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ReviewISSN 2465-8243(Print) / ISSN 2465-8510(Online)
http://dx.doi.org/10.14777/uti.2015.10.2.74Urogenit Tract Infect 2015;10(2):74-83
Changing Epidemiology of Extended Spectrum Beta-Lactamases Pathogen of Urinary Tract
Taesoo Choi, Koo Han Yoo, Sun-Ju Lee
Department of Urology, Kyung Hee University School of Medicine, Seoul, Korea
This review covers the recent findings on extended spectrum beta-lactamases (ESBL) pathogens, focusing on the epidemiology of infection due to this pathogen. Use of ESBL is growing rapidly and widely. CTX-M-15 producing ESBL Escherichia coli is the most commonly encountered in clinical practice. In general, ESBL infections are represented by urinary tract infections, but they can also cause fatal infections involving the vascular system and central nervous system. Because E. coli is a common colonizer of normal intestine, increasing prevalence of ESBL-producing pathogens is particularly troublesome. In a situation where ESBLs are disseminated in the community, the ideal control of this multidrug-resistant pathogen will be challenging. Precise data on the prevalence and risk factors of ESBL-producing microorganism are still undetermined. More epidemiological studies are needed for the question to be answered. In order to maximize efficiency of treatment, information on the trend of increasing numbers of ESBLs is also needed on persistence of ESBLs in carriers as well as better understanding of how antibiotic treatment and other risk factors affect their persistence and further dissemination. The global emergence of multidrug-resistant ESBL pathogen has recently led to critical treatment problems. Early detection, adequate antibiotic therapy, and effective prevention are necessary for achievement of a safe community.
Keywords: Beta-lactamases; Epidemiology; Pathogen; Uropathogenic Escherichia coli
Copyright 2015, Korean Association of Urogenital Tract Infection and Inflammation. All rights reserved. This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits
unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received: 30 June, 2015Revised: 27 July, 2015Accepted: 27 July, 2015
Correspondence to: Koo Han Yoo http://orcid.org/0000-0001-7952-7902
Department of Urology, Kyung Hee University Hospital at Gangdong, 892 Dongnam-ro, Gangdong- gu, Seoul 05278, KoreaTel: +82-2-440-7735, Fax: +82-2-440-7744E-mail: [email protected]
INTRODUCTION
Extended spectrum beta-lactamases (ESBLs) are the
enzymes that have been produced by microorganisms,
which weaken the effect of beta-lactam antibiotics with
broad-spectrum [1]. Beta-Lactams are one of common
regimen for the management of infections including urinary
tract infections (UTI) and pneumonia, as well as for fatal
state such as bacteremia. Beta-Lactams are also frequently
used to prevent infections perioperatively. The ESBL-producing
organism was historically first reported in 1983. The cha-
racteristics of beta-lactamase in strains of Klebsiella pneu-
moniae were described as being capable of hydrolyzing
extended-spectrum cephalosporins in Germany [2]. Recently,
ESBL-producing organisms are considered as important
cause of nosocomial and community acquired infections
[3]. The outbreak of ESBLs happens from TEM-1, TEM-2,
or SHV-1 genes by mutation, which are commonly found
in Enterobacteriaceae family [4]. The enzymes are found
in Klebsiella species and Escherichia coli mostly; however,
Taesoo Choi, et al. Current Trend of ESBL Epidemiology Worldwide 75
Urogenit Tract Infect Vol. 10, No. 2, October 2015
they have also been reported in other Enterobacteriaceae
family including Citrobacter, Serratia, Proteus, Providencia,
Shigella, Salmonella, and Enterobacter [5]. The prevalence
of isolates expressing ESBLs varies region by region with
low rates of 3-8% in Sweden, Japan, and Singapore
compared to much higher rates of 30-60% in Portugal, Italy,
New York, Latin American countries, and Turkey [1]. In
the Arabian Peninsula, ESBL detection rates range from
8.5-38.5% in Saudi Arabia and 31.7% in Kuwait [6,7]. This
diversity may be due to the fact that the studies focused
on biased study group or specific sites of infection.
