) | 43.5±41.4 | 45.4±28.8 | 0.80 |
BUN (mg/dL) | 8.2±3.2 | 8.3±3.4 | 0.81 |
Cr (mg/dL) | 0.22±0.37 | 0.23±0.89 | 0.50 |
β2-microglobulin (mg/L) | 0.69±1.87 | 1.79±7.51 | 0.45 |
Radiologic findings and outcomes | |||
Abnormal sonographic findings | 159/256 (62%) | 21/32 (66%) | 0.70 |
Hydronephrosis | 36/159 (23%) | 7/21 (33%) | 0.30 |
DMSA abnormality | 93/225 (41%) | 14/30 (47%) | 0.58 |
VUR | 44/133 (33%) | 6/22 (27%) | 0.59 |
High-grade VUR (IV, V) | 18/44 (41%) | 2/6 (33%) | 0.99 |
Sepsis | 12 (5%) | 3 (9%) | 0.23 |
Surgery |
6 (2%) | 1 (3%) | 0.57 |
Recurrence of UTI |
49 (19%) | 11 (34%) | 0.045 |
Data are presented as mean±standard deviation or number (%).
Abbreviations: WBC, white blood cell; MPV, mean platelet volume; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; BUN, blood urea nitrogen; Cr, creatine; DMSA, dimercaptosuccinic acid; VUR, vesicoureteral reflux; UTI, urinary tract infection.
Previous hospitalization excluded patients who were hospitalized without use of antibiotics. It indicates previous hospitalization with antibiotic treatment due to infection, and re-admission due to UTI occurred at least 2 weeks after the previous hospitalization.
Surgery included ureteroneocystostomy, deflux injection, and detrusorhaphy.
The date of recurrence ranged from 35 to 293 days.
Causative Organisms of UTI and Results of Treatment
Organisms | ESBL- (n=256) | ESBL+ (n=32) | ||
---|---|---|---|---|
228 (89%) | 32 (100%) | |||
11 (4%) | ||||
3 (1%) | ||||
8 (3%) | ||||
3 (1%) | ||||
Others | 3 (1%) | |||
Antibiotic response to first antibiotics | 228/228 (100%) | 31/32 (97%) |
One patient did not respond to third-generation cephalosporin and required carbapenem.
Antibiotic Susceptibility Test Results for ESBL Bacteria (n=32)
Antibiotics | Sensitivity | Resistant | Mean MIC |
---|---|---|---|
Amikacin | 32/32 (100%) | 0/32 (0%) | 2.38 |
Gentamycin | 26/32 (81%) | 6/32 (19%) | 1 |
Ampicillin | 0/32 (0%) | 32/32 (100%) | |
Ampicillin/Sulbactam | 9/32 (28%) | 23/32 (72%) | 13.33 |
Aztreonam | 15/32 (47%) | 17/32 (53%) | 2.07 |
Cefazolin | 0/32 (0%) | 32/32 (100%) | |
Cefoxitin | 32/32 (100%) | 0/32 (0%) | 7.75 |
Cefotaxime | 0/32 (0%) | 32/32 (100%) | |
Ceftazidime | 19/32 (59%) | 13/32 (41%) | 1.74 |
Cefepime | 19/32 (59%) | 13/32 (41%) | 1.85 |
Piperacillin/Tazobactam | 32/32 (100%) | 0/32 (0%) | 7.63 |
Ertapenem | 32/32 (100%) | 0/32 (0%) | 0.5 |
Meropenem | 32/32 (100%) | 0/32 (0%) | 0.25 |
Levofloxacin | 15/32 (47%) | 17/32 (53%) | 0.64 |
Cotrimoxazole | 20/32 (63%) | 12/32 (38%) | 20 |
Tigecycline | 32/32 (100%) | 0/32 (0%) | 0.5 |
Abbreviations: MIC, minimal inhibitory concentration.
Comparison between ESBL- and ESBL+ UTI Groups (Age <3 Months)
ESBL- (n=88) | ESBL+ (n=13) | ||
---|---|---|---|
Patient characteristics | |||
Sex (male/female) | 3.89 | 3.33 | 0.73 |
Admission history | 11/88 (13%) | 7/13 (54%) | 0.002 |
Hydronephrosis on antenatal sonography | 0/88 (0%) | 2/13 (15%) | 0.015 |
Duration of hospitalization (days) | 4.32±1.15 | 5.62±2.96 | 0.14 |
Duration of fever (days) | 2.70±1.35 | 3.23±1.96 | 0.22 |
Duration of fever after antibiotics (days) | 1.07±0.90 | 1.15±1.14 | 0.76 |
Gastrointestinal symptom | 14/88 (16%) | 0/13 (0%) | 0.21 |
Laboratory findings | |||
Hemoglobin (g/dL) | 10.5 | 10.2 | 0.24 |
Platelet count (×103/µL) | 452±117 | 443±124 | 0.79 |
WBC (×103/µL) | 13,720±4560 | 13440±4750 | 0.84 |
MPV (fL) | 7.8±0.7 | 7.8±0.6 | 0.99 |
ESR (mm/hr) | 27.6±20.6 | 38.6±22.9 | 0.08 |
CRP (mg/L) | 32.3±26.4 | 48.6±29.8 | 0.04 |
BUN (mg/dL) | 8.4±2.7 | 8.6±4.0 | 0.89 |
Cr (mg/dL) | 0.22±0.03 | 0.25±0.13 | 0.38 |
β2-microglobulin (mg/L) | 0.71±1.67 | 4.34±12.55 | 0.39 |
Radiologic findings and outcomes | |||
Abnormal sonographic findings | 61/88 (69%) | 8/13 (62%) | 0.54 |
Hydronephrosis | 12/61 (20%) | 3/8 (38%) | 0.36 |
DMSA abnormality | 26/74 (35%) | 5/12 (42%) | 0.75 |
VUR | 13/45 (29%) | 4/10 (40%) | 0.48 |
High-grade VUR (IV, V) | 3/13 (39%) | 2/4 (50%) | 0.99 |
Sepsis | 7/88 (8%) | 3/13 (23%) | 0.12 |
Surgery | 4/88 (2%) | 1/13 (8%) | 0.50 |
Recurrence of UTI |
23/88 (26%) | 8/13 (62%) | 0.02 |
Data are presented as mean±standard deviation or number (%).
Abbreviations: WBC, white blood cell; MPV, mean platelet volume; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; BUN, blood urea nitrogen; Cr, creatine; DMSA, dimercaptosuccinic acid; VUR, vesicoureteral reflux; UTI, urinary tract infection.
The date of recurrence ranged from 35 to 247 days.