Extended-spectrum beta-lactamases

Authors
L Silvia Munoz-Price, MD
George A Jacoby, MD
Section Editor
David C Hooper, MD
Deputy Editor
Elinor L Baron, MD, DTMH
Disclosures
Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 | This topic
last updated: Fri Apr 15 00:00:00 GMT 2011 (More)
INTRODUCTION Extended-spectrum beta-lactamases (ESBL) are enzymes that
confer resistance to most beta-lactam antibiotics, including penicillins,
cephalosporins, and the monobactam aztreonam. Infections with ESBL-producing
organisms have been associated with poor outcomes.
Community-acquired ESBL producing Enterobacteriaceae are prevalent worldwide
[1]. Reliably identification of ESBL-producing organisms in clinical laboratories is
difficult, so their prevalence is likely underestimated. Carbapenems are the best
antimicrobial agent for infections caused by such organisms.
BETA-LACTAMASES Beta-lactamases are enzymes that open the beta-lactam
ring, inactivating the antibiotic. The first plasmid-mediated beta lactamase in gramnegative bacteria was discovered in Greece in the 1960s. It was named TEM after
the patient from whom it was isolated (Temoniera) [2]. Subsequently, a closely
related enzyme was discovered and named TEM-2. It was identical in biochemical
properties to the more common TEM-1 but differed by a single amino acid with a
resulting change in the isoelectric point of the enzyme.
These two enzymes are the most common plasmid-mediated beta-lactamases in
Gram-negative bacteria, including Enterobacteriaceae, Pseudomonas aeruginosa,
Haemophilus influenzae, and Neisseria gonorrhoeae. TEM-1 and TEM-2 hydrolyze
penicillins and narrow spectrum cephalosporins, such as cephalothin or cefazolin.
However, they are not effective against higher generation cephalosporins with an
oxyimino side chain, such as cefotaxime,ceftazidime, ceftriaxone, or cefepime.
Consequently, when these antibiotics were first introduced, they were effective
against a broad group of otherwise resistant bacteria. A related but less common
enzyme was termed SHV, because sulfhydryl reagents had a variable effect on
substrate specificity. (See"Overview of the beta-lactam
antibiotics" and "Cephalosporins".)
EXTENDED SPECTRUM BETA-LACTAMASES Not long after cefotaxime came
into clinical use in Europe, strains of Klebsiella pneumoniae were discovered in
Germany with transferable resistance to the oxyimino-cephalosporins (eg,
cefotaxime, ceftazidime, and ceftriaxone) [3]. The enzyme responsible was related
to SHV and was named SHV-2. TEM-related ESBLs were discovered in France in
1984 and in the United States in 1988.

The ESBL family is heterogeneous. SHV and TEM-type ESBLs arose by amino acid
substitutions that allowed narrower spectrum enzymes to attack the new oxyiminobeta-lactams. Others, notably members of the CTX-M family, represent plasmid
acquisition of broad-spectrum beta-lactamases originally determined by
chromosomal genes.
ESBLs vary in activity against different oxyimino-beta-lactam substrates but cannot
attack the cephamycins (cefoxitin, cefotetan and cefmetazole) and the carbapenems
(imipenem, meropenem and ertapenem). They are also generally susceptible to
beta-lactamase inhibitors, such as clavulanate, sulbactam, and tazobactam, which
consequently can be combined with a beta-lactam substrate to test for the presence
of this resistance mechanism.
ESBLs have been found exclusively in Gram-negative organisms, primarily in
Klebsiella pneumoniae, Klebsiella oxytoca, and Escherichia coli but also in
Acinetobacter, Burkholderia, Citrobacter, Enterobacter, Morganella, Proteus,
Pseudomonas, Salmonella, Serratia, and Shigella spp.
ESBL varieties
TEM beta-lactamases The amino acid substitutions responsible for the ESBL
phenotype cluster around the active site of the enzyme and change its configuration,
allowing access to oxyimino-beta-lactam substrates. Single amino acid substitutions
at positions 104, 164, 238, and 240 produce the ESBL phenotype, but ESBLs with
the broadest spectrum usually have more than a single amino acid substitution.
Based upon different combinations of changes, currently 160 TEM-type enzymes
have been described. Most are ESBLs, but some are resistant to beta-lactamase
inhibitors, and a few are both ESBLs and inhibitor resistant. TEM-10, TEM-12, and
TEM-26 are among the most common in the United States.
SHV beta-lactamases ESBLs in this family also have amino acid changes around
the active site, most commonly at positions 238 or 238 and 240. More than 100 SHV
varieties are known. They have been the predominant ESBL type in the United
States and are found worldwide. SHV-5 and SHV-12 are among the most common.
CTX-M beta-lactamases These enzymes were named for their greater activity
against cefotaxime than other oxyimino-beta-lactam substrates
(eg,ceftazidime, ceftriaxone, or cefepime). Rather than arising by mutation, they
represent examples of plasmid acquisition of beta-lactamase genes normally found
on the chromosome of Kluyvera species, a group of rarely pathogenic commensal
organisms. More than 60 CTX-M enzymes have been described [4].
Despite their name, a few are more active on ceftazidime than cefotaxime. They
have been found in many different Enterobacteriaceae, including Salmonella, and
are the most common ESBL type worldwide [5] and are increasingly prevalent in the
United States [6]. A single E. coli clonal group, ST131 (O25:H24), may have
accounted for a large proportion of antimicrobial resistance in E. coli infections in the
United States in 2007 [7].
OXA beta-lactamases OXA beta-lactamases were long recognized as a less
common but also plasmid-mediated beta-lactamase variety that could

