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Cited by 1,494Antibiotic Resistance in BacteriaPharmaceutical and Antibiotic Environmental ImpactsAntibiotics Pharmacokinetics and Efficacy

Growing Group of Extended-Spectrum β-Lactamases: the CTX-M Enzymes

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Bonnet, R.·2004·Antimicrobial Agents and Chemotherapy
DOI 10.1128/aac.48.1.1-14.2004PMC PMC310187
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Abstract

The production of β-lactamases is the predominant cause of resistance to β-lactam antibiotics in gram-negative bacteria. These enzymes cleave the amide bond in the β-lactam ring, rendering β-lactam antibiotics harmless to bacteria. They are classified according to the scheme of Ambler et al. (2) into four classes, designated classes A to D, on the basis of their amino acid sequences, with classes A and C being the most frequently occurring among bacteria. Oxyimino-cephalosporins such as cefotaxime and ceftazidime, which are inherently less susceptible to β-lactamases, were introduced in the early 1980s to treat infections caused by gram-negative bacilli that were resistant to established β-lactams and that produced class A, C, and D β-lactamases. Their repetitive and increased use induced the appearance of resistant strains, which overproduced class C enzymes (42, 72) and/or which produced extended-spectrum β-lactamases (ESBLs), mainly those of class A but also those of class D (19, 61). Class A ESBLs hydrolyze oxyimino-cephalosporins and aztreonam but not 7-α-substituted β-lactams. They are generally susceptible to β-lactamase inhibitors (clavulanate, sulbactam, tazobactam). According to the functional classification scheme of Bush et al. (23), class A ESBLs are therefore clustered in group 2be, which can be subdivided on the basis of their activities against ceftazidime and cefotaxime as ceftazidimases (higher levels of hydrolytic activity against ceftazidime than against cefotaxime) and cefotaximases (higher levels of hydrolytic activity against cefotaxime than against ceftazidime), respectively (48). However, class A ESBLs form a heterogeneous molecular cluster comprising β-lactamases sharing 20 to >99% identity. The earliest class A ESBLs, which were reported from 1985 to 1987, differed from widespread plasmid-mediated TEM-1/2 and SHV-1 penicillinases by one to four point mutations, which extend their hydrolytic spectra (51, 90, 91). TEM and SVH ESBLs now comprise at least 130 members and have a worldwide distribution. Most of them are ceftazidimases, and only a few are cefotaximases. More recently, non-TEM and non-SHV plasmid-mediated class A ESBLs have been reported: ceftazidimases of the PER, VEB, TLA-1, and GES/IBC types and cefotaximases of the SFO-1, BES-1, and CTX-M types (8, 12, 13, 16, 31, 58, 62, 75, 76, 79, 81, 88, 96). The CTX-M β-lactamases are the most widespread enzymes. They were initially reported in the second half of the 1980s, and their rate of dissemination among bacteria and in most parts of the world has increased dramatically since 1995. This review focuses on the origin, epidemiology, clinical impact, enzymatic properties, and structural relationships of the CTX-M-type ESBLs.

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  • CTX-M did not derive from TEM or SHV; current evidence suggests it was likely acquired from Kluyvera spp. through horizontal gene transfer.

    “In contrast to other Ambler class A ESBLs like TEM-3, this enzyme did not derive from TEM or SHV, rather, the current evidence suggests that it was likely acquired from Kluyvera spp. (an environmental bacterium with no major human pathogenic significance) through HGT (22).”

    From Mechanisms of Antibiotic Resistance (2016) · cites this paper as [22]

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Authors
Bonnet, R.
Affiliations
Université Clermont Auvergne (FR)
Corresponding author
Bonnet, R.
ORCID
Bonnet, R.
Venue
Antimicrobial Agents and Chemotherapy
Publisher
American Society for Microbiology
Published
2004-01
Volume
48
Issue
1
Pages
1-14
ISSN
  • 0066-4804 (ISSN-L)
  • 1098-6596
DOI
10.1128/aac.48.1.1-14.2004
PMC
PMC310187
OpenAlex
W2121254474
Cited by
1,494
References
106
Citations by year
2026: 31 · 2025: 32 · 2024: 37 · 2023: 41 · 2022: 64 · 2021: 61 · 2020: 62 · 2019: 65 · 2018: 63 · 2017: 70 · 2016: 87 · 2015: 74 · 2014: 60 · 2013: 84 · 2012: 77
FWCI
6.37
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Antimicrobial Agents and Chemotherapy (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Cheng Kung University Hospital
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
  • Physical Sciences › Environmental Science › Pollution › Pharmaceutical and Antibiotic Environmental Impacts
  • Health Sciences › Medicine › Pharmacology › Antibiotics Pharmacokinetics and Efficacy
Keywords
extended-spectrum beta-lactamase, CTX-M enzymes, class A beta-lactamase, class C beta-lactamase, beta-lactam resistance, oxyimino-cephalosporins, cefotaxime, ceftazidime, beta-lactamase inhibitors, plasmid-mediated resistance, TEM beta-lactamase, SHV beta-lactamase
MeSH terms
Animals, Bacterial Infections, beta-Lactamases, Humans, Phylogeny, Structure-Activity Relationship, Drug Resistance, Bacterial

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