Clinical Microbiology Reviews, October 2001, p. 933-951, Vol. 14, No. 4
Wyeth-Ayerst Research, Pearl River, New York
0893-8512/01/$04.00+0 DOI: 10.1128/CMR.14.4.933-951.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Extended-Spectrum
-Lactamases in the 21st Century:
Characterization, Epidemiology, and Detection of This Important
Resistance Threat
SUMMARY
INTRODUCTION AND HISTORY
CHARACTERIZATION OF ESBLS
Functional and Molecular Grouping
Susceptibility and Biochemical Characteristics
TYPES OF ESBLS
TEM
Inhibitor-Resistant 
-Lactamases
SHV
CTX-M
OXA
Other ESBLs
ESBL DETECTION METHODS
Clinical Microbiology Techniques
Molecular Detection Methods
Medical Significance of Detection of ESBLs
EPIDEMIOLOGY
CONCLUSION
ACKNOWLEDGMENTS
REFERENCES
SUMMARY
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-Lactamases continue to be the leading cause of resistance to -lactam antibiotics among gram-negative bacteria. In recent years there has been an increased incidence and prevalence of extended-spectrum -lactamases (ESBLs), enzymes that hydrolyze and cause resistance to oxyimino-cephalosporins and aztreonam. The majority of ESBLs are derived from the widespread broad-spectrum -lactamases TEM-1 and SHV-1. There are also new families of ESBLs, including the CTX-M and OXA-type enzymes as well as novel, unrelated -lactamases. Several different methods for the detection of ESBLs in clinical isolates have been suggested. While each of the tests has merit, none of the tests is able to detect all of the ESBLs encountered. ESBLs have become widespread throughout the world and are now found in a significant percentage of Escherichia coli and Klebsiella pneumoniae strains in certain countries. They have also been found in other Enterobacteriaceae strains and Pseudomonas aeruginosa. Strains expressing these -lactamases will present a host of therapeutic challenges as we head into the 21st century.
INTRODUCTION AND HISTORY
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Emergence of resistance to -lactam
antibiotics began even before the first -lactam, penicillin, was
developed. The first -lactamase was identified in Escherichia
coli prior to the release of penicillin for use in medical
practice (1). The age of penicillin saw the rapid
emergence of resistance in Staphylococcus aureus due to a
plasmid-encoded penicillinase. This -lactamase quickly spread to
most clinical isolates of S. aureus as well as other species
of staphylococci.
Many genera of gram-negative bacteria possess a naturally occurring,
chromosomally mediated -lactamase. These enzymes are thought to have
evolved from penicillin-binding proteins, with which they show some
sequence homology. This development was likely due to the selective
pressure exerted by -lactam-producing soil organisms found in the
environment (61). The first plasmid-mediated -lactamase
in gram-negatives, TEM-1, was described in the early 1960s
(48). The TEM-1 enzyme was originally found in a single strain of E. coli isolated from a blood culture from a
patient named Temoniera in Greece, hence the designation TEM
(96). Being plasmid and transposon mediated has
facilitated the spread of TEM-1 to other species of bacteria. Within a
few years after its first isolation, the TEM-1 -lactamase spread
worldwide and is now found in many different species of members of the
family Enterobacteriaceae, Pseudomonas aeruginosa, Haemophilus
influenzae, and Neisseria gonorrhoeae. Another common
plasmid-mediated -lactamase found in Klebsiella
pneumoniae and E. coli is SHV-1 (for sulphydryl variable). The SHV-1 -lactamase is chromosomally encoded in the majority of isolates of K. pneumoniae but is usually plasmid
mediated in E. coli.
Over the last 20 years, many new -lactam antibiotics have been
developed that were specifically designed to be resistant to the
hydrolytic action of -lactamases. However, with each new class that
has been used to treat patients, new -lactamases emerged that caused
resistance to that class of drug. Presumably, the selective pressure of
the use and overuse of new antibiotics in the treatment of patients has
selected for new variants of -lactamase. One of these new classes
was the oxyimino-cephalosporins, which became widely used for the
treatment of serious infections due to gram-negative bacteria in the 1980s.
Not surprisingly, resistance to these expanded-spectrum -lactam
antibiotics due to -lactamases emerged quickly. The first of these
enzymes capable of hydrolyzing the newer -lactams, SHV-2, was found
in a single strain of Klebsiella ozaenae isolated in Germany
(81). Because of their increased spectrum of activity, especially against the oxyimino-cephalosporins, these enzymes were
called extended-spectrum -lactamases (ESBLs). Today, over 150 different ESBLs have been described. These -lactamases have been
found worldwide in many different genera of
Enterobacteriaceae and P. aeruginosa. This review
will focus on the characterization of ESBLs, the importance of
detection of these enzymes, and their epidemiology.
CHARACTERIZATION OF ESBLS
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Functional and Molecular Grouping
The majority of ESBLs contain a serine at the active site and
belong to Ambler's molecular class A (4). Class A enzymes are characterized by an active-site serine, a molecular mass of approximately 29,000 Da, and the preferential hydrolysis of penicillins (95). Class A -lactamases include such enzymes as
TEM-1, SHV-1, and the penicillinase found in S. aureus. The
molecular classification scheme is still used to characterize
-lactamases; however, it does not sufficiently differentiate the
many different types of class A enzymes. The classification scheme of
Richmond and Sykes was based on the substrate profile and the location
of the gene encoding the -lactamase (145). This
classification scheme was developed before ESBLs arose, and it did not
allow for the differentiation between the original TEM and SHV enzymes
and their ESBL derivatives. More recently, a classification scheme was
devised by Bush, Jacoby, and Medeiros that uses the biochemical
properties of the enzyme plus the molecular structure and nucleotide
sequence of the genes to place -lactamases into functional groups
(32). Using this scheme, ESBLs are defined as
-lactamases capable of hydrolyzing oximino-cephalosporins that are
inhibited by clavulanic acid and are placed into functional group 2be
(32).
Susceptibility and Biochemical Characteristics
ESBLs contain a number of mutations that allow them to hydrolyze
expanded-spectrum -lactam antibiotics. While TEM- and SHV-type ESBLs
retain their ability to hydrolyze penicillins, they are not
catalytically as efficient as the parent enzymes (33). In addition, the expansion of the active site that allows the increased activity against expanded-spectrum cephalosporins may also result in
the increased susceptibility of ESBLs to -lactamase inhibitors (74). ESBLs are not active against cephamycins, and most
strains expressing ESBLs are susceptible to cefoxitin and cefotetan.
However, it has been reported that ESBL-producing strains can become
resistant to cephamycins due to the loss of an outer membrane porin
protein (92, 121, 181).
TYPES OF ESBLS
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Most ESBLs are derivatives of TEM or SHV enzymes (32,
74). There are now >90 TEM-type -lactamases and >25
SHV-type enzymes (for amino acid sequences for TEM, SHV, and OXA
extended-spectrum and inhibitor-resistant -lactamases, see
http://www.lahey.org/studies/webt.htm). With both of these groups of
enzymes, a few point mutations at selected loci within the gene give
rise to the extended-spectrum phenotype. TEM- and SHV-type ESBLs are
most often found in E. coli and K. pneumoniae;
however, they have also been found in Proteus spp.,
Providencia spp., and other genera of
Enterobacteriaceae.