hydrolyze oxacillin and related anti-staphylococcal penicillins. Amino acid

substitutions in OXA enzymes can also give the ESBL phenotype. OXA-type ESBLs
have been found mainly in Pseudomonas aeruginosa isolates from Turkey and
France. OXA beta-lactamases with carbapenemase activity have also been described.
(See "Carbapenemases", section on 'Class D beta-lactamases'.)
Others Other plasmid-mediated ESBLs, such as PER-1, VEB-1, GES-1/2, have
been described but are uncommon and have been found mainly in P. aeruginosa and
at a limited number of geographic sites [8]. In addition to conferring high level
resistance to antipseudomonal beta-lactams, these ESBLs also degrade cephems and
monobactams. Other rare ESBLs found in Enterobacteriaceae are BES, SFO, and
TLA. (See "Treatment of Pseudomonas aeruginosa infections".)
LABORATORY DETECTION Detection of ESBLs is based upon the resistance
they confer to oxyimino-beta-lactam substrates
(eg, cefotaxime,ceftazidime, ceftriaxone, or cefepime) and to the ability of a betalactamase inhibitor, usually clavulanate, to block this resistance. Other enzymes
have different features that can be misleading in the laboratory. AmpC-type betalactamases, which are now determined by plasmid as well as chromosomal genes,
can provide oxyimino-beta-lactam resistance, but they are resistant to inhibition by
clavulanate and usually confer resistance to cephamycins (eg,cefoxitin, cefotetan,
and cefmetazole), which ESBLs do not.
Problems in identification arise because ESBLs are heterogeneous. OXA-type ESBLs,
for example, are poorly inhibited by clavulanate. Some ESBLs are best detected
with ceftazidime and others with cefotaxime (such as most CTX-M enzymes).
Consequently, susceptibility to several oxyimino-beta-lactams must be tested;
criteria for ESBL detection have changed over time; and clinical laboratories vary in
their success in diagnosis.
Previously, the Clinical and Laboratory Standards Institute (CLSI) recommended
screening isolates of E. coli, K. pneumoniae, K. oxytoca, P. aeruginosa or Proteus
spp by disk diffusion or broth dilution for resistance, followed by a confirmatory test
for increased susceptibility in the presence of clavulanate [9]. In 2010, however, the
CLSI published new minimum inhibitory concentration (MIC) and disk diffusion
breakpoints for the Enterobacteriaceae [10-13]. The new MIC breakpoints are one to
three doubling dilutions lower than the original breakpoints, and the new disk
diffusion criteria include larger zone diameters than those in previous guidelines.
Thus, many organisms that previously would have been categorized as susceptible
using the former breakpoints may now be considered intermediate or resistant.
These new breakpoints eliminate the need to perform ESBL screening and
confirmatory tests for making treatment decisions. While the disk diffusion
breakpoints can be implemented immediately, there are barriers to immediate
implementation of the new MIC breakpoints; clinicians should review local practices
with their own microbiology laboratories.
Nonetheless, ESBL testing may be performed for infection control purposes [10-13].
In addition to disk diffusion and broth dilution techniques, other techniques for ESBL
detection include:

Automated systems (Vitek, MicroScan, and BD Diagnostics) use disk diffusion

or broth dilution techniques.

