Changes in the incidence of community-acquired upper urinary tract infections caused by extended-spectrum beta-lactamase-producing Escherichia coli in Japanese children, 2016-2022

doi:10.21203/rs.3.rs-2969467/v1

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Changes in the incidence of community-acquired upper urinary tract infections caused by extended-spectrum beta-lactamase-producing Escherichia coli in Japanese children, 2016-2022

https://doi.org/10.21203/rs.3.rs-2969467/v1

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Background

Urinary tract infections caused by extended-spectrum beta-lactamase (ESBL)-producing bacteria are increasing worldwide. At our hospital, the number of children hospitalized with upper urinary tract infections (UUTI) caused by ESBL-producing Escherichia coli had been a major problem since 2016.

However, since the start of the COVID-19 pandemic in 2020, the proportion of ESBL-producing E. coli has changed. This study reviewed the trends in admissions of children to the hospital with UUTI caused by E. coli.

Methods

This retrospective study included patients who were hospitalized in the pediatric department of Matsue Red Cross Hospital with UUTI caused by E. coli. Medical and hospital records were reviewed to assess patient characteristics, antimicrobial use density, and days of antibiotic therapy at the hospital from January 1, 2016 to December 31, 2022.

Results

Over the study period, 80 children were admitted to the hospital with their first episode of bacterial UUTI. The total number of children hospitalized in the pediatric department decreased. However, the proportion of children with UUTI per total number of hospitalized children remained stable over the study period. Urine sample analyses showed that the proportion of ESBL-producing E. coli decreased significantly in 2020 to 2022. Antimicrobial use density and days of therapy of oral third-generation cephems was significantly correlated with the proportion of UUTI caused by ESBL-producing E. coli in pediatric patients.

Conclusion

Effective hygiene measures and appropriate use of antibiotics especially, oral third-generation cephems, are effective for reducing the incidence of ESBL-producing bacterial infections.

upper urinary tract infection

extended-spectrum beta-lactamase-producing Escherichia coli

antimicrobial stewardship

antimicrobial use density

days of therapy

Antimicrobial resistance (AMR) increases the difficulties associated with treating an infectious disease and is a serious threat to human health. Especially, the prevalence of extended-spectrum beta-lactamase (ESBL)-producing bacilli has increased dramatically worldwide [1].

Previously, ESBL-producing bacteria caused nosocomial infections, but now they cause community-acquired infections worldwide; moreover, reports of urinary tract infections caused by ESBL-producing bacteria in children have increased [2]. Upper urinary tract infections (UUTI) are caused primarily by enterobacteria that colonize in the rectum which indicates a fecal-perineal-urethral route of infection [3].

In 2016, the number of children hospitalized with UUTI caused by ESBL-producing Escherichia. coli dramatically increased in Shimane in eastern Japan [4]. Since 2016, ESBL-producing E. coli infections have become a community-acquired UUTI in this area.

The World Health Organization (WHO) and Japan declared National Action Plan on Antimicrobial Resistance 2016–2020 to try to eradicate multi-drug-resistant bacteria [5, 6]. Appropriate use of antimicrobial drugs was an important part of the plan. An antimicrobial stewardship team (AST) responsible for coordinating interventions to improve and measure the appropriate use of antimicrobial agents was established in each hospital.

In Japan, coronavirus disease (COVID-19) rapidly spread during early 2020 and the Japanese government declared a state of emergency in April 2020. The COVID-19 pandemic influenced the whole of society and resulted in major changes of lifestyle. After the start of the pandemic, hospital admissions for non-COVID reasons decreased in all age groups [7, 8], and the incidence of some diseases transmitted through contact decreased as a result of protective measures such as school closure, mask use, social distancing, and adherence to hygiene measures.

E. coli is the major cause of UUTI [9]. However, the proportion of ESBL-producing E. coli decreased from 42% from 2016 to 2019, to 13% in 2022. Such a large decrease in the incidence of community-acquired ESBL-producing E. coli has not been reported previously in Japan. Therefore, we aimed to describe the clinical characteristics of ESBL-producing E. coli that cause community-acquired UUTI in children, and the effects of antimicrobial stewardship measures.