The major types of beta-lactamases are below; TEM, SHV,
CTX-M, and OXA beta-lactamases. CTX-M ESBLs have
appeared as the most common and significant type of ESBL
worldwide, their incidence markedly exceeding those of
TEM, SHV, and OXA ESBLs. According to recent studies,
the most widely distributed CTX-M enzyme is CTX-M-15,
which was first reported in E. coli from India in 2001 [8].
CTX-M-15 producing E. coli with multidrug-resistant is
emerging globally as a virulent pathogen causing hospital
and community acquired infections since 2003 [9,10].
ESBL-producing members of the family Enterobacteriaceae
are clinically important due to the fact that they play a
role of inflammation and infections in urinary tract, central
nervous system, lower respiratory tract and bloodstream,
but are also familiar colonizers of digestive system. These
microorganisms form a heterogeneous group that enables
hydrolytic reaction against the beta-lactams while remaining
sensitive to inhibition by beta-lactamase inhibitors. This
is critical because ESBLs are resistant to common antibiotics
including penicillins, broad-spectrum cephalosporins, and
aztreonam [11]. ESBL-producing organisms are also resistant
to quinolones, aminoglycosides, and trimethoprim-sulfa-
methoxazole [1].
Previous large-scale studies demonstrate that ESBL-pro-
ducing E. coli and K. pneumonia isolates are susceptible
to carbapenems generally [12]. Nevertheless, antibiotic
resistance in gram-negative bacilli (GNB) is spreading
worldwide with variety of regional resistance. So, we need
to monitor susceptibility trends in every corner of the world
over time to understand those trends so that effective
treatments can be accomplished to meet national social
needs. We have reviewed the recent findings on epi-
demiology of ESBL-producing organisms, based on the
comparison with prior surveys.
METHODS
A systemic literature review was performed on PubMed
and Google Scholar. Keywords included “epidemiology”, “ESBL” and “ST131 E. coli”. Original articles, related articles
and their references were considered, and a summary of
each data was reorganized based on clinical basis.
THE CHARACTERISTICS OF ESCHERICHIA COLI ST131 CLONE
E. coli sequence type 131 (ST131) is a multidrug-resistant
and highly virulent clone that was first reported in 2008
and has been reported in various regions globally [13].
It is associated with numerous community and hospital
acquired infections particularly UTIs [14]. The prevalence
of ST131 isolates varies from region to region and host
population, ranging from 12.5-40% [15,16]. Generally, ST131
is resistant to fluoroquinolone, and CTX-M-15 enzyme [10],
whereas other beta-lactamases including TEM, SHV are less
likely to be [13]. Both ESBL and non-ESBL-producing E.
coli ST131 isolates are resistant to fluoroquinolones, which
may play a role as marker for ST131-positive E. coli [17].
The ways to manage E. coli ST131 infections are similar
to those of other types of E. coli [13]. Carbapenem alone
or combination therapy with amikacin has been used to
eradicate infections associated with CTX-M-producing E.
coli isolates. And the trial has become a huge success [18].
The diagnosis of ESBLs in the laboratory is not simple.
Since the ESBL has emerged as important pathogen, specific
guidelines for ESBL detection were proposed in 1999 by
the National Committee for Clinical Laboratory Standards
(NCCLS). We can suspect the existence of ESBL in case that
bacterial growth is present despite 1 g/ml of broad-spectrum
cephalosporins (ceftazidime, ceftriaxone, or cefotaxime),
or aztreonam, or growth occurs despite the use of 4 g/ml
of cefpodoxime. Multiple antibiotics for screening improve
the sensitivity of ESBLs detection. Confirmatory tests include
the supplement of clavulanic acid to both ceftazidime and
cefotaxime. Double disk approximation test, three-dimen-
sional test, E-test and Vitek automated susceptibility system
(bioMérieux, Marcy l’Etoile, France) has been applied to
detect ESBLs in clinical isolates. The superiority of one
test over the other is not clear in respect of sensitivity
and technically challenging.