The double disk test, in which a disk with clavulanate placed near a disk with
an oxyimino-beta-lactam enhances susceptibility to the latter compound

An E-test strip with clavulanate added to one side of a dual oxyimino-betalactam gradient

A three-dimensional test for the ability of a culture of the test organism to

distort the zone of inhibition around an oxyimino-beta-lactam disk

Identifying of the ESBL present in a particular strain is generally limited to research

laboratories.
Clinical laboratories vary greatly in their success in identifying ESBLs. In a study of
77 rural hospitals in the United States, only eight percent reported specifically
screening for ESBLs in Gram-negative bacilli [14]. In another study ESBL-producing
K. pneumoniae and E. coli isolates were sent to 38 clinical laboratories in
Connecticut [15]. Eight of the laboratories failed to identify any resistant bacteria
and only seven were able to identify at least one isolate as an ESBL-producer.
EPIDEMIOLOGY
Distribution ESBL-producing Enterobacteriaceae have been reported worldwide,
most often in hospital specimens but also in samples from the community.
Prevalence rates vary from hospital to hospital and from country to country as
illustrated by the following observations:

In a sample of more than 4600 K. pneumoniae isolates from 1997 to 1999,

the percentage expressing an ESBL phenotype was highest in isolates from
Latin America (45 percent), the Western Pacific (25 percent), and Europe (23
percent) and lowest in strains from the United States and Canada (7.6 and
4.9 percent, respectively) [16].

Comparable percentages for the ESBL phenotype in more than 12,800 E. coli
strains were: Latin America (8.5 percent), Western Pacific (7.9 percent),
Europe (5.3 percent), Canada (4.2 percent), and the United States (3.3
percent) [16].

E. coli producing a CTX-M type ESBL is an emerging cause of communityacquired urinary tract infection in young women in the United States [17],
Europe [18], Hong Kong [19], India [20] and elsewhere.

In a prospective study of 455 consecutive episodes of K. pneumoniae

bacteremia in 12 hospitals in seven countries in 1996 and 1997, 85 (19
percent) were due to an ESBL-producing organism [21]. The rate was higher
in the 253 nosocomial infections (31 percent), particularly those acquired in
the intensive care unit (43 percent) [22].

When the frequency of such isolates is high in a single institution, it is more likely
that a single ESBL type is involved. Outbreaks have been due both to a single ESBLproducing strain and to a single ESBL plasmid carried by unrelated strains. A
resistant strain or plasmid may cause problems in several hospitals locally or involve
a large geographic area. Community clinics and nursing homes have also been
identified as potential reservoirs for ESBL-producing K. pneumoniae and E. coli [23].
Risk factors Risk factors for the development of colonization or infection with
ESBL-producing organisms include [22,24-29]:

Length of hospital stay

Length of ICU stay

Presence of central venous or arterial catheters

Emergency abdominal surgery

Presence of a gastrostomy or jejunostomy tube

Gut colonization

Low birth weight

Prior administration of any antibiotic

Prior residence in a long-term care facility (eg, nursing home)

Severity of illness

Presence of a urinary catheter

Ventilatory assistance

Undergoing hemodialysis

It has been postulated that the digestive tract constitutes the main reservoir for
ESBL-producing Enterobacteriaceae [30]. Travel to Asia also appears to be an
emerging risk factor; gastroenteritis while traveling may be a surrogate parameter
for contact with fecally contaminated water or food. This was illustrated in a
prospective study including 100 Swedish adults; upon return home (median trip
duration, two weeks), 24 of them were found to be colonized with ESBL-producing E.
coli [31].
A foodborne nosocomial outbreak among 156 patients in Spain provided further
evidence that food can be a transmission vector for ESBL Enterobacteriaceae. Up to
35 percent of the kitchen surfaces were colonized, and 14 percent of food handlers

were fecal carriers of a single strain of SHV-1 and CTX-M-15 producing K.