TEM
TEM-1 is the most commonly encountered -lactamase in
gram-negative bacteria. Up to 90% of ampicillin resistance in E. coli is due to the production of TEM-1 (85). This
enzyme is also responsible for the ampicillin and penicillin resistance
that is seen in H. influenzae and N. gonorrhoeae
in increasing numbers. TEM-1 is able to hydrolyze penicillins and early
cephalosporins such as cephalothin and cephaloridine. TEM-2, the first
derivative of TEM-1, had a single amino acid substitution from the
original -lactamase (10). This caused a shift in the
isoelectric point from a pI of 5.4 to 5.6, but it did not change the
substrate profile. TEM-3, originally reported in 1989, was the first
TEM-type -lactamase that displayed the ESBL phenotype
(157). In the years since that first report, over 90 additional TEM derivatives have been described (for amino acid
sequences for TEM, SHV, and OXA extended-spectrum and
inhibitor-resistant -lactamases, see
http://www.lahey.org /studies/webt.htm). Some of these
-lactamases are inhibitor-resistant enzymes, but the majority of the
new derivatives are ESBLs.
As shown in Fig. 1, the amino acid
substitutions that occur within the TEM enzyme occur at a limited
number of positions. The combinations of these amino acid changes
result in various subtle alterations in the ESBL phenotypes, such as
the ability to hydrolyze specific oxyimino-cephalosporins such as
ceftazidime and cefotaxime, or a change in their isoelectric points,
which can range from a pI of 5.2 to 6.5 (Table
1). A number of amino acid residues are
especially important for producing the ESBL phenotype when
substitutions occur at that position. They include glutamate to lysine
at position 104, arginine to either serine or histidine at position
164, glycine to serine at position 238, and glutamate to lysine at
position 240 (Fig. 1). In addition to -lactamases TEM-1 through
TEM-92 shown in Fig. 1 and Table 1, there has been a report of a
naturally occurring TEM-like enzyme, TEM-AQ, that contained a number of
amino acid substitutions and one amino acid deletion that have not been
noted in other TEM enzymes (127).
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It is interesting that laboratory mutants of TEM-1 that contain
mutations at positions other than the ones described in nature have
been constructed (18, 130, 180, 182). It has been
suggested that the naturally occurring TEM-type ESBLs are the result of fluctuating selective pressure from several -lactams within a given
institution rather than selection with a single agent
(18). Although TEM-type -lactamases are most often
found in E. coli and K. pneumoniae, they are also
found in other species of gram-negative bacteria with increasing
frequency. TEM-type ESBLs have been reported in genera of
Enterobacteriaceae such as Enterobacter aerogenes, Morganella morganii, Proteus mirabilis, Proteus rettgeri, and Salmonella spp. (19, 91, 101, 120, 128, 166).
Furthermore, TEM-type ESBLs have been found in
non-Enterobacteriaceae gram-negative bacteria. The TEM-42
-lactamase was found in a strain of P. aeruginosa (103). Additionally, a recent report found the TEM-17
-lactamase being expressed from a plasmid in a blood culture isolate
of Capnocytophaga ochracea (146).
Inhibitor-Resistant -Lactamases
Although the inhibitor-resistant -lactamases are not
ESBLs, they are often discussed with ESBLs because they are also
derivatives of the classical TEM- or SHV-type enzymes. In the early
1990s -lactamases that were resistant to inhibition by clavulanic
acid were discovered. Nucleotide sequencing revealed that these enzymes were variants of the TEM-1 or TEM-2 -lactamase. These enzymes were
at first given the designation IRT for inhibitor-resistant TEM
-lactamase; however, all have subsequently been renamed with numerical TEM designations. There are at least 19 distinct
inhibitor-resistant TEM -lactamases (for amino acid sequences for
TEM, SHV and OXA extended-spectrum and inhibitor resistant
-lactamases, see http://www.lahey.org/studies/webt.htm). Inhibitor-resistant TEM -lactamases have been found mainly in clinical isolates of E. coli, but also some strains of
K. pneumoniae, Klebsiella oxytoca, P. mirabilis, and
Citrobacter freundii (31, 83). Although the
inhibitor-resistant TEM variants are resistant to inhibition by
clavulanic acid and sulbactam, thereby showing clinical resistance to
the -lactam--lactamase inhibitor combinations of
amoxicillin-clavulanate, ticarcillin-clavulanate, and
ampicillin-sulbactam, they remain susceptible to inhibition by
tazobactam and subsequently the combination of piperacillin and
tazobactam (23, 37). To date, these -lactamases have
primarily been detected in France and a few other locations within
Europe (37). In a recent survey of
amoxicillin-clavulanate-resistant E. coli in a hospital in France, Leflon-Guibout et al. found that up to 41% of these isolates produced inhibitor-resistant TEM variants (82). Although
these enzymes have not yet been reported in isolates originating in the
United States, it is likely that they will eventually be detected here
as well.
As shown in Fig. 2, point mutations that
lead to the inhibitor-resistant phenotype occur at a few specific amino
acid residues within the structural gene for the TEM enzyme, Met-69,
Arg-244, Arg-275, and Asn-276 (16, 66, 191). The sites of
these amino acid substitutions are distinct from those that lead to the
ESBL phenotype. Laboratory mutants that contain amino acid
substitutions which are common to both the IRT and the ESBL
phenotype have been constructed (159). These strains were
found to possess either the ESBL or IRT phenotype, but not both.
However, the TEM-50 enzyme, which had amino acid substitutions common
to both the ESBL and inhibitor-resistant TEMs, was recently identified.
This enzyme was resistant to inhibition by clavulanate, but it also
conferred a slight resistance to the expanded-spectrum cephalosporins
(154). This could indicate the possibility of a new group
of -lactamases with a complex phenotype sharing some characteristics
of ESBLs and inhibitor-resistant enzymes. In addition to the variants
of TEM, inhibitor-resistant variants of SHV-1 and the related enzyme OHIO-1 have been detected (22, 137).
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SHV
The SHV-1 -lactamase is most commonly found in K. pneumoniae and is responsible for up to 20% of the
plasmid-mediated ampicillin resistance in this species
(172). In many strains of K. pneumoniae, blaSHV-1 or a related gene is integrated into the
bacterial chromosome (85). Although it has been
hypothesized that the gene encoding SHV-1 may exist as part of a
transposable element, it has never been proven (75).
Unlike the TEM-type -lactamases, there are relatively few
derivatives of SHV-1 (Table 2).
Furthermore, the changes that have been observed in
blaSHV to give rise to the SHV variants occur in
fewer positions within the structural gene (Fig.
3). The majority of SHV variants
possessing an ESBL phenotype are characterized by the substitution of a
serine for glycine at position 238. A number of variants related to
SHV-5 also have a substitution of lysine for glutamate at position 240. It is interesting that both the Gly238Ser and Glu240Lys amino acid
substitutions mirror those seen in TEM-type ESBLs. The serine residue
at position 238 is critical for the efficient hydrolysis of
ceftazidime, and the lysine residue is critical for the efficient
hydrolysis of cefotaxime (69).
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To date, the majority of SHV-type derivatives possess the ESBL phenotype. However, one variant, SHV-10, is reported to have an inhibitor-resistant phenotype. This enzyme appears to be derived from SHV-5 and contains one additional amino acid substitution of glycine for serine 130 (137). It is interesting that the inhibitor-resistant phenotype conferred by the Ser140Gly mutation seems to override the strong ESBL phenotype usually seen in enzymes containing the Gly238Ser and the Glu240Lys mutations seen in other SHV-5-type enzymes. The majority of SHV-type ESBLs are found in strains of K. pneumoniae. However, these enzymes have also been found in Citrobacter diversus, E. coli, and P. aeruginosa (27, 51, 108, 139).
CTX-M
In recent years a new family of plasmid-mediated ESBLs, called
CTX-M, that preferentially hydrolyze cefotaxime has arisen. They have
mainly been found in strains of Salmonella enterica serovar
Typhimurium and E. coli, but have also been described in
other species of Enterobacteriaceae (Table
3). They include the CTX-M-type enzymes
CTX-M-1 (formerly called MEN-1), CTX-M-2 through CTX-M-10 (9, 11,
12, 13, 21, 29, 58, 59, 64, 148; A. Oliver, J. C. Pérez-Díaz, T. M. Coque, F. Baquero, and R. Cantón, 40th Intersci. Conf. Antmicrob. Agents Chemother., abstr.
