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1（ 1 ）〈Original Article〉

Extended-spectrum beta-lactamase-producing
Escherichia coli isolates from patients withurinary tract infections in an acute care hospital:
Epidemiology and antibiogram1
Kosuke Jo and Kenji Kono
Department of Infectious Diseases, Fukuoka Kinen Hospital(Received for publication November 30, 2022)

Objective: To investigate the epidemiology and antibiogram of the extendedspectrum beta-lactamase (ESBL)-producing Escherichia coli (ESBL-EC) isolated
from urine samples collected from an acute-care hospital in Japan.
Methods: A descriptive epidemiological study was conducted to compare isolatesof ESBL-EC (n＝129) and non-ESBL-EC (n＝279) between April 1, 2019 andMarch 30, 2020. Data were collected from the microbiology laboratory and medical
charts. Multivariate logistic regression analysis was used to assess patientsʼ
background, infection risk factors, and ESBL-EC and non-ESBL-EC antibiograms.
Results: E. coli was the most common bacteria (30.0%) isolated from urine
samples, while urine was the most common (61.0%) source of this bacteria. Among
408 isolates of E. coli strains from urine, 129 (31.6%) ESBL-EC and 279 (68.4%)
non-ESBL-EC were detected. The background investigation of patients from whom
ESBL-EC was isolated revealed worsened performance status and use of antibiotics inthe past two months as risk factors. Antibiogram of ESBL-EC showed high resistanceto levoﬂoxacin and third-generation cephalosporins, such as ceftazidime andcefotaxime, with high susceptibility to cefmetazole, minocycline, and fosfomycin.
Conclusions: ESBL-EC is one of the most important multidrug-resistant bacteria,along with methicillin-resistant Staphylococcus aureus, causing serious
Correspondence author: Kosuke Jo, Department of Infectious Diseases, Fukuoka Kinen Hospital, 1–1–35 Nishijin,
Sawara-ku, Fukuoka city, Fukuoka, Japan, Tel.: ＋81–92–821–4731; Fax: ＋81–92–821–6449, E-mail: kousuke-j@oita-u.ac.jp
1

Abbreviations: ESBL, extended-spectrum beta-lactamase; ESBL-EC, extended-spectrum beta-lactamase (ESBL)-producing

Escherichia coli; UTIs, urinary tract infections; AMR, antimicrobial resistant; MDRP, multidrug-resistant Pseudomonas
aeruginosa; CRE, carbapenem-resistant Enterobacteriaceae; LVFX, levoﬂoxacin; CPFX, ciproﬂoxacin; MINO, minocycline;
ST, trimethoprim/sulfamethoxazole; FOM, fosfomycin; ABPC, ampicillin; CMZ, cefmetazole; CTM, cefotiam; CAZ,
ceftazidime; CFPM, cefepime; MEPM, meropenem

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complications in hospital settings, with antibiotic administration being a risk factor.
Meropenem, cefmetazole, minocycline, or fosfomycin should be used as ﬁrst-line
treatment for urinary tract infections caused by ESBL-EC.
Key words: Extended-spectrum beta-lactamase, Escherichia coli, urinary tract
infections, cefmetazole, fosfomycin

Introduction
Escherichia coli is one of the major infectious pathogens in hospital-acquired infections,commonly isolated from patients with urinary tract infections (UTIs). In recent years, an increasein extended-spectrum beta-lactamase-producing E. coli (ESBL-EC) strains have been observed inclinical settings in Japan1), which has caused diﬃculties in the treatment of infectious diseases.
Along with methicillin-resistant Staphylococcus aureus (MRSA), ESBL-EC has gradually become the most prevalent antimicrobial resistant (AMR) bacteria in our hospital, although occasionally multidrug-resistant Pseudomonas aeruginosa (MDRP), multidrug-resistant Acinetobacter baumannii, and carbapenem-resistant Enterobacteriaceae (CRE) are also found.
In this study, we aimed to determine the epidemiology and clinical signiﬁcance of ESBLEC, including sample distribution, backgrounds of the patients from whom this strain was isolated, risk factors for ESBL-EC infection, and antibiogram. Based on the ﬁndings of the study, we
aimed to establish the best strategy to treat UTIs caused by ESBL-EC. In addition, we compared
the frequency of isolation of ESBL-EC with those of other resistant bacteria to rank the importance of ESBL-EC among resistant bacteria in a hospital environment.