pneumoniae [32].
A case-control study suggested that the use of beta-lactamase inhibitors can be
protective factor for infection or colonization with ESBL-producing K. pneumoniae
[33].
TREATMENT OPTIONS The only current proven therapeutic option for severe
infections caused by ESBL-producing organisms is the carbapenem family
(imipenem, meropenem, and ertapenem).
In vitro studies ESBL-producing organisms vary in their susceptibility to
different oxyimino-beta-lactams; despite resistance to some, they may appear
sensitive to others. Strains making TEM and SHV-type ESBLs usually appear
susceptible to cefepime and to piperacillin-tazobactam, but both drugs show an
inoculum effect with diminished susceptibility as the inoculum is raised from 10(5) to
10(7) organisms [34]. Some CTX-M- and OXA-type ESBLs test resistant to cefepime
despite use of a low inoculum.
Strains producing only ESBLs test susceptible to cephamycins
(eg, cefoxitin, cefotetan, and cefmetazole) and carbapenems in vitro and show little
if any inoculum effect with these agents [35].
ESBL-producing isolates typically show greater than average resistance to other
agents including aminoglycosides and fluoroquinolones. These relationships were
illustrated in a review of 85 episodes of bacteremia due to ESBL-producing K.
pneumoniae from 12 hospitals in seven countries [21]. All isolates were susceptible
to imipenem or meropenem, while 71 percent were resistant to gentamicin, 47
percent to piperacillin-tazobactam, and 20 percent to ciprofloxacin.
The emergence of multidrug resistance (MDR) in ESBL-producing E. coli and K.
pneumoniae spp (ESBL-EK) was illustrated during a surveillance study conducted
from June 1997 to December 2002 [36]. During the study period, the prevalence of
MDR (resistance to trimethoprim-sulfamethoxazole, aminoglycosides, and
fluoroquinolones) increased from 12.5 to 26.9 percent.
Human studies There are no randomized controlled trials of therapy for ESBL
infections. Most of the reports are a compilation of a small number of cases treated
with different antibiotics, mainly in outbreak settings. Whether results can be
generalized to infections with other ESBL types is generally not known.
The choice of an appropriate antibiotic is essential since failure to treat with an
antibiotic active against ESBL-producing K. pneumoniae is associated with lack of an
adequate response and increased mortality [21,37]. The potential magnitude of this
effect was illustrated in a review cited above of 85 patients with ESBL-producing K.
pneumoniae infection from 12 hospitals in seven countries; 20 patients (24 percent)
died [21]. The following findings were noted:

Failure to treat with an antibiotic that had in vitro activity against the cultured
isolate during the first five days after the culture result was known was

associated with a significantly higher mortality rate compared to treatment

with active antibiotics (64 versus 14 percent).

Administration of a carbapenem (imipenem, meropenem, and

perhaps ertapenem) alone or with other antibiotics was associated with a
significantly lower mortality than those treated with active noncarbapenem
antibiotics (5 versus 28 percent). On multivariate analysis, carbapenem use
was independently associated with reduced mortality (odds ratio 0.09, 95%
CI 0.01-0.65).