76 Taesoo Choi, et al. Current Trend of ESBL Epidemiology Worldwide
Urogenit Tract Infect Vol. 10, No. 2, October 2015
Table 1. The prevalence rates of ESBL worldwide
Location First author, year ESBL (+)/total clinical samples in strains Total number (%) of ESBL (+) pathogen
Australia [26] Hawser, 2009 A (1/13), B (0/3), C (0/0) 1 (6.3)Benin [27] Ahoyo, 2007 A (31/143) 31 (21.7)Central African Republic [28] Bercion, 2009 A (29/357), B (17/57), F (3/3), G (1/1) 50 (12.0)China [29] Hawkey, 2008 A (158/287), B (25/91), C (1/4) 184 (48.2)Egypt [30,31] Fam, 2011 A (55/291), B (23/165) 78 (17.1)
Saied, 2011 A (9/23), B (130/162) 139 (75.1)Hong Kong [29] Hawkey, 2008 A (8/45), B (0/0), C (0/0) 8 (17.8)India [32] Varaiya, 2008 A (264/334), B (77/111), C (15/15) 356 (77.4)Kenya [33] Kohli, 2010 A (10/69), B (5/38) 15 (14.0)Morocco [34,35] Barguigua, 2013 B (34/453) 34 (7.5)
Barguigua, 2011 A (10/767), B (2/36) 12 (1.5)New Zealand [26] Hawser, 2009 A (3/94), B (1/14), C (1/5) 5 (4.4)Nigeria [36,37] Aibinu, 2012 A (14/109) 14 (12.8)
Ogbolu, 2011 A (7/28), B (8/63), D (3/11), F (2/2), G (2/3), H (1/1) 23 (21.3)Philippines [26] Hawser, 2009 A (9/53), B (8/20), C (0/2) 17 (22.7)Senegal [38] Sire, 2007 A (38/1,010) 38 (3.8)Singapore [26] Hawser, 2009 A (17/51), B (12/32), C (0/1) 29 (34.5)South Africa [39-43] Keddy, 2012 E (4/263) 4 (1.5)
Bamford, 2012 A (29,066/358,843) 29,066 (8.1)Brink, 2012 A (43/566), B (59/171), D (8/71) 110 (13.6)Habte, 2009 A (84/482), B (30/239), D (8/85) 122 (15.1)Brink, 2007 A (1,420/28,412), B (1,954/7,514), F (484/4,031) 3,858 (9.7)
South Korea [44] Ko, 2008 A (10/44), B (12/37), C (1/4) 23 (27.1)Taiwan [45] Chambers, 2005 A (33/260), B (30/164), C (2/14) 65 (14.8)Tanzania [46] Blomberg, 2005 A (9/36), B (9/52), C (1/37) 19 (15.2)Thailand [29] Hawkey, 2008 A (33/65), B (15/33), C (0/2) 48 (48.0)Tunisia [47] Ben Haj Khalifa, 2012 B (40/198) 40 (20.2)Vietnam [48] Jones, 2006 A (42/122), B (9/23), C (2/4) 53 (35.6)
ESBL: extended spectrum beta-lactamases, A: Escherichia coli, B: Klebsiella pneumoniae, C: Klebsiella oxytoca, D: Proteus mirabilis, E: Shigella, F: Enterobacter spp., G: Morganella morganii, H: Serratia odorifera.
A few recent studies using multilocus sequencing typing
identified a single clone of ST131 from several countries
in Europe (Spain, France, Portugal, and Switzerland), North
America (Canada), and Asia (Lebanon, India, Kuwait, and
Korea) [9,10]. Serogroup O25 is associated with it. Clone
ST131 belongs to phylogenetic group B2 which is highly
virulent, and harbors multidrug-resistant incompatibility
group FII plasmids. These previous studies proved that
CTX-M-15 producing ST131 have also been emerged in
various countries. ST131 isolates have also been associated
with other types of beta-lactamases, as well as ciprofloxacin
resistant E. coli isolates that do not have ESBLs [19-21].
