JAC Advance Access originally published online on October 28, 2008
Journal of Antimicrobial Chemotherapy 2009 63(1):1-4; doi:10.1093/jac/dkn444
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Leading articles |
Redefining extended-spectrum β-lactamases: balancing science and clinical need
1 Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden 2 Department of Microbiology and Infection Control, University Hospital of Northern Norway, Norway 3 Section for Microbiology and Virology, Department of Medical Biology, University of Tromsø, Tromsø, Norway 4 Department of Clinical Microbiology, Central Hospital, Växjö, Sweden 5 Antibiotic Resistance Monitoring and Reference Laboratory, Centre for Infections, Health Protection Agency, London, UK 6 Service de Bactériologie-Virologie, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine, Université Paris-Sud, France 7 University of Queensland Centre for Clinical Research and Royal Brisbane and Women's Hospital, Brisbane, Australia 8 Servicio de Microbiología, Hospital Universitario Ramón y Cajal, Madrid, Spain 9 School of Medicine, Cardiff University, Cardiff, Wales, UK
* Corresponding author. Tel: +46-8-517-73574; Fax: +46-8-30-8099; E-mail: christian.giske{at}karolinska.se
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Abstract |
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 Top Abstract IntroductionNomenclature historyProposed new β-lactamase...ConclusionsTransparency declarationsReferences |
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The current β-lactamase classifications have reached a high level of complexity, making them less accessible to clinicians, infection control professionals, hospital management and politicians. From the clinical perspective, a revised comprehensible nomenclature scheme is therefore needed. The term extended-spectrum β-lactamases (ESBLs) has reached a broader audience over time, but is currently restricted to functional class 2be/molecular class A, clavulanic acid inhibited enzymes with activity against extended-spectrum cephalosporins. The proposed new classification expands the definition of ESBL to other clinically important acquired β-lactamases with activity against extended-spectrum cephalosporins and/or carbapenems. The classical class A ESBLs have been designated ESBLA in this classification, whereas plasmid-mediated AmpC and OXA-ESBLs are classed as miscellaneous ESBLs (ESBLM). Lastly, the carbapenemases have been designated ESBLCARBA, ESBLs with hydrolytic activity against carbapenems. We believe that this simplified classification may encourage new groups of healthcare professionals to engage in the effort to prevent the spread of acquired β-lactamases.
Keywords: classification , ESBLs , metallo-β-lactamases , OXA , KPC
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Introduction |
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TopAbstractIntroductionNomenclature historyProposed new β-lactamase...ConclusionsTransparency declarationsReferences |
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The increasing number of highly efficient β-lactamases challenges all healthcare professionals in various ways. From a nomenclature point of view, taxonomic classification schemes have reached a high level of complexity. The two most widely cited classification schemes are currently the Bush–Jacoby–Medeiros functional classification and the Ambler structural classification.1,2 These schemes are adapted to the needs of researchers, and their complexity makes them less accessible to clinicians, infection control professionals, hospital management and politicians. Critically, the fundamental purpose of detecting antimicrobial resistance is to benefit the patient and to limit its impact within the healthcare setting, i.e. to guide therapy and implement appropriate infection control measures. We propose that from a clinical perspective we need a revised, comprehensible nomenclature scheme, which facilitates smooth communication of clinically important β-lactamases. Especially, this nomenclature is needed from an infection control perspective, since guidance on the selection of therapy will be mostly available through antimicrobial susceptibility testing.
While the details of β-lactamase terminology often appear to be esoteric for groups other than β-lactamase researchers, certain terms have reached a broader audience. The most important example is the term ‘extended-spectrum β-lactamase’ (ESBL), which now attracts media interest.3 While the semantics of the term ESBL have been debated,4 it is important to acknowledge its increasing use by a broad range of healthcare professionals. Precise definitions are of paramount importance for scientific purposes, but a more generic use of the term ‘ESBL’ may well be an advantage when targeting a broader audience in clinical practice.