Carbapenems Treatment with imipenem or meropenem has produced the best

outcomes in terms of survival and bacteriologic clearance.Ertapenem has good in
vitro activity [35], but there are limited clinical data regarding its use. In a series of
20 ICU patients with ventilator-associated pneumonia due to ESBL producing
organisms, for example, ertapenem was effective treatment in 16 patients [38].
Ertapenem resistance, however, may develop on therapy [39].
The efficacy of carbapenem therapy was best illustrated in an observational study
cited above of 85 episodes of bacteremia due to ESBL-producing K. pneumoniae
[21]. Among 27 patients treated with carbapenem monotherapy (imipenem in 24
and meropenem in 3), there was only one death (3.7 percent) at 14 days. In
contrast, there were seven deaths among the 11 patients (64 percent) who did not
receive any antibiotic active against these organisms and four deaths in nine
patients (44 percent) treated with cephalosporin monotherapy or a betalactam/beta-lactamase inhibitor combination such as piperacillin-tazobactam. Similar
efficacy to imipenem was noted in a smaller study of ten patients: eight had a
complete response and two failed therapy [40].
Cephalosporins When an oxyimino-beta-lactam
(eg, cefotaxime, ceftazidime, ceftriaxone, or cefepime) is used to treat severe
infections caused by ESBL-producing K. pneumoniae, treatment failure is likely even
if the organism tests susceptible to the antibiotic in vitro [21,37]. The Clinical and
Laboratory Standards Institute recommends that such ESBL-producing organisms
should be reported as resistant [41].
In a review of 28 patients with ESBL-producing Klebsiella pneumoniae with reported
susceptibility to cephalosporins, 15 failed to respond to cephalosporin therapy [37].
A possible explanation for the inferior outcomes in patients treated with apparently
active cephalosporins may be the inoculum effect, in which there is a marked
increase in MIC with increased inoculum [34].
Cefepime Cefepime may be effective against ESBL-producing organisms if it is
administered in high doses [42,43] but not in standard doses (1 g every 12 hours)
[44]. In a European study of nosocomial pneumonia due to ESBL-producing
pathogens, nine of thirteen patients treated with high-dose cefepime (2 g every
eight hours) responded clinically [42]. However, most available data do not
encourage cefepime use for ESBL-producing pathogens.

Piperacillin-tazobactam Many failures have been described with piperacillintazobactam for treatment of ESBL isolates [21,45-47]. In addition, resistance may
develop during therapy [46].
Piperacillin-tazobactam may be effective for ESBL isolates with piperacillintazobactam MIC 16/4 mcg/mL and for urinary tract infections, regardless of
susceptibility [48]. The latter observation is a presumed reflection of the much
higher drug concentrations seen in urine compared to plasma.
Other drugs Data regarding the use of quinolones and/or aminoglycosides are
also sparse. One study evaluated bacteremia caused by ESBL-producing K.
pneumoniae that were susceptible to ciprofloxacin [40]. Among seven patients
treated with ciprofloxacin, five failed treatment and two had a partial response;
patients treated with imipenem did much better (complete response in eight of ten).
There are no clinical data supporting the use of double antibiotic coverage for
treatment of ESBL producing organisms.
CLINICAL OUTCOMES Studies evaluating clinical outcomes in patients with ESBL
infections have shown a trend toward higher mortality, longer hospital stay, greater
hospital expenses, and reduced rates of clinical and microbiologic response
[21,49,50]. As mentioned above, mortality rates of 3.7 percent have been described
with carbapenems, with much higher rates with antibiotics not active against these
organisms (7 of 11 [64 percent]) and in patients treated with cephalosporin
monotherapy or a beta-lactam/beta-lactamase inhibitors combination such
as piperacillin-tazobactam (4 of 9 [44 percent]) [21].
OUTBREAK CONTROL Two main strategies to control outbreaks due to ESBLproducing bacteria have been reported: class restriction of oxyimino-beta-lactams
and barrier protection of colonized and/or infected patients. A study performed in
Spain showed that there was a marked decrease in the number of infections caused
by ESBL-producing K. pneumoniae (from 4.9 episodes to 0.6 episodes per 1000
patient-days) after institution of barrier protections (gloves and gowns) and
restriction of oxyimino cephalosporins [25]. A similar result was observed in New
York where the number of cases with ESBL-producing K. pneumoniae declined
significantly after the institution of barrier precautions and restriction
of ceftazidime use at one hospital [50].
The institution of barrier methods without antibiotic restriction was reported in a
French study [51]. All personnel in contact with patients infected with or carriers of
ESBL-producing Enterobacteriaceae were required to use gowns and gloves. There
was a decrease in the incidence of hospital-acquired ESBL from 172 patients in 1992
down to 19 patients during 1995, despite increased the use of cephalosporins.
Gut decontamination with ciprofloxacin in addition to barrier precautions and hand
hygiene proved to be effective to control an ESBL-producing E. coli outbreak in a
liver transplantation unit [52].
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