It is not obvious what has facilitated ST131 to spread
so widely and rapidly. ST131 is clearly more extensively
antibiotic-resistant than other types of E. coli and contains
a plenty of virulence factors. It may have a tendency to
be transmitted from host to colonize the intestine followed
by UTI [22,23]. The risk factors for intestinal colonization
with ST131 in different populations, possible differences
between colonizing and clinical ST131 isolates, and the
reservoirs and transmission courses have not been closely
surveyed [16]. The possible reservoirs of ST131 have been
evaluated for decades, which included food or water
sources, travel history from nations with a high prevalence
of the clone, long-term care facilities, and commercial
animals [24,25].
THE EMERGENCE AND DISTRIBUTION OF ESBLs BY REGIONAL GROUPS
Until 1990s, enterobacteria, mainly K. pneumoniae, produ-
cing SHV and TEM types of ESBLs have traditionally been
causative of serious nosocomial infections. This trend has
changed significantly, and E. coli producing CTX-M
beta-lactamases has emerged and cause of community-onset
infections, mostly UTIs. Most infections caused by ESBL-pro-
ducing E. coli or K. pneumoniae had mostly been described
as nosocomially acquired or nursing home related. These
Taesoo Choi, et al. Current Trend of ESBL Epidemiology Worldwide 77
Urogenit Tract Infect Vol. 10, No. 2, October 2015
outbreaks are usually clonal, the strains are mainly spread
through cross-transmission, and the risk factors are similar
to those found for other multidrug-resistant pathogens. Each
ESBL genotypes have different specificities for the various
beta-lactam antibiotics. Some recent data suggest that
infections related to ESBL-producing organisms might be
a critical problem in outpatients worldwide, but detailed
epidemiological data were not collected in most studies
(Table 1) [26-48].
ESBLs were first reported in 1983 from Germany and
England, in Europe [2]. Most ESBL-producing Klebsiella
isolates harbored enzymes belonging to the TEM and SHV
families. And the prevalence of ESBLs differs with countries.
In Netherlands, below 1% of E. coli and K. pneumoniae
were identified as ESBL-producing pathogens [49]. In France
and Italy, up to 40% of ESBL producing K. pneumoniae
has been reported [50]. The studies on the genotypes of
ESBLs also have been undertaken actively. In Sweden,
50-60% of ESBL-producing E. coli harbor CTX-M-15
followed by 10-15% of CTX-M-14 [51]. About 50% of
genotypes in Norway and 20% in Denmark proved to be
CTX-M-15 and CTX-M-14 [52,53]. In Finland, predominance
of CTX-M-1 group (including CTX-M-15) was reported
[54,55]. The different genotypes are found in other parts
of Europe. In Spain, high prevalence of CTX-M-14 and
CTX-M-9 is remarkable, and in Poland, CTX-M-3 has been
frequently reported, which is similar to several countries
in eastern Europe [56,57].
The first emergence of ESBL pathogen in USA was
reported in 1988 [58]. Its prevalence rate ranges from 0-25%
with average 3% [59]. In previous study of intensiive care
unit patients in USA, the rate of E. coli resistant to
broad-spectrum cephalosporin increased 48% compared
with that in the past 5 years. A recent study from the USA
presents results from the SENTRY surveillance program
including 26 hospitals from 20 states. The resistance levels
to cephalosporins and/or aztreonam in invasive Entero-
bacteriaceae was 6.4%. CTX-M-15 is the most frequent and
increasing in USA and Canada, where SHV phenotypes
used to be the most common [60]. A Canadian study reported
ESBL-production in almost 5% of the E. coli population−numbers similar to northern Europe. In Latin America, it
seems that ESBLs are more common than other continents.
The 8.5% of E. coli and 45% of K. pneumoniae were ESBL
positive in large scaled, multicenter study [61]. South
America stands out with a wide distribution of the CTX-M-2.
Also the CTX-M-8 is found in South America which is rare
on the outermost regions [62,63]. In the Africa and Australia,
CTX-M-15 is predominant [63].
There are also several reports on the epidemiology of
ESBL pathogens in Asia. Various differences are observed
between Asian countries. The rate of multiresistant E. coli
was 5% in Korea compared with 23.3% in Indonesia [64].