Materials and Methods
Facility
Fukuoka Kinen Hospital is a 239-bed acute-care hospital, located at downtown Fukuoka, thelargest city in the southwestern region of Japan. Since 2010, the hospital has operated a microbiallaboratory with two dedicated personnel.

Bacteriological Examination
Between 1 April 2019 and 30 March 2020, urine samples were collected from hospital
outpatients and inpatients with UTIs to culture and identiﬁed E. coli in our laboratory. UTI was
diagnosed using pyuria, deﬁned as ＞10 white blood cells per high-power ﬁeld in centrifugedMar. 2023

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urine, regardless of symptoms. Microbial identiﬁcation and antimicrobial susceptibility tests werecarried out using VITEK®2 system (bioMérieux, Ink, Craponne, France) and VITEK®2 GN & GP
ID card (bioMérieux, Japan, Tokyo). Antibiotic susceptibility of E. coli isolates was determinedwith VITEK® 2 cards (bioMérieux) using the disk diﬀusion method based on Clinical and Laboratory Standards Institute (CLSI) criteria2). The results were expressed as susceptible (S), intermediate (I), or resistant (R). The 11 tested antibiotics were as follows: levoﬂoxacin (LVFX), ciproﬂoxacin (CPFX), minocycline (MINO), trimethoprim/sulfamethoxazole (ST), fosfomycin(FOM), ampicillin (ABPC), cefmetazole (CMZ), cefotiam (CTM), ceftazidime (CAZ), cefepime(CFPM), and meropenem (MEPM).
ESBL production was screened by measuring the size of inhibition rings using cefotaxime(≤27 mm) and CAZ (≤22 mm). The ESBL conﬁrmation test was performed using cefotaxime-clavulanate and CAZ-clavulanate disks2). S. aureus isolates resistant to cefoxitin and oxacillin wereclassiﬁed as MRSA according to CLSI guidelines2) using the disc diﬀusion method. MDRP wasdeﬁned as P. aeruginosa resistant to ﬂuoroquinolones (minimum inhibitory concentration[MIC] ≥ 4 µg/mL), carbapenems (MIC ≥ 16 µg/mL), and amikacin (MIC ≥ 32 µg/mL), in accordance with the criteria speciﬁed by the Ministry of Health, Labour, and Welfare of Japan. AmpC
beta-lactamase was detected according to CLSI guidelines2).
Data collection
Patient data were collected retrospectively, and the parameters investigated were based on
previous reports3–7). The following data was collected: age, gender, out- or in-patient, worsened
performance status, nursing home admission, use of antibiotics in the past two months, indwelling urinary catheter, prior administration, and co-morbidities (diabetes mellitus, cerebrovasculardisease, solid tumor, urinary tract abnormality, and immune compromise). Performance status(PS) is a method developed by Eastern Cooperative Oncology Group (ECOG) for evaluating thepatientʼs overall status. PS 3 and 4 (on a scale of 0 to 4) were considered as worsened PS8). These
factors were statistically analyzed as variables.
The microbial laboratory data system was used to extract the microbiological data of E. coli
isolates from urine.
We evaluated and compared the patient characteristics and antibiograms of ESBL-EC isolates to those of non-ESBL-EC isolates. Among the 267 patients with E. coli detected in theirurine, 198 patients with a urine bacterial content of ≥105 colony forming units/mL were enrolled
in this study.
Statistical analysis
Descriptive statistics were used to represent all variables. The proportion of sensitive or resis-4（ 4 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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tant isolates was expressed numerically and as a percentage. Statistical analyses were carried out
using SPSS software (IBM, Armonk, NY, USA, Version 25). Mann–Whitney U test was used forcontinuous variables. A chi-square test or Fisherʼs exact test was used for categorical variables. A pvalue of less than 0.05 was considered statistically signiﬁcant. In the risk factor analysis for ESBLEC, patient characteristics were analyzed using multivariate logistic regression analysis. Cochran–Armitage test was used to analyze the prevalence trends of MRSA and ESBL-EC.
Ethics committee of the hospital (Project No. 2021007) approved this study.