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Nomenclature history |
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TopAbstractIntroductionNomenclature historyProposed new β-lactamase...ConclusionsTransparency declarationsReferences |
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The term ESBL was first proposed in 19885 to define those plasmid-mediated β-lactamases mediating resistance to extended-spectrum cephalosporins as a counterpart of ‘broad-spectrum β-lactamases’, mainly represented by TEM-1, which do not affect these cephalosporins.6 In the late 1980s, this new term seemed eminently sensible as ESBLs were only ascribed to the TEM or SHV variety and their molecular and biochemical complexity was limited.6 However, two decades later much has changed. At present, an ESBL sensu stricto is a functional class 2be, molecular class A, clavulanate-inhibited β-lactamase (MBL), which can hydrolyse oxyimino-cephalosporins at rates at least 10% of that for benzylpenicillin.1 This definition is narrow and excludes all other β-lactamases with a wider spectrum, including many of the more recent bacterial ‘inventions’ such as plasmid-borne AmpC or OXA-type cephalosporinases.4 Also excluded are the transferable carbapenemases, such as the metallo-β-lactamases (MBL), OXA-type carbapenemases, the Klebsiella pneumoniae class A carbapenemases (KPC) and certain GES-variant β-lactamases.7 Although most of these excluded β-lactamases belong to different functional and/or structural classes, they all certainly share an extended spectrum of β-lactam hydrolysis. More important, the clinical consequences of transmission of these β-lactamases, which confer resistance to essentially all β-lactam antibiotics, are no less worrying than those associated with the classical ESBLs. Owing to the presence of other resistance genes on the same transferable genetic elements, bacteria acquiring such elements may also become resistant to a number of non-β-lactam antibiotics.8 Although the implications of these β-lactamases should be understood by all healthcare professionals dealing with bacterial infections, it can be questioned whether this is truly the case. This probably reflects the fact that carbapenemases have not yet become as prevalent as the extended-spectrum cephalosporinases in most countries, but possibly also that we lack a common and simple term to describe them.
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Proposed new β-lactamase classification |
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TopAbstractIntroductionNomenclature historyProposed new β-lactamase...ConclusionsTransparency declarationsReferences |
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The potential problems arising from the complexity of current scientific terminology could have a relatively simple solution through establishing a simplified β-lactamase terminology for clinical and infection control uses. Indeed, this was recently suggested by Livermore, who launched a broad ESBL definition, always accompanied by mentioning the enzyme's family, e.g. TEM-ESBL or OXA-ESBL.4 Although this would be an adequate strategy for scientific publications, this approach still demands that large groups of diverse healthcare professionals need to relate to names of a great number of enzyme families. It must be considered that the infection control response will be similar irrespective of the β-lactamase type. Therefore, it could be argued that even more simplified terms are needed within the broadened ESBL definition. It would appear to be prudent to preserve the term ESBL in such a definition, since it is already in wide use. A certain level of discrimination would be needed in a novel β-lactamase classification. We therefore propose that the classical, functional class 2be β-lactamases could be designated ‘class A ESBLs’ (ESBLA), whereas plasmid-mediated AmpC and OXA-ESBLs could be labelled ‘miscellaneous ESBLs’ (ESBLM). By using this classification, the guidelines for detection of ESBLs would still apply to the category ESBLA, whereas genotypic methods in addition to other phenotypic approaches would, to a certain degree, be needed for detection and definition of ESBLM enzymes. The ESBLM category could be subdivided into two categories, ESBLM-C (plasmid-mediated AmpC; class C) and ESBLM-D (OXA-ESBLs; class D), in order to increase the semantic precision within the novel classification. Probably, a lot of clinical laboratories would not be able to detect or discriminate all ESBLM enzymes, but the new terminology could prove to be an incentive for national and international methodology committees to develop guidelines for the detection of such enzymes for epidemiological surveillance purposes. For clinical purposes, we would recommend the current EUCAST strategy to revise breakpoints in such a manner that they will correctly categorize isolates with clinically significant resistance, irrespective of enzymatic activity of the involved β-lactamase.9
Regarding carbapenemases, a completely novel concept would be needed to describe all currently known acquired β-lactamases with hydrolytic activity against carbapenems. We believe that ‘ESBLs with hydrolytic activity against carbapenems’ (ESBLCARBA) could potentially be a useful term to describe the carbapenemases. A further subdivision of this group into class A, B and D β-lactamases represents an attractive refinement of the classification. Contrary to the situation with other ESBL classes, carbapenems cannot usually be regarded as drugs of choice for treatment of infections caused by bacteria harbouring ESBLCARBA, although some strains may appear to be susceptible to the carbapenems in vitro. Since many of the ESBLCARBA enzymes have relatively low hydrolytic capacities of carbapenems, we suggest that only enzymes demonstrating imipenemase activity (kcat/Vmax) of >1 (µM–1 s–1) are designated ESBLCARBA. This would differentiate the GES, KPC and OXA carbapenemases from the non-carbapenemase homologues. In practice, clinical laboratories will not have to use spectrophotometric methods to assign enzymes to the correct ESBL categories, but should rather rely on phenotypic and genotypic operational criteria.