Data used for this study were retrospectively collected from medical records in an electronic database at Matsue Red Cross Hospital. We collected medical records of patients who were admitted to the pediatric department with UUTI between January 1, 2016, and December 31, 2022. Their medical records were reviewed and data were extracted on age at hospitalization, sex, hospitalization history, degree of vesicoureteral reflux (VUR) detected by voiding cystogram, white blood cell (WBC) count, and C-reactive protein (CRP) and procalcitonin (PCT) levels at the time of hospitalization.

The bacterial profile was determined using urine culture results, blood culture results, and antibiotic treatment. UUTI was diagnosed based on the finding of more than 10⁴ CFU/mL bacteria in urine caught by a catheter and clinical symptoms.

Infection relapse was defined as the presence of bacteria in urine and associated clinical symptoms within 1 month after the completion of the primary treatment. Exclusion criteria were treatment with immunosuppressive drugs, history of UUTI, and major congenital anomalies.

Microbiological identification of E. coli was performed using the VITEK 2 GN identification card. Screening for ESBL production was performed using an assumed ceftriaxone (CTRX)-resistant strain of ESBL-producing bacteria and an identification test disk (AmpC/ESBL differentiation disk; Kanto Chemical Co., Inc., Japan). Differentiation of ESBL-producing bacteria was based on the Clinical and Laboratory Standards Institute (CLSI) criteria. Antibiotic susceptibility was evaluated according to the CLSI definitive method. The test for drug sensitivity was examined by performing agar plate diffusion, based on the CLSI method [10].

All patients included in this study were hospitalized for UUTI caused by E. coli. The patients were divided into two groups based on whether they were admitted during 2016 to 2019 or 2020 to 2022.

During study period, the antimicrobial use density (AUD) and days of therapy (DOT) of intravenous broad-spectrum antibiotics and overall oral antibiotic use were evaluated by the AST of the hospital. To assess the appropriate use of antimicrobials, we collected medical records on the AUD and DOT of oral and intravenous antibiotics in the hospital between January 1, 2017, and December 31, 2022. The AUD and DOT were calculated as follows using the defined daily dose (DDD) value recommended by WHO [11]:

AUD (DDD/1,000 patient-days) = [Total dose (g) of antimicrobial used / DDD × Total days of hospital stay] × 1000

DOT (DOT/1,000 patient-days) = [Total days (day) antimicrobials were used / Total days of hospital stay] × 1000

Statistical analysis

Continuous variables were reported as the mean ± standard deviation. The Kruskal-Wallis H-test and Mann-Whitney U-test were used to compare age, WBC, CRP, and PCT.

The Chi-squared test was used to assess the correlation between number of children admitted with E. coli and ESBL-producing E. coli, sex, history of hospitalization, VUR greater than grade 2, blood cultures, and relapse.

Spearman’s rank correlation coefficient (ρ) test was used to assess the correlations between proportion of UUTI caused by ESBL-producing E. coli and AUD and DOT of antibiotics.

All analyses were performed using Microsoft Excel (Microsoft Corporation, WA, USA) and the Ystat 2000 statistical software package (Igakutosho-Shuppan Co., Ltd., Saitama, Japan). For all analyses, two-tailed p-values < 0.05 were considered statistically significant.

Participant characteristics

Eighty children with UUTI who were admitted to the department of pediatrics at the hospital and who met the inclusion criteria were enrolled in the study. The secular trend in the number of UUTI admissions in children is shown in Fig. 1. The total number of patients hospitalized in the department of pediatrics decreased over the study period. However, the proportion of UUTI cases among hospitalized children did not show an obvious change (1.0% in 2016–2019, and 1.9% in 2020–2020).