1480, 2000) as well as Toho enzymes 1 and 2 (72, 88).
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These enzymes are not very closely related to TEM or SHV -lactamases
in that they show only approximately 40% identity with these two
commonly isolated -lactamases (174). Previously, the most closely related enzymes outside this family were thought to be the
chromosomally encoded class A cephalosporinases found in K. oxytoca, C. diversus, Proteus vulgaris, and Serratia
fonticola (73 to 77% homology) (13, 19). However, it
was recently reported by Humeniuk et al. that there is a high degree of
homology between the chromosomal AmpC enzyme of Kluyvera
ascorbata (designated Klu-1 and Klu-2) and the CTX-M-type enzymes,
suggesting that the latter probably originated from this species (G. Humeniuk, G. Arlet, R. Labia, P. Grimont, and A. Philippon, Abstr.
Reunion Interdis. Chimiother. Anti-infect., abstr. 20/C4, 2000)
A phylogenetic study of the CTX-M family of -lactamases showed four
major types: the CTX-M-1 type, including CTX-M-1, and CTX-M-3; the
CTX-M-2 type, including CTX-M-2, CTX-M-4, CTX-M-5, CTX-M-6, CTX-M-7,
and Toho-1; Toho-2; and CTX-M-8, the latter two groups containing only
one member to date (21). The evolutionary distances
between each of these groupings suggest an early divergence from a
common ancestor (21).
Kinetic studies have shown that the CTX-M-type -lactamases
hydrolyze cephalothin or cephaloridine better than benzylpenicillin and
they preferentially hydrolyze cefotaxime over ceftazidime (29,
174). Although there is some hydrolysis of ceftazidime by these
enzymes, it is usually not enough to provide clinical resistance to
organisms in which they reside. It has been suggested that the serine
residue at position 237, which is present in all of the CTX-M enzymes,
plays an important role in the extended-spectrum activity of the
CTX-M-type -lactamases (174). Although it has been
shown not to be essential, the Arg-276 residue lies in a position
equivalent to Arg-244 in TEM- or SHV-type ESBLs, as suggested by
molecular modeling, and may also play a role in the hydrolysis of
oxyimino-cephalosporins (56). Recent crystallographic data for the Toho-1 enzyme suggested that there was increased flexibility of
the interacting 3 strand and 
loop of this enzyme in comparison to other class A -lactamases. Furthermore, the lack of hydrogen bonds in the vicinity of the loop could account for the
extended-spectrum phenotype (71). In addition to the rapid
hydrolysis of cefotaxime, another unique feature of these enzymes is
that they are inhibited better by the -lactamase inhibitor
tazobactam than by sulbactam and clavulanate (29, 88, 148,
174).
Strains expressing CTX-M-type -lactamases have been isolated from
many parts of the world, but have most often been associated with focal
outbreaks in eastern Europe (29, 57, 64), South America,
and Japan (88). There have been a few reports of these enzymes in isolates from patients in western Europe, mostly in isolates
from immigrants from the outbreak areas (173). However, Sabeté et al. recently reported that 23 strains of E. coli and Salmonella isolated in Spain expressed the
CTX-M-9 -lactamase, suggesting that there may be an endemic focus of
this enzyme in western Europe as well (148). Moreover, a
CTX-M-3-producing strain of Enterobacter cloacae was
recently isolated in France (50). Several institutions in
the areas where outbreaks have occurred reported that the CTX-M-type
enzyme is the most frequently isolated ESBL among clinical isolates in
their laboratories (148).
Interestingly, a number of these enzymes have been found among isolates
of Salmonella enterica serovar Typhimurium (11, 29,
57, 58, 173). Large outbreaks of isolates of S. enterica serovar Typhimurium expressing CTX-M -lactamases have
occurred in both South America and eastern Europe. These isolates have also been found to express a variety of CTX-M-type variants. Therefore, it is unlikely that a single origin for the occurrence and propensity of this type of -lactamase among S. enterica serovar
Typhimurium can be found.
OXA
The OXA-type enzymes are another growing family of ESBLs. These
-lactamases differ from the TEM and SHV enzymes in that they belong
to molecular class D and functional group 2d (32). The OXA-type -lactamases confer resistance to ampicillin and cephalothin and are characterized by their high hydrolytic activity against oxacillin and cloxacillin and the fact that they are poorly inhibited by clavulanic acid (32). The OXA -lactamase family was
originally created as a phenotypic rather than a genotypic group for a
few -lactamases that had a specific hydrolysis profile. Therefore, there is as little as 20% sequence homology among some of the members
of this family. However, recent additions to this family show some
degree of homology to one or more of the existing members of the OXA
-lactamase family.
While most ESBLs have been found in E. coli, K. pneumoniae,
and other Enterobacteriaceae, the OXA-type ESBLs have been
found mainly in P. aeruginosa (Table
4). Several of the OXA-type ESBLs have
been derived from OXA-10 (OXA-11, -14, -16, and -17) (44, 45, 65,
104). OXA-14 differs from OXA-10 by only one amino acid residue,
OXA-11 and OXA-16 differ by two, and OXA-13 and OXA-19 differ by nine
(Table 4). Among the enzymes related to OXA-10, the ESBL variants have
one of two amino acid substitutions: an asparagine for serine at
position 73, or an aspartate for glycine at position 157. In
particular, the Gly157Asp substitution may be necessary for high-level
resistance to ceftazidime (44). It appears that either of
these mutations may be required to confer the ESBL phenotype on the
OXA-type variant. In addition to the OXA-10 group, OXA-15 is a
derivative of OXA-2, and OXA-18 is not directly derived from other
OXA-type enzymes (closest relative is OXA-9, with 42% homology) (Table
4) (131).
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The OXA-type ESBLs provide weak resistance to oxyimino-cephalosporins
when cloned into E. coli, but provide fairly high-level resistance in P. aeruginosa transconjugants
(65). In contrast to the majority of the OXA-type ESBLs,
which confer resistance to ceftazidime, the OXA-17 -lactamase
confers resistance to cefotaxime and ceftriaxone but provides only
marginal protection against ceftazidime (44). With respect
to -lactamase inhibitors, the original OXA enzymes were
characterized by their lack of inhibition by clavulanic acid; however,
the OXA-18 -lactamase was reported to be inhibited by this compound
(131). One additional OXA-type enzyme has been identified,
OXA-21 (184). This enzyme was found in a strain of
Acinetobacter baumannii and is the first incidence of an
OXA-type enzyme's originating in this organism. Because the clinical
isolate of A. baumannii also expressed two other -lactamases, it is unclear whether OXA-21 is an ESBL or an
original-spectrum enzyme (184).
In addition to the OXA-type ESBLs, a number of recent OXA derivatives
that are not ESBLs have also been described. These include OXA-20
(110), OXA-22 (115), OXA-24
(24), OXA-25, -26, and -27 (2), and OXA-30
(155). Many of the newer members of the OXA -lactamase
family have been found in bacterial isolates originating in Turkey and
in France. It is not certain whether these two countries represent foci
of strains harboring these enzymes or if they represent the locale of
the investigators studying these -lactamases.
