Overview of the Epidemiological Profileand Laboratory Detection of Extended-Spectrum β-Lactamases

SUPPLEMENT ARTICLE Overview of the Epidemiological Profile and Laboratory Detection of Extended-Spectrum b-Lactamases 1 Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and 2Department of Medicine, Rush Medical College of Rush University, Chicago, Illinois Extended-spectrum b-lactamases (ESBLs) are plasmid-mediated bacterial enzymes that confer resistance to a broad range of b-lactams. They are descended by genetic mutation from native b-lactamases found in gramnegative bacteria, especially infectious strains of Escherichia coli and Klebsiella species. Genetic sequence modifications have broadened the substrate specificity of the enzymes to include third-generation cephalosporins, such as ceftazidime. Because ESBL-producing strains are resistant to a wide variety of commonly used antimicrobials, their proliferation poses a serious global health concern that has complicated treatment strategies for a growing number of hospitalized patients. Another resistance mechanism, also common to Enterobacteriaceae, results from the overproduction of chromosomal or plasmid-derived AmpC b-lactamases. These organisms share an antimicrobial resistance pattern similar to that of ESBL-producing organisms, with the prominent exception that, unlike most ESBLs, AmpC enzymes are not inhibited by clavulanate and similar b-lactamase inhibitors. Recent technological improvements in testing and in the development of uniform standards for both ESBL detection and confirmatory testing promise to make accurate identification of ESBLproducing organisms more accessible to clinical laboratories. Extended-spectrum b-lactamases (ESBLs) are plasmidmediated bacterial enzymes that are able to hydrolyze a wide variety of penicillins and cephalosporins. Most ESBLs have evolved by genetic mutation from native b-lactamases, particularly TEM-1, TEM-2, and SHV-1. These parent enzymes are commonly found in gramnegative bacteria, particularly Enterobacteriaceae [1]; they are highly active against penicillins and modestly active against early-generation cephalosporins [2]. The genetic mutations that give rise to ESBLs broaden the parental resistance pattern to a phenotype that includes resistance to third-generation cephalosporins (e.g., cefotaxime and ceftazidime) and monobactams (e.g., aztreonam) [3]. In general, ESBL-producing isolates remain susceptible to cephamycins (e.g., cefoxitin) and Reprints or correspondence: Dr. Michael A. Pfaller, University of Iowa, 200 Hawkins Dr., Dept. of Pathology C606B GH, Iowa City, IA 52242 (michael-pfaller @uiowa.edu). Clinical Infectious Diseases 2006; 42:S153–63  2006 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2006/4208S4-0002$15.00 carbapenems [3]. Nevertheless, their resistance to a wide variety of common antimicrobials has made the proliferation of ESBL-producing strains a serious global health concern that has complicated treatment strategies for a growing number of patients. In this context, routine screening for ESBL-producing organisms is of great importance. Unfortunately, the overall adherence to routine screening among diagnostic microbiology laboratories is relatively low. Efforts are now under way to improve this situation. ESBLS: CLASSIFICATION AND PROPERTIES Although ESBLs have been reported most frequently in Escherichia coli and Klebsiella species [2], they have been found in other bacterial species as well, including Salmonella enterica, Pseudomonas aeruginosa, and Serratia marcescens [4–6]. The first definitively characterized ESBL, TEM-3 (cefotaxime-hydrolyzing enzyme type 1), was discovered in Klebsiella pneumoniae isolates recovered from intensive care unit patients in France [7]. Epidemiology and Detection of ESBLs • CID 2006:42 (Suppl 4) • S153 Michael A. Pfaller1 and John Segreti2 b-lactamase inhibitors is a defining property of ESBLs, there are several examples of enzymes derived from TEM and SHV that have a resistance spectrum similar to that of ESBLs but are resistant to inhibitors [1]. In addition to the TEM- and SHV-types, 2 other classes of ESBLs have been identified (table 1). The cefotaxime-hydrolyzing (CTX-M)–type b-lactamases are carried on plasmids and have been found in Klebsiella species [11], Salmonella typhimurium, and E. coli [1, 13]. These enzymes are not closely related to TEM and SHV b-lactamases [1]. Instead, they show a very high degree of sequence homology with the chromosome-encoded AmpC-type b-lactamase of Kluyvera georgiana, suggesting that the CTX-M–type b-lactamases might represent genetic variants descended from the b-lactamase of Kluyvera species [14]. The CTX-M enzymes show a preference for hydrolyzing cefotaxime, and members of the class are susceptible to inhibition by clavulanate, sulbactam, and tazobactam [1, 15, 16]. The oxacillin-hydrolyzing (OXA)–type b-lactamases are unique among the ESBLs because they are most often found in P. aeruginosa, rather than in members of the Enterobacteriaceae [1]. In the Bush-Jacoby-Medeiros classification scheme, the OXA enzymes are assigned to group 2d, apart from most other ESBLs [2]. Their preferred substrates are penicillins and cloxacillin [17, 18], rather than third-generation cephalosporins. The OXA class of ESBLs exhibits appreciable diversity in the properties of its enzymes. For example, although most OXA-type enzymes are resistant to b-lactamase inhibitors [1, 17, 18], OXA-18 has been reported to be totally inhibited by clavulanic acid [19]. Although most OXA-type b-lactamases have significant activity against ceftazidime, OXA-17 has little effect on the MIC of ceftazidime, but has substantial activity against cefotaxime [18]. Selection of ESBLs. Generally speaking, the emergence of ESBLs has been tied to the overuse and misuse of third-generation cephalosporins and other antimicrobials. However, the emergence of one ESBL variant over another at a given medical center can be the result of a complex set of factors, with an- Table 1. Properties of extended-spectrum b-lactamases (ESBLs) and plasmid-mediated AmpC. Type TEM, SHV Bush-JacobyMedeiros group 2be Preferred substrates Resistance or susceptibility to b-lactamase inhibitors Major sources Penicillins, narrow- and extended-spectrum cephalosporin, and monobactams Susceptible Escherichia coli and Klebsiella pneumoniae Cefotaxime hydrolyzing … Penicillins and cefotaxime Susceptible Salmonella enterica, E. coli, and K. pneumoniae Oxacillin hydrolyzing 2d Penicillins and cloxacillin Resistant (except oxacillin hydrolyzing–18) Pseudomonas aeruginosa Plasmid-mediated AmpC 1 Penicillins and cephalosporins Resistant K. pneumoniae, Klebsiella oxytoca, Salmonella species, and Proteus mirabilis NOTE. Data are from [1, 2, 11, 12]. S154 • CID 2006:42 (Suppl 4) • Pfaller and Segreti Since that initial report, TEM-type enzymes have become the most abundant class of ESBLs, with 1100 genetic variants now re (...truncated)