Contrastively, the rate of multiresistant K. pneumoniae
was 48.8% in Korea and 20-40% in China and Japan. A
single center study of 493 isolates in South Korea of
Enterobacter, Serratia marcescens, Citrobacter freundii, and
Morganella morganii revealed rates of ESBL-positive isolates
of 12.8%, 12.4%, 4.9%, and 0%, respectively [65]. Some
authors in South Korea described 22.4% of K. pneumoniae
isolates and 10.2% of E. coli isolates as ESBL producers
[44]. In Thailand, up to 52% of health workers carrying
ESBL pathogen has been reported. In a recent study from
Taiwan, 28.4% of K. pneumoniae from various body sites
proved to be ESBL positive. A study in Vietnam reported
that, of 350 isolates from specimens, 87.4% were GNB.
The 88.9% of them were Enterobacteriaceae, of which 14.7%
were ESBL positive [48]. In India, the reports are also
alarming with high numbers seen among patients. A study
from two hospitals in India collected isolates from patients
with abscesses, UTI, blood and found ESBL pathogen in
69% of E. coli. Another study from India, the rate of
ESBL-positive isolates was similarly elevated with 23.1%
of ESBL positive [32]. Of the isolates, 48.4% were E. coli
and 51.6% were K. pneumoniae. In Japan, the CTX-M-9
is dominant and in China, CTX-M-14 is more commonly
reported [66,67]. In India, CTX-M-15 is exclusively found
[68]. Notably, all of the ESBL-producing isolates were
consistently susceptible to carbapenems. Asia is almost
certainly a part of the world in which ESBLs have emerged,
with early antimicrobial resistance studies showing elevated
levels of ESBL phenotypes, particularly among Klebsiella
isolates and particularly in China, South Korea, Japan, and
India [29].
THE DISSEMINATION OF ESBL-PRODU-CING PATHOGENS VIA VARIOUS FACTORS
ESBL-producing E. coli is spreading extensively and
quickly in our community. Although a reliable explanation
78 Taesoo Choi, et al. Current Trend of ESBL Epidemiology Worldwide
Urogenit Tract Infect Vol. 10, No. 2, October 2015
Table 2. Outbreaks of infection due to ESBL-producing Enterobacteriaceae
High risk patient Intensive care units History of transplantation Long-term care facilitiesRisk factor Severity of disease Length of hospital/intensive care units stay Arterial/central venous catheter Infusion of total parenteral nutrition Mechanical ventilator Feeding tube Urethral catheter Age Hemodialysis Bedsore Altered nutrition Premature baby Previous antibiotics treatment; fluoroquinolones,
broad-spectrum cephalosporins, aztreonam, aminoglycosides, metronidazole
Reservoir Hospital workers hand Medical devices; thermometers, ultrasound gel,
oxygen probes, liquid soap
ESBL: extended spectrum beta-lactamases.
is not yet known, different factors may explain this spread
such as acquisition of ESBL-producing E. coli by food [69,70],
person-to-person transmission from fecal carriers [71-73],
dissemination of ESBL-producing E. coli in the environment
[74], carriage by domestic [70,75,76] and wild animals [77-79],
and the existence of reservoirs like long-term care facilities
(Table 2) [80,81]. Sewage sludge is also a reservoir of
ESBL-producing E. coli [74]. In 141 healthy individuals in
Thailand, 51.8% had ESBL-producing E. coli in stool samples
[82]. In China, the fecal colonization rate of ESBL-producing
E. coli was 7% among 270 elderly people [71]. Seven of
105 healthy humans (6.7%) from Spain were carriers of
ESBL-producing E. coli [72]. In healthy children from
Portugal, the carriage rate was 2.7% [73]. In another study,
the fecal carriage of ESBL-producing E. coli in patients
with UTI caused by these pathogens was 67%, but the
household members and the non-household relatives of
these patients also had ESBL-producing E. coli in fecal
samples, 27.4% and 15.6% respectively, while in healthy
unrelated controls the fecal carriage rate was 7.4% [83].
Long-term care centers may also represent a significant
reservoir for multi-resistant ESBL-producing E. coli isolates,
and infection control efforts must be addressed in these
settings. Among 294 nursing home residents in Northern
Ireland, 119 nursing home residents (40.5%) were gut
carriers of ESBL-producing E. coli [80], a carriage rate about
40 times higher than that for community patients with acute
diarrhea in the same area; fluoroquinolones use and
previous UTI were the risk factors for ESBL-producing E.
coli carriage [80]. In Italy, 41.4% of residents and 11.6%
of staff members in a long-term care facility were colonized
with ESBL-producing E. coli [81].