Results
A total of 4154 clinical samples were cultured in the laboratory between April 2019 andMarch 2020. The distribution of the samples was as follows: sputum (1362; 32.8%), urine (1151;
27.7%), blood (727; 17.5%), (pus 215; 5.2%), serous ﬂuid (201; 4.8%), feces (146; 3.5%), genital
mucus (134; 3.2%), nasopharyngeal mucus (100; 2.4%), bile (75; 1.8%), and others (43; 1.0%)(Fig. 1). A total of 846 bacterial strains were isolated from urine samples including 273 (32.3%)
E. coli, 125 (14.8%) Enterococcus sp., 88 (10.4%) Staphylococcus sp., 75 (8.9%) Klebsiellapneumoniae, 63 (7.4%) other Gram negative bacilli, 58 (6.9%) P. aeruginosa, 47 (5.6%)
Streptococcus sp., 39 (4.6%) Citrobacter sp., 32 (3.8%) Corynebacterium, 25 (3.0%) other Gram
positive cocci, 18 (2.1%) Enterobacter, and 3 (0.4%) other strains (Fig. 2). ESBL production was
detected in 82 isolates (30.0%) of E. coli, 12 isolates (30.8%) of Citrobacter sp., ﬁve isolates
Fig. 1. Distribution of samples examined in one year, April 2019 to March 2020 (N＝4154)

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5（ 5 ）(27.8%) of Enterobacter sp., and 13 isolates (17.3%) of K. pneumoniae. E. coli was isolated from438 samples, the majority of which were urine (267 isolates; 61.0%) and sputum (81 isolates;
18.5%) (Fig. 3). In addition, among the 1409 isolates of the nine bacterial species, 403 (28.6%)
strains exhibited multi-drug resistance (MDR) (Fig. 4). The detected MDR strains as a proportion
Fig. 2. Distribution of bacterial species isolates in urine samples, April 2019 to March 2020
(N＝846)

Fig. 3. Distribution of Escherichia coli isolates in various samples, April 2019 to March 2020
(N＝438)

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Fig. 4. Distribution of multidrug-resistant bacteria in the hospital, April 2019 to March 2020
(N＝1409)

Abbreviations: S. aureus, Staphylococcus aureus, P. aeruginosa, Pseudomonas aeruginosa, E. coli, Escherichia coli, K.
pneumoniae, Klebsiella pneumoniae, E. cloacae, Enterobacter cloacae, E. aerogens, Enterobacter aerogenes, E. asburiae,Enterobacter asburiae, Cit koseri, Citrobacter koseri, Cit. freundii, Citrobacter freundiiof the total isolates of that species were as follows: ESBL-EC (129/408, 31.6%); MRSA
(207/406, 51.0%); ESBL-producing strains of K. pneumoniae (23/248, 9.3%); MDRP (1/150,
0.7%); 10 ESBL-producing, two AmpC-producing, and one CRE strains of Enterobacter cloacae(13/91, 14.3%); two ESBL-producing strains of Citrobacter koseri (12/36, 33.3%); six ESBLproducing and two AmpC-producing strains of Enterobacter aerogenes (8/33, 24.2%); three
ESBL-producing strains of Citrobacter freundii (3/25, 12.0%); two ESBL-producing strains andﬁve AmpC-producing strains of Enterobacter asburiae (7/12, 58.3%) (Fig. 4).
Figure 5 depicts the annual change in hospital prevalence of two major MDR bacteria,
MRSA, and ESBL-EC. The prevalence of MRSA gradually decreased, while that of ESBL-EC
gradually increased from 2011 to 2019.
The mean age, sex, number of outpatients, nursing home admissions, indwelling urinary catheters,
prior hospitalization, and co-morbidities did not diﬀer signiﬁcantly between patients in the ESBL
and non-ESBL groups. However, PS was worse in patients in the ESBL group, and the use of antibiotics in the past two months was more frequent in this group (Table 1).
We compared the antimicrobial susceptibility of ESBL-EC to that of non-ESBL-EC. As
shown in Table 2, ESBL-EC strains were completely resistant to CTM, CAZ, CTX, CFPM, and
ABPC and highly resistant to LVFX and CPFX. Non-ESBL-EC were highly susceptible to CTM,
CAZ, CTX, and CFPM, and less susceptible to ABPC, LVFX, and CPFX. However, no diﬀerences between ESBL-EC and non-ESBL-EC were identiﬁed with regards to susceptibility to
MINO, CMZ, FOM, or MEPM.

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Fig. 5. Trend of %resistance in S. aureus and E. coli, 2011–2019%Resistance of S. aureus indicates prevalence of MRSA, and %Resistance of E. coli indicates prevalence of ESBL-EC.