Among the 38 cases of UUTI caused by E. coli in 2016–2019, 21 (55%) were caused by ESBL-nonproducing E. coli, and 17 (45%) were caused by ESBL-producing E. coli. Among the 31 cases of UUTI caused by E. coli in 2020–2022, 20 (65%) were caused by ESBL-nonproducing E. coli and 11 (35%) were caused by ESBL-producing E. coli. The proportion of UUTI cases caused by ESBL-producing E. coli decreased significantly from 47% in 2020 to 13% in 2022 (p = 0.036). Similarly, the proportion of ESBL-producing E. coli is confirmed in whole urine and blood culture samples in hospitalized patients decreased from 2020 to 2022. (Fig. 2).

Patient demographics and clinical characteristics at the time of hospitalization are summarized in Table 1, and the antibiotic susceptibility of ESBL-producing E.coli detected in pediatric urine samples is shown in Table 2. There was no significant differences in antibiotic susceptibility, sex, age at the time of hospitalization, history of hospitalization, relapse number, bacteremia cases, proportion of patients born in the hospital, WBC count, or CRP and PCT levels among children hospitalized in 2016–2019 and 2020–2022.

Table 1

Demographics, clinical characteristics, and examination data of pediatric patients with UUTI caused by *E. coli*
period	2016–2019	2020-2022			P value
n (ESBL-producing E.Coli)	42 (17)		38 (11)
n (ESBL-producing E.Coli)	42 (17)	2020 17 (8)	2021 13 (2)	2022 8 (1)
Male	30	26			0.76
Age (month)	2–96 (Median 5)	0-168 (Median 3)			0.61
Born at our hospital	13	6			0.18
VUR (greater than Grade 2)	6/25	4/10			0.59
History of hospitalization	5 (11.9%)	5(13.2%)			0.86
WBC (/µl)	17746 ± 6222	16750 ± 6212			0.46
CRP (mg/dl)	7.69 ± 5.99	7.52 ± 6.21			0.83
PCT (mg/dl)	5.58 ± 10.79	3.64 ± 5.76			0.32
Case of bacteremia	2 (4.7%)	2 (5.3%)			0.68
Case of relapse	1	4			0.18
WBC, white blood cell; CRP, C-reactive protein; PCT, procalcitonin; VUR, vesicoureteral reflux.

Table 2

Antimicrobial resistance profiles of ESBL-producing *E. coli* detected in pediatric urine samples each year
			ESBL-producing E.Coli
year	2016	2017	2018	2019	2020	2021	2022
n	5	4	5	3	8	2	1
Antibiotic susceptibility (%)
ABPC	0	0	0	0	0	0	0
PIPC	0	0	0	0	0	0	0
SBT/ABPC	60	100	100	100	100	100	0
CEZ	0	0	0	0	0	0	0
CAZ	0	0	0	0	0	0	0
CTRX	0	0	0	0	0	0	0
CFPM	0	0	0	0	0	0	0
CMZ	100	100	100	100	100	100	100
FMOX	100	100	100	100	100	100	100
IPM	100	100	100	100	100	100	100
MEPM	100	100	100	100	100	100	100
AZT	0	0	0	0	0	0	0
GM	60	100	100	100	100	100	0
AMK	100	100	100	100	100	100	100
MINO	80	100	100	100	100	100	100
CPFX	80	100	100	100	100	100	0
LVFX	80	100	100	100	100	100	0
CP	100	100	100	100	100	100	100
Ampicillin (ABPC), piperacillin (PIPC), sulbactam/ampicillin (SBT/ABPC), cefazolin (CEZ), ceftazidime (CAZ), ceftriaxone (CTRX), cefepime (CFPN), cefmetazole (CMZ), flomoxef (FMOX), imipenem (IPM), meropenem (MEPM), aztreonam (AZT), gentamicin (GM), amikacin (AMK), minocycline (MINO), ciprofloxacin (CPFX), levofloxacin (LVFX), chloramphenicol (CP)

Antimicrobial use density and days of antibiotic therapy

The AUD and DOT of intravenous broad-spectrum antibiotics such as quinolone, carbapenem, fourth-generation cephems, and piperacillin/tazobactam (TAZ/PIPC) and the AUD and DOT of oral antibiotics are shown in Fig. 3. The reduction in the use of oral third-generation cephems was significant (p = 0.0026), and was significantly correlated with the proportion of ESBL-producing E. coli in UUTI cases, as shown in Fig. 4 (ρ = 0.93745; Y = 0.06X + 0.15).