RISK FACTORS OF ESBL-PRODUCING ESCHERICHIA COLI INFECTION
Treatment options for multi-resistant ESBL-producing
pathogens are restrictive and initial empirical antibiotic
therapy is occasionally inappropriate. As a result, the
information of risk factors for ESBL-related infections is
important for early detection and adequate initial treatment.
In hospitalized cancer patients, 17 of 135 bacteremia caused
by E. coli were ESBL-producing E. coli; several factors
including female sex, hematological malignancy and previous
antibiotic therapy were found to be remarkable for ESBL
acquisition [84]. One control study in Switzerland found
that previous antibiotic treatment and mechanical ventilation
were risk factors for ESBL-related infection [85]. Typically,
the most common risks factors for community acquired
ESBL-producing E. coli infections are correlated to healthcare
centers including recent admission history, residence in a
long-term care facility, urethral catheterization. Other signifi-
cant factors include recent use of antibiotics, older age,
and diabetes mellitus. However, considerable cases of
infections due to ESBL-producing E. coli occur without
obvious risk factors [86]. This may be induced by increasing
incidence of healthy carriers. One survey has reported the
risk factors for ESBL-producing E. coli infections in 890
non-hospitalized patients. Remarkable risk factors were
recent antibiotic use, residence in long-term care facilities,
recent admission history, older age, and male sex [87].
Some studies on community acquired infections have
been undertaken in Spanish hospitals [86]. The risk factors
included older age, female sex, diabetes mellitus, recurrent
UTIs, previous invasive procedures of urinary tract such
as catheterization, and previous antibiotic use including
cephalosporins, and fluoroquinolones. In the other study
on community acquired bacteremia [86], long-term care
facilities, urethral catheter, and previous antibiotic use (es-
pecially fluoroquinolones) were risks factors of ESBL-producing
E. coli bacteremia [86]. Mostly, community-acquired ESBL-pro-
ducing E. coli infections are originated in urinary tract;
Taesoo Choi, et al. Current Trend of ESBL Epidemiology Worldwide 79
Urogenit Tract Infect Vol. 10, No. 2, October 2015
in a recent study, over three UTI episodes in the last year,
use of a beta-lactam antibiotic in the past 3 months and
the history of prostatic disease were found to be associated
with ESBL-producing E. coli [88]. The history of international
travel as a risk factor for ESBL-producing E. coli has been
reported in previous studies. In Switzerland, the beginning
of symptoms, or recent antibiotic treatment in foreign
country, proved to be a risk factor for ESBL-producing E.
coli infection [85]. In Calgary, 44% of patients with community
acquired ESBL-producing E. coli infection had a history
of trip abroad. Journey to India was the most dangerous
factor [89]. In New Zealand, considerable patients suffered
with UTIs by CTX-M-15producing E. coli had a history
of travel or recent emigration from India [90].
CONCLUSIONS
The current epidemiology of ESBL-producing organisms
is complex. Several species of the Enterobacteriaceae family
with different types of enzymes are causing troublesome
infections in patients in the hospital and outside of the
hospital. The dominant subtype of ESBL organism is
changing from SHV, TEM to CTX-M recently. Infection
related to ESBLs occurs more commonly in Southern Asia
than Eastern Asia, Southern Europe and Northern Europe
in order. The cumulative effect of antibiotics on the disse-
mination and persistence of resistant bacteria should not
be underestimated. To use appropriate antibiotics as far
as possible, we need to understand how resistance arises
and all the factors that influence dissemination, which allows
practitioners to identify high-risk patients and avoid inap-
propriate empirical antibiotic therapy consequentially.
Finally, there is an obvious goal to investigate the epi-
demiological aspect of the influx of ESBL-producing
organisms in order to plan adequate infection management.
CONFLICT OF INTEREST
No potential conflict of interest relevant to this article
was reported.
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