Table 1. Comparison of patient characteristics between ESBL-EC and non-ESBL-EC
ESBL-EC(n＝63)

non-ESBL-EC(n＝135)Age
Male
Outpatient
Worsened Performance Status
Nursing home admission
Use of antibiotics in the past two months
Indwelling urinary catheter
Prior hospitalization

84.6±9.7
19 (30.2)
31 (49.2)
47 (74.6)
29 (46.0)
26 (41.3)
20 (31.7)
25 (39.7)

Co-morbidities
Diabetes mellitus
Cerebrovascular disease
Solid tumor
Urinary tract abnormality
Immune compromise

22 (34.9)
32 (50.8)
11 (17.5)
27 (42.9)
3 (4.8)Risk factorORCI

p-value80.5±14.7
27 (20.0)
69 (51.1)
56 (41.5)
44 (32.6)
29 (21.5)
41 (30.4)
43 (31.9)

1.722
0.927
4.113
1.759
2.555
1.066
1.405

0.81–3.60
0.49–1.76
2.05–8.60
0.91–3.40
1.27–5.15
0.53–2.12
0.72–2.73

0.171
0.148
0.879
＜0.001
0.082
0.006
0.870
0.335

41 (30.4)
69 (51.1)
29 (21.5)
61 (45.2)
2 (1.5)

1.229
0.987
0.774
0.910
3.303

0.62–2.42
0.52–1.88
0.32–1.75
0.47–1.73
0.37–40.52

0.518
1.000
0.573
0.878
0.329

Discussion
This study revealed that ESBC-EC ranks alongside MRSA as one of the most important
AMR bacteria at our hospital. Notably, the prevalence of ESBL-EC increased to 31.6% in thehospital, while the prevalence of MRSA gradually declined but remained high at 51.0% (Fig. 5).
Other MDR bacteria, such as CRE and MDRP, were detected in fewer instances. Thus, ESBL-EC
appears to be the most prevalent drug-resistant bacteria in our facility. Therefore, we were required to establish treatment guidelines and infection control strategies.
Previous reports revealed that prior hospitalization and antibiotic use within the past 60 days
were independent risk factors associated with ESBL production6,7). ESBL-EC is assumed to be8（ 8 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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Table 2. Antimicrobial susceptibility of ESBL-EC and non-ESBL-EC
Antimicrobial
agent

Total number*

LVFX
CPFX
MINO
ST
FOM
CTM
CAZ
CTX
CFPM
CMZ
MEPM
ABPC

198
198
198
67
67
188
198
188
198
198
198
188

%Susceptibility**
ESBL-EC

non-ESBL-EC

12.7 (8/63)
12.7 (8/63)
87.3 (55/63)
64.7 (11/17)
88.2 (15/17)
0 (0/58)
0 (0/58)
0 (0/58)
0 (0/58)
87.3 (55/63)
100 (63/63)
0 (0/58)

55.3 (72/135)
55.3 (72/135)
91.9 (124/135)
78 (39/50)
94 (47/50)
91.5 (119/130)
91.1 (123/135)
91.5 (119/130)
91.1 (123/135)
94.1 (127/135)
100 (135/135)
60.7 (82/135)

ORCI

p-value

4.18
4.18
1.05
1.2
0.86
Inf
Inf
Inf
Inf
1.15
1.15
Inf

1.86–10.67
1.86–10.67
0.66–1.67
0.47–3.20
0.35–2.11
13.46-Inf
14.60-Inf
13.46-Inf
14.60-Inf
0.73–1.81
0.73–1.81
8.87-Inf

＜0.01
＜0.01

0.825
0.827
0.836
＜0.01
＜0.01
＜0.01
＜0.01
0.582
0.582
＜0.01

*Total number of E. coli strains examined for susceptibility. The maximum number of ESBL-EC and non-ESBL-EC were 63

and 135, respectively.

**%Susceptibility means the percentage of susceptible strains (excluding the number of resistant and intermediate strains)divided by the number of total strains of ESBL-EC/ non-ESBL-EC isolated.