Other ESBLs
While the majority of ESBLs are derived from TEM or SHV
-lactamases and others can be categorized with one of the newer
families of ESBLs, a few ESBLs have been reported that are not closely related to any of the established families of -lactamases (Table 5). The PER-1 -lactamase was
first discovered in strains of P. aeruginosa isolated from
patients in Turkey (113). Later, it was also found among
isolates of S. enterica serovar Typhimurium and A. baumanii (176, 177, 179). The PER-1 -lactamase is
widespread across Turkey and is found in up to 60% of
ceftazidime-resistant strains of A. baumanii, which
represent 46% of total isolates (179). A common plasmid
encoding PER-1 was found in multiple nosocomial isolates of S. enterica serovar Typhimurium, suggesting that the strains acquired
the resistance plasmids in the hospital setting (176). A
related enzyme, PER-2, which has 86% amino acid homology with PER-1,
was found among S. enterica serovar Typhimurium strains in
Argentina. (14). It is interesting that PER-1 is found
almost exclusively in Turkey, while PER-2 has been found almost
exclusively in South America.
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Another enzyme that is somewhat related to PER-1 is the VEB-1
-lactamase (135). VEB-1 was first found in a single
isolate of E. coli in a patient from Vietnam, but was
subsequently also found in a P. aeruginosa isolate from a
patient from Thailand (109). A third related enzyme is
CME-1, which was isolated from Chryseobacterium
meningosepticum (147). A fourth enzyme in this group
is TLA-1, which was identified in an E. coli isolate from a
patient in Mexico (153). The PER-1, PER-2, VEB-1, CME-1,
and TLA-1 -lactamases are related but show only 40 to 50% homology. These enzymes all confer resistance to oxyimino-cephalosporins, especially ceftazidime, and aztreonam. They also show some homology to
the chromosomal cephalosporinases in Bacteroides spp. and
may have originated from this genus (147).
An unusual feature of SFO-1, which is highly related to a class A
-lactamase from Serratia fonticola, is that it is a
transferable -lactamase that can be induced to high-level production
of -lactamase by imipenem (94). The plasmid carrying
the gene encoding the SFO-1 -lactamase also carries the
ampR regulatory gene that is necessary for the induction of
class C -lactamases. However, unlike class C -lactamases, SFO-1
cannot hydrolyze cephamycins and is inhibited well by clavulanic acid
(94). GES-1 is another uncommon ESBL enzyme that is not
closely related to any other plasmid-mediated -lactamase but does
show 36% homology to a carbenicillinase from Proteus
mirabilis (136).
A dendrogram of the phylogeny of ESBL sequences is shown in Fig.
4. The TEM and SHV families are tightly
clustered and are related to each other. All of the class A ESBLs are
more closely related to each other than they are to any of the class D
OXA-type enzymes.
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ESBL DETECTION METHODS
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The increased prevalence of Enterobacteriaceae
producing ESBLs creates a great need for laboratory testing methods
that will accurately identify the presence of these enzymes in clinical isolates. Although most ESBLs confer resistance to one or more of the
oxyimino--lactam antibiotics, the -lactamase does not always increase the MICs to high enough levels to be called resistant by the National Committee for Clinical Laboratory Standards (NCCLS) interpretive guidelines (78, 111). The sensitivity and
specificity of a susceptibility test to detect ESBLs vary with the
cephalosporin tested. A number of investigators have suggested that
either dilution tests or disk diffusion susceptibility tests performed
with cefpodoxime detected more ESBLs than other cephalosporins such as
ceftazidime, cefotaxime, and ceftriaxone (52, 100).
However, more recent data suggest that susceptibility testing with
cefpodoxime can lead to a high number of false-positives if the current
NCCLS interpretive criteria are applied (F. C. Tenover, P. Raney,
P. P. Williams, K. L. Brittan, C. D. Steward, S. K. Fridkin, R. P. Gaynes, and J. E. McGowan, Jr., 40th Intersci.
Conf. Antimicrob. Agents Chemother., abstr. 1606, 2000). The NCCLS is
currently reevaluating the testing procedures and interpretive criteria that should be used for the detection of ESBLs.
The failure of either MIC or disk tests alone to accurately detect the presence of an ESBL in all strains of E. coli and K. pneumoniae has been well documented (52, 73). In a recent survey conducted through the World Health Organization, 5.4% of laboratories using disk diffusion tests found an ESBL-producing challenge strain to be susceptible to all cephalosporins (165). In that study, Tenover et al. reported that only 2 of the 130 laboratories surveyed specifically reported the isolate as an ESBL producer (165). It also appears that there is a difference in the ability of various susceptibility-testing methods used for detecting cephalosporin resistance in an ESBL-producing strain. Steward et al. reported the results of a proficiency test assessing the ability of hospital laboratories participating in Project ICARE (Intensive Care Antimicrobial Resistance Epidemiology) to detect specific types of antimicrobial resistance (160). Only 35% of laboratories using the Vitek system reported an ESBL challenge strain of K. pneumoniae as being resistant to ceftazidime and ceftriaxone. In contrast, 100% of the laboratories using the MicroScan system reported the same strain as being resistant. However, only 29% of the laboratories using MicroScan reported the strain as being resistant to ceftriaxone (160).
This lack of sensitivity and specificity in traditional susceptibility tests to detect ESBLs has prompted the search for an accurate test to detect the presence of ESBLs in clinical isolates. In the years since ESBLs were first described, a number of different testing methods have been suggested.
Clinical Microbiology Techniques
Clinical microbiology tests employ a -lactamase
inhibitor, usually clavulanate, in combination with an
oxyimino-cephalosporin such as ceftazidime or cefotaxime. In these
tests, the clavulanate inhibits the ESBL, thereby reducing the level of
resistance to the cephalosporin.
Several ESBL detection tests that have been proposed are based on the
Kirby-Bauer disk diffusion test methodology. One of the first detection
tests to be described was the double-disk approximation test described
by Jarlier et al. (76). In this test, the organism is
swabbed onto a Mueller-Hinton agar plate. A susceptibility disk
containing amoxicillin-clavulanate is placed in the center of the
plate, and disks containing one of the oxyimino--lactam antibiotics
are placed 30 mm (center to center) from the amoxicillin-clavulanate disk. As shown in Fig. 5, enhancement of
the zone of inhibition of the oxyimino--lactam caused by the synergy
of the clavulanate in the amoxicillin-clavulanate disk is a positive
result (76). This test remains a reliable method for the
detection of ESBLs. However, it has been suggested that the sensitivity
of this test can be increased by reducing the distance between the
disks to 20 mm (169, 171). The use of cefpodoxime as the
expanded-spectrum cephalosporin of choice for use in double-disk tests
for ESBL detection has been suggested (41). Alternatively,
the addition of clavulanate (4 µg/ml) to the Mueller-Hinton agar can
be used to potentiate the zone of inhibition of one or more disks
containing expanded-spectrum cephalosporins (67).
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A similar test was designed by Jacoby and Han, in which 20 µg of
sulbactam was added to susceptibility disks containing one of the
oxyimino--lactam antibiotics (73). An increase of 5 mm
in the zone of inhibition in a disk containing sulbactam compared to
the drug alone was considered a positive test. Although many ESBL-producing strains were detected with this method, a significant number of strains were not. In addition, a number of AmpC-producing strains also showed an enhancement of the zone diameter with the addition of sulbactam (73). Recently, several commercial
manufacturers have developed disks that contain an expanded-spectrum
cephalosporin plus clavulanate. A differential between results obtained
with 10-µg disks containing cefpodoxime, ceftazidime, or cefotaxime with or without the addition of 1 µg of clavulanate was shown to
accurately detect the presence of an ESBL (35, 105).
