þ-Lactamases are most commonly classified according to two general schemes: the Ambler molecular classification scheme and the Bush-Jacoby-Medieros functional classifica- tion system (10, 66, 338). The Ambler scheme divides þ-lac- tamases into four major classes (A to D). The basis of this classification scheme rests upon protein homology (amino acid similarity), and not phenotypic characteristics. In the Ambler classification scheme, þ-lactamases of classes A, C, and D are serine þ-lactamases. In contrast, the class B enzymes are me- tallo-þ-lactamases. The Bush-Jacoby-Medeiros classification scheme groups þ-lactamases according to functional similari- ties (substrate and inhibitor profile). There are four main groups and multiple subgroups in this system. This classifica- tion scheme is of much more immediate relevance to the phy- sician or microbiologist in a diagnostic laboratory because it considers þ-lactamase inhibitors and þ-lactam substrates that are clinically relevant.There is no consensus of the precise definition of ESBLs. A commonly used working definition is that the ESBLs are þ-lac- tamases capable of conferring bacterial resistance to the pen- icillins, first-, second-, and third-generation cephalosporins, and aztreonam (but not the cephamycins or carbapenems) by hydrolysis of these antibiotics, and which are inhibited by þ-lactamase inhibitors such as clavulanic acid. For the purpose of this review, the term ESBL will be taken to mean those þ-lactamases of Bush-Jacoby-Medeiros group 2be and those of group 2d which share most of the fundamental properties of group 2be enzymes (66).The 2be designation shows that these enzymes are derived from group 2b þ-lactamases (for example, TEM-1, TEM-2, and SHV-1); the e of 2be denotes that the þ-lactamases have an extended spectrum. Group 2b enzymes hydrolyze penicillin and ampicillin, and to a lesser degree carbenicillin or cephalo- thin (66). They are not able to hydrolyze extended-spectrum cephalosporins or aztreonam to any significant degree. TEM-1 is the most common plasmid-mediated þ-lactamase of ampi- cillin resistant enteric gram-negative bacilli (for example, Esch- erichia coli), while SHV-1 is produced by the vast majority of Klebsiella pneumoniae (219). TEM-2 is a less common member of the same group with identical biochemical properties to TEM-1. The ESBLs derived from TEM-1, TEM-2, or SHV-1 differ from their progenitors by as few as one amino acid. This results in a profound change in the enzymatic activity of the ESBLs, so that they can now hydrolyze the third-generation cephalosporins or aztreonam (hence the extension of spectrum compared to the parent enzymes).With the exception of OXA-type enzymes (which are class Denzymes), the ESBLs are of molecular class A, in the classifi- cation scheme of Ambler. They are able to hydrolyze the pen- icillins, narrow-spectrum and third-generation cephalosporins, and monobactams. The ESBLs have hydrolysis rates for cefta- zidime, cefotaxime, or aztreonam (aminothiazoleoxime þ-lac- tam antibiotics) at least 10% that for benzylpenicillin. They are inhibited by clavulanic acid (66).
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