isolated older patients, those with worsened overall status, and who have repeatedly undergone
treatments using antibiotics in a short period. Similarly, in our study, only two risk factors (worsened PS and antibiotic use in the past two months) showed a signiﬁcant correlation with ESBLEC isolation, while prior hospitalization did not. These two factors may serve as predictors of
ESBL-EC infection, and the results suggested that ESBL-EC was easily isolated from disabled
and immunocompromised patients, who were repeatedly administered antimicrobial agents. Contrary to our expectations, age, nursing home admissions, prior hospitalizations, and co-morbidities were not correlated with ESBL-EC infection.
According to the antibiogram (Table 1), use of CMZ, MINO, FOM, and MEPM are recommended to treat UTIs caused by ESBL-EC because of its superior susceptibility to these agents.
Non-ESBL-EC strains were also susceptible to these agents. On the other hand, cephalosporins
such as CTM, CAZ, CTX, and CFPM, and quinolones such as LVFX and CPFX were not recommended for ESBC-EC infections because of its low susceptibility to these antibiotics.
Carbapenems, such as MEPM, have been recommended as the “gold standard” for severe
UTIs caused by ESBL-producing organisms9). However, prior exposure to carbapenems is a signiﬁcant risk factor for the CRE development; hence, carbapenem administration should be restricted to severe conditions, such as bacteremia10,11). Therefore, if ESBL-EC is isolated in culture
examination, carbapenems should be de-escalated to CMZ, ﬂomoxef, or FOM12), in combination
with aminoglycosides, such as gentamycin and amikacin9). Moreover, bacteremia-related mortality caused by ESBL-producing E. coli did not diﬀer between the carbapenem group and β-lactam/
β-lactamase inhibitor combination groups, such as tazobactam/piperacillin (TAZ/PIPC) or CMZ
groups9). In addition, a retrospective multicenter study using a propensity score-adjusted analysis

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showed that empirical treatment with CMZ or ﬂomoxef for ESBL-EC bacteremia was not associated with mortality, and demonstrated comparable clinical success rates compared to carbapenem
treatment10).
MINO, despite being an old tetracycline antibiotic, possesses a broad spectrum of activity
against bacteria as well as non-bacterial pathogens such as Chlamydophila and Mycoplasma. In
addition, minocycline demonstrates antibacterial activity not only against AMR Enterobacteriaceae, such as ESBL-EC, but also against CRE13). Studies re-evaluating MINO for ESBL-EC
treatment are limited. Yamamoto et al. reported that MINO in combination with FOM was eﬀective in the treatment of mild cases of UTIs caused by ESBL-EC14). On the other hand, FOM has
been strongly recommended for ESBL-EC UTI treatment in many studies. In previous reports,
more than 90% of ESBL-EC isolates were susceptible to FOM15–17). In general, oral FOM administration has been recommended for the treatment of lower UTIs, such as cystitis, in the ambulatory setting16,17). Oral FOM is considered non-inferior to intravenous carbapenems in the treatment of lower UTIs, whereas intravenous FOM could be superior to TAZ/PIPC in the treatmentof upper UTIs, such as pyelonephritis18).
Based on these ﬁndings, we could propose a possible strategy for the management of UTIs.
As E. coli remains the major pathogen involved in UTIs, we can initiate treatment with cephamycin antibiotics such as CMZ. In addition, CMZ is eﬀective against both ESBL-EC and nonESBL-EC. If CMZ is determined to be ineﬀective, association with other Enterobacteriaceae or
anaerobes is expected, or the patient develops a septic state, we may step-up the treatment tobroad-spectrum antimicrobial agents, such as carbapenems, including MEPM. If symptoms improve after CMZ administration, we can transition from parenteral to oral treatment (also called“switching”) and use oral forms of MINO or FOM, with the patient being discharged early andcontinuing ambulatory treatment. For lower UTIs, we may initiate treatment with oral FOM or
MINO.
Our study had a few limitations. Genotyping was not conducted because of the lack of capacity and facilities in our laboratory. Although we analyzed the background of the patients fromwhom ESBL-EC was isolated, we did not discriminate between upper and lower UTIs or evaluate
their clinical courses including the eﬃcacy of the antimicrobial agents administered, the use ofdrainage catheters, or the clinical outcome.
In the future, we intend to investigate the treatment of ESBL-EC, taking into account the
UTI type and clinical eﬃcacy of antimicrobial agents.
Conﬂict of interestNone.

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Funding
This research did not receive any speciﬁc grants from public, commercial, or not-for-proﬁt
funding agencies.
Acknowledgements
We thank Mr. Makoto Takeshita, the chief of microbiological laboratory, for his precise bacterial data collection.
We would like to thank Editage (www.editage.com) for their assistance with English language editing.
Authorship statement
Kosuke Jo was the chief investigator and was responsible for the data analysis. Kenji Kono
was responsible for the organization and coordination of the trial. All authors contributed to thewriting of the ﬁnal manuscript.

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