Another method suggested for the detection of ESBLs is the three-dimensional test described by Thomson and Sanders (169). In this test, following inoculation of the test organism onto the surface of a Mueller-Hinton agar plate, a slit is cut into the agar, into which a broth suspension of the test organism is introduced. Subsequently, antibiotic disks are placed on the surface of the plate 3 mm from the slit. Distortion or discontinuity in the expected circular zone of inhibition is considered a positive test (169). This test was determined to be very sensitive in detecting ESBLs, but it is more technically challenging and labor intensive than other methods. All of the tests utilizing one of the variations of a disk diffusion technique require some interpretation and therefore should be performed by clinical microbiologists experienced in reading these tests.
It has also been suggested that dilution tests performed with an
expanded-spectrum cephalosporin with and without the addition of
clavulanic acid or another -lactamase inhibitor be used for the
detection of ESBLs in a clinical isolate. In general, these tests look
for a reduction in the MIC of the cephalosporin in the presence of a
-lactamase inhibitor. However, the question of which cephalosporin
to use has not been definitively resolved (170).
Currently, the NCCLS recommends an initial screening by testing for
growth in a broth medium containing 1 µg/ml of one of five
expanded-spectrum -lactam antibiotics. A positive result is to be
reported as suspicious for the presence of an ESBL (111). This screen is then followed by a phenotypic confirmatory test that
consists of determining MICs of either ceftazidime or cefotaxime with
and without the presence of clavulanic acid (4 µg/ml). A decrease in
the MIC of 
3 twofold dilutions in the presence of clavulanate
is indicative of the presence of an ESBL. If an ESBL is detected, the
strain should be reported as nonsusceptible to all expanded-spectrum
cephalosporins and aztreonam regardless of the susceptibility testing
result (111).
Several commercial manufacturers have developed ESBL detection tests that can be used along with MIC test methods already in place in the clinical laboratory. Etest ESBL strips (AB Biodisk, Solna, Sweden) are two-sided strips that contain a gradient of ceftazidime on one end and ceftazidime plus clavulanate on the other end. As shown in Fig. 5, a positive test for an ESBL is a >3-dilution reduction in the MIC of ceftazidime in the presence of clavulanic acid. This test was shown to be more sensitive than the double-disk approximation test in detecting ESBLs in clinical isolates (39). This method is convenient and easy to use, but it is sometimes difficult to read the test when the MICs of ceftazidime are low because the clavulanate sometimes diffuses over to the side that contains ceftazidime alone (Fig. 5) (183).
The automated microbial susceptibility test system Vitek (Biomerieux,
Hazlewood, Mo.) has also produced an ESBL test that utilizes either
ceftazidime or cefotaxime alone and in combination with clavulanic acid
(4 µg/ml). A predetermined reduction in growth in wells containing
clavulanate compared to those containing drug alone indicates the
presence of an ESBL. In a study of Klebsiella spp. and
E. coli expressing well-characterized -lactamases,
Sanders et al. showed that the Vitek ESBL test was 99% sensitive and
specific for the detection of ESBLs (149). Furthermore,
updated computer algorithms in the new Vitek system have also been
shown to categorize the -lactamases present in many gram-negative
clinical isolates based on the phenotype of susceptibility patterns
with various -lactam antibiotics (150).
While each of these tests has its merit, none of these methods can
accurately detect all strains producing ESBLs. Vercauteren et al.
showed that the Etest ESBL test with ceftazidime only detected 81% of
ESBLs tested in their laboratory, compared to 97 and 91% for the
double-disk test and the three-dimensional test, respectively (183). Tzelepi et al. have reported that the Vitek ESBL
detection test failed to detect the majority of ESBL-producing strains
of Enterobacter spp. (171). In a recent survey
of detection of ESBLs in clinical isolates, Tenover et al. found that
only 18% of laboratories correctly identified challenge organisms as
potential ESBL producers using susceptibility to one or more
expanded-spectrum -lactam antibiotics as the method of detection
(164). Furthermore, a survey in Europe found that 37% of
ESBL-producing organisms were mistakenly reported as being susceptible
to expanded-spectrum cephalosporins (86).
The merits and shortcomings of each of the detection tests are outlined
in Table 6. Of the tests that have been
developed to date, the double-disk approximation test recommended by
Jarlier et al. (76), and the broth-dilution MIC reduction
method (NCCLS confirmatory test) (111) are the easiest and
most cost-effective methods for use by many clinical laboratories.
However, none of the detection tests that are based on the phenotype of
the -lactamase produced are 100% sensitive or specific for the
accurate detection of ESBLs among clinical isolates of gram-negative
bacteria. The need for improved detection of ESBLs in clinical isolates
is well recognized (123).
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It should also be noted that caution must be employed when interpreting
ESBL detection tests because there have been reports of false-positive
results for ESBL phenotypic screening tests that can occur with strains
that do not possess an ESBL. Several groups have reported that the
high-level expression of SHV-1 in K. pneumoniae can cause
the MIC of ceftazidime to rise to levels at which an ESBL would be
suspected (99, 129, 141). In addition, Rasheed et al.
reported that the production of SHV-1 in a strain of K. pneumoniae that was also lacking an outer membrane porin protein
caused a false-positive in ESBL detection tests that looked at the
differential between MICs of oxyimino--lactam antibiotics with and
without clavulanate (139). The presence of an ESBL can also be masked by the expression of an AmpC-type enzyme in the same
strain (28).
Molecular Detection Methods
The tests described above only presumptively identify the presence
of an ESBL. The task of identifying which specific ESBL is present in a
clinical isolate is more complicated. In the early days of studying
ESBLs, determination of the isoelectric point was usually sufficient to
identify the ESBL that was present. However, with >90 TEM-type
-lactamases, many of which possess identical isoelectric points,
determination of the ESBL by isoelectric point is no longer possible. A
similar situation is found in the SHV, CTX-M, and OXA families of ESBLs.
Early detection of -lactamase genes was performed using DNA probes
that were specific for TEM and SHV enzymes (7, 55, 70).
However, using DNA probes can sometimes be rather labor intensive. The
easiest and most common molecular method used to detect the presence of
a -lactamase belonging to a family of enzymes is PCR with
oligonucleotide primers that are specific for a -lactamase gene.
Oligonucleotide primers can be chosen from sequences available in
public databases such as Genbank (GenBank, National Center for
Biotechnology Information,
http://www.ncbi.nlm.nih.gov/Genbank/index.html). These primers are
usually chosen to anneal to regions where various point mutations are
not known to occur. However, PCR will not discriminate among different
variants of TEM or SHV. Several molecular methods that will aid in the
detection and differentiation of ESBLs without sequencing have been suggested.
The first molecular method for the identification of -lactamase was
the oligotyping method developed by Ouellette et al., which was used to
discriminate between TEM-1 and TEM-2 (117). This method
used oligonucleotide probes that are designed to detect point mutations
under stringent hybridization conditions. Subsequently, Mabilat and
Courvalin developed additional oligonucleotide probes to detect
mutations at six positions within the blaTEM
gene (89). Using this method, several new TEM variants
were identified within a set of clinical isolates. The probes used in
oligotyping tests for TEM -lactamases have been labeled either with
a radioisotope or with biotin (89, 167). Another approach
for molecular characterization of the TEM -lactamase gene was to add
restriction fragment length polymorphism analysis to PCR (PCR-RFLP)
(6). In this test, amplified PCR products were subjected
to digestion with several restriction endonucleases, and the subsequent
fragments were separated by electrophoresis. The sizes of the fragments
generated by each restriction enzyme indicate point mutations within
the blaTEM structural gene.
A number of different tests have been proposed for the detection and
identification of SHV derivatives. The simplest of these was suggested
by Nüesch-Inderbinen et al. and employs PCR-RFLP (116). Following PCR, the amplified DNA is digested with
restriction enzyme NheI, which detects the G-to-A nucleotide
change that gives rise to the glycine-to-serine substitution at
position 238 that is common to many of the early SHV-type ESBLs.