During this study period, the highest incidence of hospitalization due to UUTI was in infants aged less than 6 months. The age and sex profile of the children in this study was similar to that of Japanese children with UUTI in a previous study [9]. The total number of patients hospitalized in the pediatric department decreased from 2016 to 2022; however, the decrease in the number of patients with UUTIs was more gradual and less evident than the overall decrease in the number of patients.

Some studies have evaluated the changes in urinary tract infection (UTI) incidence rates in children during the COVID-19 pandemic in Japan [7, 8]. In a study by Kishimoto et al [8], a decrease in hospitalizations due to upper respiratory infection, lower respiratory infection, and gastrointestinal infection, which are more clearly related to social distancing and viruses, was observed in the pediatric age group during the COVID-19 period compared with the pre-COVID-19 period, whereas the hospitalization rate for urinary tract infections did not change.

The major cause of UUTI in this study was E. coli, as in previous studies [2, 4, 9]. Since 2016, almost 50% of all UUTI cases in Matsue City have been caused by ESBL-producing E. coli. However, the proportion of UUTI caused by community-acquired ESBL-producing E. coli decreased markedly during the period from 2020 to 2022.

In Matsue City, the number of patients with COVID-19 increased from 209 in 2020 to 136,079 in 2022 [10]. The COVID-19 pandemic led to radical changes in hygienic measures worldwide. People began wearing face masks, physical distancing from others, washing hands, disinfecting hands with alcohol, and avoiding crowded places in order to prevent transmission.

ESBL-producing bacilli are often multi-drug resistant, and related genes are encoded by plasmids that are transferred from species to species. Previously, the digestive tract was thought to be the main reservoir from which ESBLs were derived [3]. However, Matsumoto et al. [13], reported that ESBL-producing E. coli were also isolated from respiratory samples. Traditionally, UUTI is defined as a non-communicable disease. However, it is possible that both the reduction in hospital admissions and hygienic measures such as washing hands and widespread use of alcohol disinfectants in public places and home, could have reduced the transmission of ESBL plasmids from person-to-person or from the gut to the urinary tract via the hands.

One of the goals of the AMR action plan is the appropriate use of antimicrobial agents by reduction of the use of broad-spectrum antimicrobial agents, such as cephalosporins, fluoroquinolones, and macrolides [6]. During the study period, even before the onset of the COVID-19 pandemic, the AUD and DOT of intravenous broad-spectrum antibiotics and overall oral antibiotics decreased, which indicated a reduction in the amount used and a shorter period of use of these antibiotics. These results indicate that the AST plays a crucial role in the surveillance of antimicrobial usage and interventions to ensure appropriate antimicrobial use.

The reduction of oral third-generation cephem use was significantly correlated with the proportion of community-acquired ESBL-producing E. coli detected in urine samples. Previously, several studies have shown that the cephem-containing β-lactam rings are able to induce ESBL production and that exposure to third-generation oral cephems is can induce conjugative transfer of ESBL plasmids [13–16].

Furthermore, removal of antibiotic pressure results in loss of resistance plasmids and reduces the number of antibiotic-resistant bacteria because of a fitness cost in the absence of selection [17]. A natural history study of multidrug-resistant Enterobacteriaceae colonization rates in the community decreased during the 12-month follow-up period [18].

These results suggest that there is a close relationship between reduction of oral third-generation cephem use and infections with ESBL-producing bacilli.

However, some types of ESBL producing plasmids require little fitness cost for bacterium despite absence of antibiotic pressure [19]. Further studies focusing on the effect costs of ESBL-producing bacteria and antibiotic pressure are required to investigate the decrease in the prevalence of AMR bacteria after reduction in the use of third-generation cephems.