In Figure 1, we present a proposal for the classification of currently known clinically important acquired β-lactamases into the three categories ESBLA, ESBLM and ESBLCARBA, as well as subclasses within each of the main categories. The subclasses are mainly included to allow increased precision for scientists, whereas the three main categories will probably be sufficient for infection control and clinical use. Hence, the figure can be approached at various levels, depending on the user's needs. Operational criteria for each category of β-lactamases are proposed, in order to enable clinical laboratories to designate various β-lactamases to the correct classes. For ESBLA enzymes, non-susceptibility to extended-spectrum cephalosporins and clavulanic acid synergy are the two criteria that need to be met. For ESBLM enzymes, many laboratories will only be able to detect ESBLM-C enzymes, since these can be detected with phenotypic methods,10,11 whereas the other enzymes in this class can only be detected with genotypic methods. Also, in order to separate chromosomal hyperproduction of AmpC from plasmid-mediated AmpC in Escherichia coli, PCR targeting the ESBLM-C variants will be needed.12 The combination of an ESBLA or ESBLM enzyme and porin loss in a clinical isolate may lead to non-susceptibility to carbapenems.13 In order to avoid classifying this phenotype as ESBLCARBA, phenotypic tests for ESBLCARBA-A/ESBLCARBA-B8 or genotypic tests (targeting bla genes in the two former groups and/or the corresponding bla genes for ESBLCARBA-D enzymes) should be performed to confirm the presence of an ESBLCARBA enzyme. For most of the ESBL classes, an international consensus on appropriate phenotypic and genotypic tests is lacking, and we believe that working out such guidelines should be a prioritized task for national and international methodology committees.
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β-Lactam treatment options for isolates harbouring the various categories of β-lactamases can vary substantially among the different enzyme variants in each of the groups. Generally, isolates harbouring ESBLA and ESBLM are resistant to most β-lactams except the carbapenems, whereas isolates featuring ESBLCARBA in many cases will be resistant to all β-lactams. However, there are a lot of exceptions to this general rule, and we believe that selection of therapy should not be determined by the detected ESBL enzyme, but rather by the antibiogram derived from antimicrobial susceptibility testing.
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Conclusions |
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TopAbstractIntroductionNomenclature historyProposed new β-lactamase...ConclusionsTransparency declarationsReferences |
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Possibly the grouping of β-lactamases in a simplified classification scheme may preclude important differences between various categories of enzymes within the groups. However, our proposed ‘pragmatic scheme’ is not intended to replace the current precise classifications, but rather to complement them for the benefit of healthcare professionals not involved in β-lactamase research. The scheme would be a powerful tool for infection control professionals, and for public health scientists aiming to determine the clinical and economical impact of transmission of β-lactamases. For infectious disease clinicians, the classification could provide a framework to improve understanding of the interrelation between clinically important β-lactamases that largely impact empirical therapies and treatment routines, and which should be combated not only by infection control personnel. We believe that the novel classification would encourage new groups to endeavour to prevent further dissemination of these resistance determinants. After all, the spread of β-lactamases is a matter of great concern for all healthcare professionals—not just for β-lactamase scientists.
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Transparency declarations |
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TopAbstractIntroductionNomenclature historyProposed new β-lactamase...ConclusionsTransparency declarationsReferences |
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D. L. P. has received grants from Centers for Disease Control and Prevention, National Institutes of Health and Astrazeneca. He has also been a consultant to Merck, Johnson and Johnson, Three Rivers Pharmaceuticals and Acureon. Other authors: none to declare.
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References |
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Ruppe E, Bidet P, Verdet C, et al. First detection of the Ambler class C 1 AmpC β-lactamase in Citrobacter freundii by a new, simple double-disk synergy test. J Clin Microbiol (2006) 44:4204–7.
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Perez-Perez FJ, Hanson ND. Detection of plasmid-mediated AmpC β-lactamase genes in clinical isolates by using multiplex PCR. J Clin Microbiol (2002) 40:2153–62.
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