Although this method cannot determine which SHV-type ESBL is present,
it can detect the specific mutation at position 238 (116).
Another method used to characterize SHV-type ESBLs is PCR single-strand
conformational polymorphism (PCR-SSCP) analysis. This method has been
used to detect a single base mutation at specific locations within the blaSHV gene (106, 107). In this
test, a 475-bp amplimer is generated using oligonucleotide primers that
are internal to the coding sequence of the
blaSHV gene, digested with restriction enzyme PstI. The fragments are then denatured and separated on a
20% polyacrylamide gel. Genes for SHV-1, -2, -3, -4, -5, and -7 -lactamases can be identified by the electrophoretic pattern of the
digested amplimer (106, 107). With the identification of a
number of additional SHV-type -lactamase genes, PCR-RFLP was
developed to help with the identification of some of the newer SHV
variants (38). Following PCR, Chanawong et al. used a
variety of restriction endonucleases to detect 12 mutations at 11 positions within the blaSHV structural gene. The
combination of PCR-SSCP with PCR-RFLP allows the identification of 17 different SHV genes (38).
Another method proposed for the identification of SHV genes is the use of ligase chain reaction (LCR) (80). LCR allows the discrimination of DNA sequences that differ by a single base pair by the use of a thermostable ligase with four oligonucleotide primers that are complimentary to the target sequence and hybridize adjacent to each other. A single base mismatch in the oligonucleotide junction will not be ligated and subsequently amplified. In this LCR test, the target DNA containing the blaSHV gene is denatured in a thermocycler and annealed with biotinylated oligonucleotide primers that detect mutations at four positions. The LCR product is detected by an enzymatic reaction using NADPH-alkaline phosphatase. This method was able to detect seven of the SHV variants.
For OXA-10-derived ESBLs, the presence of an OXA-type gene in clinical
isolates of P. aeruginosa was first detected using a colony
hybridization technique (178). Subsequently, positive isolates were subjected to PCR with specific OXA primers and then digested with restriction endonucleases that would distinguish several
groups of related OXA enzymes based on the sizes of the restriction
fragments. While this technique does not completely identify which OXA
gene is present in a strain, it can distinguish the ESBL OXA-type
-lactamases from non-ESBLs that are also related to OXA-10
(178).
Nucleotide sequencing remains the standard for determination of the
specific -lactamase gene present in a strain. However, this too can
give variable results depending on the method used (25).
It is possible that some of the variability seen in the sequences for
some of the SHV -lactamases was due to compressions and difficulty
in reading traditional sequencing autoradiographs, rather than actual
differences in the sequence (25).
Medical Significance of Detection of ESBLs
It is generally thought that patients having infections caused by
an ESBL-producing organism are at an increased risk of treatment failure with an expanded-spectrum -lactam antibiotic. Therefore, it
is recommended that any organism that is confirmed for ESBL production
according to NCCLS criteria be reported as resistant to all
expanded-spectrum -lactam antibiotics, regardless of the susceptibility test result (111). While some
ESBL-producing strains have overt resistance to expanded-spectrum
-lactam antibiotics, many isolates will not be phenotypically
"resistant" according to guidelines such as those previously used
by the NCCLS. Therefore, it is important for the clinical microbiology
lab to be aware of isolates that may show increased MICs of
oxyimino-cephalosporins even though they may not be reported as
resistant, as this might suggest the presence of an ESBL. It is also
important for the clinical microbiology lab to then implement one or
more methods to detect ESBLs. In contrast, the susceptibility test
results of the -lactam--lactamase inhibitor combinations can be
reported as is. There have been several reports that these inhibitor
combinations may provide a viable alternative for the treatment of
infections caused by ESBL-producing organisms (124, 125).
The concern for the accurate detection of ESBLs is twofold. First, there is an increasing prevalence of ESBLs worldwide (see below). Second, many strains producing ESBLs demonstrate an inoculum effect in that the MICs of expanded-spectrum cephalosporins rise as the inoculum increases (36, 74, 158). Medeiros and Crellin found that the MICs of most cephalosporins rose dramatically when the inoculum of susceptibility tests was raised from 105 to 107 CFU/ml (97). This in vivo inoculum effect has also been demonstrated in animal models of endocarditis and intra-abdominal abscesses (34, 53, 144). There are many types of infections in which the bacterial load could reach these levels. Therefore, it is imperative that the detection of ESBLs accurately reflect the level of resistance that would be achieved by strains expressing these enzymes in vivo.
EPIDEMIOLOGY
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ESBLs are now a problem in hospitalized patients worldwide. The
ESBL phenomenon began in western Europe, most likely because expanded-spectrum -lactam antibiotics were first used there
clinically. However, it did not take long before ESBLs had been
detected in the United States and Asia. The prevalence of ESBLs among
clinical isolates varies from country to country and from institution
to institution. In the United States, occurrence of ESBL production in
Enterobacteriaceae ranges from 0 to 25%, depending on the
institution, with the national average being around 3% (CDC National
Nosocomial Infections Surveillance,
http://www.cdc.gov/ncidod/hip/SURVEILL/NNIS.HTM) Among isolates of
K. pneumonia, the percentage of ceftazidime resistance
ranges from 5 to 10% for non-intensive care unit (non-ICU) and ICU
isolates, respectively (D. Mathai, R. N. Jones, M. Stilwell, and
M. A. Pfaller, 40th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 1027, 2000). Some hospitals with low levels of ESBLs may not
find it cost-effective to test for ESBLs on a routine basis (52). However, these institutions should monitor the rates
of resistance in their own hospitals and be aware of an increase in resistance.
In Europe, the prevalence of ESBL production among isolates of
Enterobacteriaceae varies greatly from country to country. In the Netherlands, a survey of 11 hospital laboratories showed that
<1% of E. coli and K. pneumoniae strains
possessed an ESBL (161). However, in France, as many as
40% of K. pneumoniae isolates were found to be ceftazidime
resistant (30). Across Europe, the incidence of
ceftazidime resistance among K. pneumoniae strains was 20%
for non-ICU isolates and 42% for isolates from patients in the ICU
(Mathai et al., abstr. 1027). In Japan, the percentage of -lactam
resistance due to ESBL production in E. coli and K pneumoniae remains very low. In a recent survey of 196 institutions across the country, <0.1% of E. coli and
0.3% of K. pneumoniae strains possessed an ESBL
(187). Elsewhere in Asia, the percentage of ESBL
production in E. coli and K. pneumoniae varies,
from 4.8% in Korea (119) to 8.5% in Taiwan
(188) and up to 12% in Hong Kong (68).
It is interesting that specific ESBLs appear to be unique to a certain
country or region. For example, TEM-10 has been responsible for several
unrelated outbreaks of ESBL-producing organisms in the United States
for a number of years (26, 112, 143, 175). However, TEM-10
has only recently been reported in Europe with the same frequency
(8, 84). Similarly, TEM-3 is common in France, but has not
been detected in the United States (114, 156). In recent
years, there have been reports of outbreaks of TEM-47-producing
organisms in Poland (62), and the prevalence of TEM-52 in
Korea is unique to that country (119). Another recent survey of Korea revealed that the SHV-12 and SHV-2a -lactamases are
the most common ESBLs found in Korea (79). In contrast, the SHV-5 -lactamase is commonly encountered worldwide and has been
reported in Croatia, France, Greece, Hungary, Poland, South Africa, the
United Kingdom, and the United States (15, 43, 54, 63, 133, 152,
163, 181).
