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Review
. 2001 Oct;14(4):933-51, table of contents.
doi: 10.1128/CMR.14.4.933-951.2001.

Extended-spectrum beta-lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance threat

P A Bradford  1
Affiliations
Review

Extended-spectrum beta-lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance threat

P A Bradford. Clin Microbiol Rev. 2001 Oct.

Abstract

Beta-lactamases continue to be the leading cause of resistance to beta-lactam antibiotics among gram-negative bacteria. In recent years there has been an increased incidence and prevalence of extended-spectrum beta-lactamases (ESBLs), enzymes that hydrolyze and cause resistance to oxyimino-cephalosporins and aztreonam. The majority of ESBLs are derived from the widespread broad-spectrum beta-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 beta-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 beta-lactamases will present a host of therapeutic challenges as we head into the 21st century.

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Figures

FIG. 1
FIG. 1
Amino acid substitutions in TEM ESBL derivatives. The amino acids listed within the grey bar are those found in the structural gene of the TEM-1 β-lactamase (162). The amino acid numbering is according to the scheme of Ambler et al. (5). Substitutions found in TEM-type ESBL derivatives are shown under the amino acids of TEM-1. TEM-type variants may contain more than one amino acid substitution. ∗, TEM-2 is not an ESBL but is included in the figure as a derivative of TEM-1. The Gln39Lys substitution does not contribute to the ESBL phenotype, but a number of ESBLs are derived from TEM-2. ∗∗, TEM-50 and TEM-68 contain amino acid substitutions that are common to both the ESBL and the IRT phenotypes. Only the amino acid substitutions that are common to TEM-type ESBLs are shown in this figure.
FIG. 2
FIG. 2
Amino acid substitutions in TEM IRT derivatives. The amino acids listed within the grey bar are those found in the structural gene of the TEM-1 β-lactamase (162). The amino acid numbering is according to the scheme of Ambler et al. (5). Substitutions found in TEM-type IRT derivatives are shown under the amino acids of TEM-1. TEM-type variants may contain more than one amino acid substitution. ∗∗, TEM-50 and TEM-68 contain amino acid substitutions that are common to both the ESBL and the IRT phenotypes. Only the amino acid substitutions that are common to TEM-type IRTs are shown in this figure.
FIG. 3
FIG. 3
Amino acid substitutions in SHV ESBL derivatives. The amino acids listed within the grey bar are those found in the structural gene of the SHV-1 β-lactamase (25). The amino acid numbering is according to the scheme of Ambler et al. (5). Substitutions found in SHV-type ESBL derivatives are shown under the amino acids of SHV-1. SHV-type variants may contain more than one amino acid substitution. ∗, SHV-11 is not an ESBL but is included in the figure as a derivative of SHV-1.
FIG. 4
FIG. 4
Phylogeny of ESBLs. Representative sequences of various ESBLs were obtained from GenBank. The PC1 (class A, S. aureus enzyme), IMP-1 (class B, metallo-enzyme), and ACT-1 (class C, AmpC-type enzyme) β-lactamases were included for comparison. Signal peptides were identified with SPSScan and removed prior to alignment. Sequences were aligned using Clustal X (168). Trees were constructed with Clustal X, which uses the neighbor-joining method, with a bootstrap value of 1,000. The IMP-1 sequence was used to root the tree. Trees were visualized with TREEVIEW (118).
FIG. 5
FIG. 5
Double-disk diffusion and Etest ESBL detection tests. (A) The double-disk diffusion ESBL detection test as suggested by Jarlier et al. is shown (76). A disk containing amoxicillin-clavulanate (AMC) is placed in proximity to a disk containing ceftazidime (CAZ) or another oxyimino-cephalosporin. The clavulanate in the amoxicillin-clavulanate disk diffuses through the agar and inhibits the β-lactamase surrounding the ceftazidime disk. Enhancement of the zone of the ceftazidime disk on the side facing the amoxicillin-clavulanate disk is interpreted as a positive test. (B) Etest ESBL strip (AB Biodisk, Solna, Sweden). The zone of inhibition is read from two halves of the strip containing ceftazidime alone (TZ) or ceftazidime plus clavulanate (TZL). A reduction in the MIC of ceftazidime of ≥3 dilutions in the presence of clavulanate is interpreted as a positive test. (C) The Etest ESBL strip is sometimes difficult to interpret with weak enzyme producers such as the strain expressing TEM-12 shown in this panel. The clavulanate from the ceftazidime plus clavulanate half of the strip diffuses into the agar and interferes with the reading of the MICs for the half of the strip containing ceftazidime alone.
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