Pathogen resistance in UTI varies according to geographic location. The incidence rate of infections cause by ESBL-producing bacilli has been relatively low in Japan [1, 20], but has increased in neighboring countries [1]. The hospital is located in an area of Japan that has a has experienced a major influx of foreign-born residents from South American and other Asian countries [21]. ESBL-producing bacteria have been detected not only at medical centers but also in food, animals, and travelers [1, 22]. Previous studies conducted in America and Europe have shown that ESBL-producing bacilli in the stool are strongly correlated with international travel, especially in travelers returning from Asian and African countries. [16, 22].

After the start of the COVID-19 pandemic in 2020, restrictions were placed on travel to other countries, and the number of foreign individuals living in Matsue City decreased [21]. Limitations of international travel might have reduced the transfer of regional antibiotic resistance genes. Therefore, as the world emerges from the COVID-19 pandemic, the movement of people, foods, goods, and animals will recover and the number of ESBL-producing bacilli outbreaks might increase.

This study has several limitations. We conducted a retrospective review of patient medical records; therefore, maternal and neonatal medical records of pediatric patients who were born in other hospitals were not available for review. Medications prescribed by other hospitals and other factors preceding the child’s UUTI hospitalization were not assessed. Prior exposure to antibiotics could have affected the results. Furthermore, we did not have data regarding the onset of the UUTI before hospitalization. Therefore, further prospective studies are necessary to explore the factors associated with ESBL-producing E. coli and UUTI in children.

The study results suggest that hygienic measures and appropriate use of antimicrobials, especially reduction in the use of oral third-generation cephems are effective for reducing the incidence of ESBL-producing bacterial infections such as UUTI. However, as the world emerges from the COVID-19 pandemic, the movement of people, foods, goods, and animals will recover and the incidence of ESBL-producing bacterial infections may increase. Therefore, it is necessary for the AST in each hospital to focus on use of antibiotics and maintain ongoing surveillance of the prevalence of ESBL-producing bacteria.

AMR, antimicrobial resistance; AST, antimicrobial stewardship team; AUD, antimicrobial use density; CLSI, Clinical and Laboratory Standards Institute; COVID-19, coronavirus disease; CRP, C-reactive protein; CTRX, ceftriaxone; DDD, defined daily dose; DOT, days of therapy; ESBL, extended-spectrum beta-lactamase; PCT, procalcitonin; TAZ/PIPC, piperacillin/tazobactam; UTI, urinary tract infection; UUTI, upper urinary tract infection(s); VUR, vesicoureteral reflux; WBC, white blood cell; WHO, World Health Organization.

Ethics approval and consent to participate

The study was approved by the Ethics Committee of Matsue Red Cross Hospital of Japan, where the study was conducted (IRB approval number: 554). Any potential identifers were eliminated to ascertain confidentiality. All procedures performed were carried out in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments and the institutional ethics guidelines. The consent to participate is not applicable because it was not required for ethical approval, we did not perform any extra interventions, only the necessary and usual therapeutic and diagnostic methods were used. The requirement to obtain informed consent to participate was waived by the Ethics Committee of Matsue Red Cross Hospital of Japan.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

None.

Author contributions

AH contributed to the study conception and design, performed material preparation, data collection, and analysis, and wrote the first draft of the manuscript. MS, MN, SH, YM, YH, TF, MM, and AN contributed to the study conception and design, performed material preparation, data collection, and analysis, and provided comments on drafts of the manuscript. All authors read and approved the final manuscript.

Acknowledgements

We would like to thank Editage (www.editage.jp) for English language editing.

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No competing interests reported.

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Changes in the incidence of community-acquired upper urinary tract infections caused by extended-spectrum beta-lactamase-producing Escherichia coli in Japanese children, 2016-2022

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Abstract

Figures

Background

Methods

Statistical analysis

Results

Participant characteristics

Antimicrobial use density and days of antibiotic therapy

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1