A common theme among hospitals plagued by organisms that produce ESBLs
is the high volume and indiscriminate administration of
expanded-spectrum cephalosporins (140, 142). Specific risk factors include length of hospital stay, severity of illness, time in
the ICU, intubation and mechanical ventilation, urinary or arterial
catheterization, and previous exposure to antibiotics (126,
140). Many of the patients infected with ESBLs are found in
ICUs, but they can occur in surgical wards as well as most other areas
of the hospital. ESBLs are also being isolated with increasing
frequency from patients in extended-care facilities (27, 143,
186). In addition, whereas early outbreaks of ESBL-producing strains were caused by isolates that produced only a single
-lactamase, more recently outbreaks have been caused by organisms
with multiple -lactamases (26, 27, 189). This
combination of non-ESBL class A enzymes and AmpC-type enzymes along
with ESBLs often compounds the resistance, so that many of these
strains are now resistant to -lactam--lactamase inhibitor
combinations, cephamycins, and even carbapenems in addition to the
oxyimino-cephalosporins and aztreonam (28). In addition,
there is a high association with ciprofloxacin resistance in strains
that produce ESBLs (122).
Many hospitals have experienced outbreaks of ESBL-producing organisms. These outbreaks are often fueled by the large number of patient transfers between units and between hospitals (87). It was found that barrier precautions were often difficult to enforce with a mobile patient population. Eventually, many of the reported outbreaks were successfully managed using infection control methods (87), restriction of the use of oxyimino-cephalosporins (125, 138), and antibiotic cycling (49, 77). A successful approach to the control of the spread of ESBL-producing organisms involved switching to different classes of broad-spectrum antibiotics for the treatment of serious infections (140). The two most successful replacement antibiotics have been imipenem and piperacillin-tazobactam (98, 124, 125, 142, 143).
In the mid-1990s, Rice et al. reported that an outbreak of
TEM-6-producing ceftazidime-resistant K. pneumoniae in a
Veterans Administration hospital was successfully controlled after the institution switched from ceftazidime to piperacillin-tazobactam for
empiric therapy for gram-negative infections (142).
Although the ceftazidime-resistant strains causing the outbreak were
originally resistant to piperacillin-tazobactam, they saw a rapid
decrease in the isolation of K. pneumoniae strains resistant
to both ceftazidime and piperacillin-tazobactam. The incidence of
ESBL-producing K. pneumoniae has remained low since that
time in that institution (142). This phenomenon of a
reduction in the resistance rate to piperacillin-tazobactam following
the switch from expanded-spectrum cephalosporin use to
piperacillin-tazobactam has been confirmed by several other
investigators (124, 125). Moreover, it has been reported
that the use of -lactam--lactam inhibitor combinations results
in a protective effect, in that they are associated with a lower
incidence of colonization with an ESBL-producing isolate (132).
Many investigators are using molecular methods such as pulsed-field gel electrophoresis (PFGE) to examine epidemiology with the strains involved in outbreaks of infections caused by ESBLs (30, 40, 54). Other methods for studying the epidemiology of these strains include plasmid profiles, ribotyping, random amplified polymorphic DNA (RAPD), and arbitrarily primed PCR (17, 43, 151, 185, 190). These outbreaks often start in an ICU and then spread to other parts of the hospital by the usual transmission routes (17). Very often, the exact source of outbreaks caused by ESBL-producing organisms is never identified. However, some interesting epidemiology of these resistant bacteria has been reported. In one hospital in France, ceftazidime-resistant K. pneumoniae expressing SHV-5 was isolated from six peripartum women and two neonates. Plasmid and PFGE profiles of the strains revealed that all of the strains were identical to a strain that was cultured from contaminated ultrasonography coupling gel (54). Another study demonstrated that cockroaches infesting a neonatal ICU in South Africa carried the same PFGE strain types of ESBL-producing K. pneumoniae that were responsible for an outbreak of infections and high mortality rate among neonates in that institution (40).
ESBLs are most often encoded on plasmids, which can easily be transferred between isolates. In an outbreak of ESBL-producing K. pneumoniae and E. coli in Chicago, it was shown that a common plasmid expressing TEM-10 was found in isolates from numerous patients in several hospitals and nursing homes (26, 186). Because this plasmid was found in multiple different strain types, as demonstrated by PFGE, it was presumed that this promiscuous plasmid expressing TEM-10 was transferred to the normal flora of some of the patients. In another report from France, a 180-kb self-transmissible plasmid expressing TEM-24 was found in four different species of Enterobacteriaceae (E. coli, K. pneumoniae, E. aerogenes, and P. rettgeri) isolated from a single patient (91).
CONCLUSION
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In the last 15 years, ESBLs have gone from being an interesting
scientific observation to a reality of great medical importance. The
introduction of the oxyimino--lactam antibiotics was met with the
emergence of new -lactamases. Some of these new -lactamases, like
the TEM- and SHV-type ESBLs, result from simple point mutations in
existing -lactamase genes that lead to a changed substrate profile.
Other new -lactamases, such as the CTX-M-type enzymes, have been
borrowed from the chromosomally encoded -lactamases that occur
naturally in other species of Enterobacteriaceae. The development and spread of ESBLs have most likely been caused by the
overuse of expanded-spectrum cephalosporins in the hospital setting.
Numerous methods have been proposed for the detection of ESBLs in
clinical isolates. Regardless of the method used for detection, it is
important to note that none of the methods that rely on phenotypic
expression of the -lactamase will detect every ESBL-producing isolate. Nevertheless, increased awareness of the ESBL problem among
clinical microbiology laboratory and infection control personnel will
help in the interpretation of these tests.
Current therapy for strains of Enterobacteriaceae that
express ESBLs is limited to such broad-spectrum agents as imipenem. However, there have already been reports of therapeutic failures of
this drug with strains that produce multiple -lactamases
(3). There are limited therapeutic options left for some
of these organisms. Strains expressing extended-spectrum -lactamases
will present a host of challenges for clinical microbiologists and
clinicians alike as we head into the 21st century.
ACKNOWLEDGMENTS
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I thank Ellen Murphy for the sequence alignments and creating the dendrogram, Steven J. Projan for critical review of the manuscript, and Melissa Visalli and David Correa for help in gathering references.
FOOTNOTES
* Mailing address: Wyeth-Ayerst Research, 401 N. Middletown Rd., Pearl River, NY 10965. Phone: (845) 732-4386. Fax: (845) 732-5671. E-mail: bradfop{at}war.wyeth.com.
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Clinical Microbiology Reviews, October 2001, p. 933-951, Vol. 14, No. 4
0893-8512/01/$04.00+0 DOI: 10.1128/CMR.14.4.933-951.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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(2007). Identification of CTX-M-Type Extended-Spectrum-{beta}-Lactamase Genes Using Real-Time PCR and Pyrosequencing. Antimicrob. Agents Chemother.
51: 223-230
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Ahmed, A. M., Furuta, K., Shimomura, K., Kasama, Y., Shimamoto, T.
(2006). Genetic characterization of multidrug resistance in Shigella spp. from Japan.. J Med Microbiol
55: 1685-1691
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Mamlouk, K., Boutiba-Ben Boubaker, I., Gautier, V., Vimont, S., Picard, B., Ben Redjeb, S., Arlet, G.
(2006). Emergence and Outbreaks of CTX-M {beta}-Lactamase-Producing Escherichia coli and Klebsiella pneumoniae Strains in a Tunisian Hospital. J. Clin. Microbiol.
44: 4049-4056
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al Naiemi, N., Duim, B., Bart, A.
(2006). A CTX-M extended-spectrum {beta}-lactamase in Pseudomonas aeruginosa and Stenotrophomonas maltophilia.. J Med Microbiol
55: 1607-1608
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Chouchani, C., Berlemont, R., Masmoudi, A., Galleni, M., Frere, J.-M., Belhadj, O., Ben-Mahrez, K.
(2006). A Novel Extended-Spectrum TEM-Type {beta}-Lactamase, TEM-138, from Salmonella enterica Serovar Infantis.. Antimicrob. Agents Chemother.
50: 3183-3185
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Spanu, T., Sanguinetti, M., Tumbarello, M., D'Inzeo, T., Fiori, B., Posteraro, B., Santangelo, R., Cauda, R., Fadda, G.
(2006). Evaluation of the New VITEK 2 Extended-Spectrum Beta-Lactamase (ESBL) Test for Rapid Detection of ESBL Production in Enterobacteriaceae Isolates.. J. Clin. Microbiol.
44: 3257-3262
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Mugnaioli, C., Luzzaro, F., De Luca, F., Brigante, G., Perilli, M., Amicosante, G., Stefani, S., Toniolo, A., Rossolini, G. M.
(2006). CTX-M-Type Extended-Spectrum {beta}-Lactamases in Italy: Molecular Epidemiology of an Emerging Countrywide Problem.. Antimicrob. Agents Chemother.
50: 2700-2706
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Novais, A., Canton, R., Valverde, A., Machado, E., Galan, J.-C., Peixe, L., Carattoli, A., Baquero, F., Coque, T. M.
(2006). Dissemination and Persistence of blaCTX-M-9 Are Linked to Class 1 Integrons Containing CR1 Associated with Defective Transposon Derivatives from Tn402 Located in Early Antibiotic Resistance Plasmids of IncHI2, IncP1-{alpha}, and IncFI Groups.. Antimicrob. Agents Chemother.
50: 2741-2750
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Fonseca, E. L., Mykytczuk, O. L., Asensi, M. D., Reis, E. M. F., Ferraz, L. R., Paula, F. L., Ng, L. K., Rodrigues, D. P.
(2006). Clonality and Antimicrobial Resistance Gene Profiles of Multidrug- Resistant Salmonella enterica Serovar Infantis Isolates from Four Public Hospitals in Rio de Janeiro, Brazil.. J. Clin. Microbiol.
44: 2767-2772
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Mena, A., Plasencia, V., Garcia, L., Hidalgo, O., Ayestaran, J. I., Alberti, S., Borrell, N., Perez, J. L., Oliver, A.
(2006). Characterization of a Large Outbreak by CTX-M-1-Producing Klebsiella pneumoniae and Mechanisms Leading to In Vivo Carbapenem Resistance Development.. J. Clin. Microbiol.
44: 2831-2837
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al Naiemi, N., Bart, A., de Jong, M. D., Vandenbroucke-Grauls, C. M., Rietra, P. J. G. M., Debets-Ossenkopp, Y. J., Wever, P. C., Spanjaard, L., Bos, A. J., Duim, B.
(2006). Widely Distributed and Predominant CTX-M Extended-Spectrum {beta}-Lactamases in Amsterdam, The Netherlands.. J. Clin. Microbiol.
44: 3012-3014
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Lavollay, M., Mamlouk, K., Frank, T., Akpabie, A., Burghoffer, B., Ben Redjeb, S., Bercion, R., Gautier, V., Arlet, G.
(2006). Clonal Dissemination of a CTX-M-15 {beta}-Lactamase-Producing Escherichia coli Strain in the Paris Area, Tunis, and Bangui.. Antimicrob. Agents Chemother.
50: 2433-2438
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Cleven, B. E. E., Palka-Santini, M., Gielen, J., Meembor, S., Kronke, M., Krut, O.
(2006). Identification and characterization of bacterial pathogens causing bloodstream infections by DNA microarray.. J. Clin. Microbiol.
44: 2389-2397
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Davis, K. A.
(2006). Ventilator-Associated Pneumonia: A Review. J Intensive Care Med
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Mesa, R. J., Blanc, V., Blanch, A. R., Cortes, P., Gonzalez, J. J., Lavilla, S., Miro, E., Muniesa, M., Saco, M., Tortola, M. T., Mirelis, B., Coll, P., Llagostera, M., Prats, G., Navarro, F.
(2006). Extended-spectrum {beta}-lactamase-producing Enterobacteriaceae in different environments (humans, food, animal farms and sewage). J Antimicrob Chemother
58: 211-215
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Yan, J.-J., Hsueh, P.-R., Lu, J.-J., Chang, F.-Y., Shyr, J.-M., Wan, J.-H., Liu, Y.-C., Chuang, Y.-C., Yang, Y.-C., Tsao, S.-M., Wu, H.-H., Wang, L.-S., Lin, T.-P., Wu, H.-M., Chen, H.-M., Wu, J.-J.
(2006). Extended-Spectrum {beta}-Lactamases and Plasmid-Mediated AmpC Enzymes among Clinical Isolates of Escherichia coli and Klebsiella pneumoniae from Seven Medical Centers in Taiwan.. Antimicrob. Agents Chemother.
50: 1861-1864
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Luzzaro, F., Mezzatesta, M., Mugnaioli, C., Perilli, M., Stefani, S., Amicosante, G., Rossolini, G. M., Toniolo, A.
(2006). Trends in Production of Extended-Spectrum {beta}-Lactamases among Enterobacteria of Medical Interest: Report of the Second Italian Nationwide Survey.. J. Clin. Microbiol.
44: 1659-1664
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al Naiemi, N., Schipper, K., Duim, B., Bart, A.
(2006). Application of Minimal Sequence Quality Values Prevents Misidentification of the blaSHV Type in Single Bacterial Isolates Carrying Different SHV Extended-Spectrum {beta}-Lactamase Genes.. J. Clin. Microbiol.
44: 1896-1898
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Bagattini, M., Crivaro, V., Di Popolo, A., Gentile, F., Scarcella, A., Triassi, M., Villari, P., Zarrilli, R.
(2006). Molecular epidemiology of extended-spectrum {beta}-lactamase-producing Klebsiella pneumoniae in a neonatal intensive care unit. J Antimicrob Chemother
57: 979-982
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Schwaber, M. J., Navon-Venezia, S., Kaye, K. S., Ben-Ami, R., Schwartz, D., Carmeli, Y.
(2006). Clinical and Economic Impact of Bacteremia with Extended- Spectrum-{beta}-Lactamase-Producing Enterobacteriaceae.. Antimicrob. Agents Chemother.
50: 1257-1262
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Bozdogan, B., Tristram, S., Appelbaum, P. C.
(2006). Combination of altered PBPs and expression of cloned extended-spectrum {beta}-lactamases confers cefotaxime resistance in Haemophilus influenzae. J Antimicrob Chemother
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Dashti, A. A., West, P., Paton, R., Amyes, S. G. B.
(2006). Characterization of extended-spectrum {beta}-lactamase (ESBL)-producing Kuwait and UK strains identified by the Vitek system, and subsequent comparison of the Vitek system with other commercial ESBL-testing systems using these strains.. J Med Microbiol
55: 417-421
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Sturenburg, E., Storm, N., Sobottka, I., Horstkotte, M. A., Scherpe, S., Aepfelbacher, M., Muller, S.
(2006). Detection and Genotyping of SHV {beta}-Lactamase Variants by Mass Spectrometry after Base-Specific Cleavage of In Vitro-Generated RNA Transcripts.. J. Clin. Microbiol.
44: 909-915
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Fujii, R., Kitaoka, M., Hayashi, K.
(2006). RAISE: a simple and novel method of generating random insertion and deletion mutations. Nucleic Acids Res
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Tumbarello, M., Spanu, T., Sanguinetti, M., Citton, R., Montuori, E., Leone, F., Fadda, G., Cauda, R.
(2006). Bloodstream Infections Caused by Extended-Spectrum-{beta}-Lactamase-Producing Klebsiella pneumoniae: Risk Factors, Molecular Epidemiology, and Clinical Outcome. Antimicrob. Agents Chemother.
50: 498-504
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