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CTX-M-type β-lactamases: A successful story of antibiotic resistance

https://doi.org/10.1016/j.ijmm.2013.02.008Get rights and content

Abstract

Production of extended-spectrum β-lactamases (ESBLs) is the principal mechanism of resistance to oxyimino-cephalosporins evolved by members of the family Enterobacteriaceae. Among the several ESBLs emerged among clinical pathogens, the CTX-M-type enzymes have proved the most successful in terms of promiscuity and diffusion in different epidemiological settings, where they have largely replaced and outnumbered other types of ESBLs. Originated by the capture and mobilization of chromosomal β-lactamase genes of strains of Kluyvera species, the blaCTX-M genes have become associated with a variety of mobile genetic elements that have mediated rapid and efficient inter-replicon and cell-to-cell dissemination involving highly successful enterobacterial lineages (e.g. Escherichia coli ST131 and ST405, or Klebsiella pneumoniae CC11 and ST147) to yield high-risk multiresistant clones that have spread on a global scale. The CTX-Mβ-lactamase lineage exhibits a striking plasticity, with a large number of allelic variants belonging in several sublineages, which can be associated with functional heterogeneity of clinical relevance. This review article provides an update on CTX-M-type ESBLs, with focus on structural and functional diversity, epidemiology and clinical significance.

Introduction

The introduction of expanded-spectrum cephalosporins in clinical practice, in the early 1980s, represented a major breakthrough for the treatment of infections caused by Enterobacteriaceae and other Gram-negative pathogens. At the same time, the massive use of expanded-spectrum cephalosporins generated a selective pressure that was followed by the rapid emergence of new β-lactamases that were able to degrade and confer resistance to these compounds, named extended-spectrum β-lactamases (ESBLs).

Two major strategies of ESBL evolution have been exploited by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Salmonella enterica and other members of the family Enterobacteriaceae: (i) the selection of mutants with expanded substrate specificity from the plasmid-mediated TEM- and SHV-type β-lactamases, that were already prevalent among Enterobacteriaceae since the 1970s; and (ii) the capture of novelβ-lactamase genes from the environmental metagenome, encoding enzymes that are naturally endowed with ESBL activity. Among the latter enzymes, the CTX-M type β-lactamases have proved by far the most successful in disseminating in the clinical setting and have overall become the most prevalent ESBLs worldwide.

A number of review articles on CTX-M-type β-lactamases have been published in recent years (Bonnet, 2004, Walther-Rasmussen and Hoiby, 2004, Canton and Coque, 2006, Rossolini et al., 2008, Naseer and Sundsfjord, 2011, Canton et al., 2012, Zhao and Hu, 2013). However, the epidemiology of CTX-M-type ESBLs is evolving rapidly, together with knowledge of their structural and functional properties, and clinical significance. The objective of this paper is to provide a concise update on CTX-M-type β-lactamases, with focus on aspects related with structural and functional diversity, epidemiology and clinical significance.

Section snippets

Diversity and origin of CTX-M-type β-lactamases

The CTX-M-type β-lactamases belong in a quite heterogeneous lineage of molecular class A active site-serine β-lactamases, which includes at least six sublineages or groups (CTX-M-1, CTX-M-2, CTX-M-8, CTX-M-9, CTX-M-25 and KLUC, named after the archetypal enzymes of each group) that differ from each other by ≥10% amino acid residues (Fig. 1). Each group, in turn, includes a number of minor allelic variants which differ from each other by one or few amino acid substitutions (≤5% amino acid

Capture and dissemination mechanisms of blaCTX-M genes

Acquired blaCTX-M genes found in clinical isolates of Enterobacteriaceae are generally carried by conjugative plasmids (Carattoli, 2009, Carattoli, 2011, Zhao and Hu, 2013), although in some strains (mostly of Proteus mirabilis but occasionally also of other species) they were found integrated into the chromosome (Coque et al., 2008, Navon-Venezia et al., 2008, Fabre et al., 2009, Coelho et al., 2010, Song et al., 2011, Mahrouki et al., 2012).

Analysis of the genetic environment of acquired bla

Functional properties of CTX-M-type β-lactamases and contribution to β-lactam resistance

The CTX-M-type β-lactamases derive their name from the potent cefotaximase activity, which is a functional hallmark of these enzymes. This feature depends on a peculiar electrostatic environment and flexibility of the catalytic pocket, in combination with other structural elements (e.g. the conserved Arg276 residue, which acts as a mobile electrostatic arm tracking cefotaxime toward the binding site), that allow an efficient recognition and hydrolysis of the bulky cefotaxime molecule with

Epidemiology of CTX-M-producers and clinical impact

Since the first sporadic reports in the late 1980s from Japan, Europe and South America (Matsumoto et al., 1988, Bauernfeind et al., 1990, Bauernfeind et al., 1992), the CTX-M-type ESBLs have experienced a global diffusion, outnumbering and partially replacing the TEM- and SHV-type ESBLs, and becoming overall the most prevalent type of ESBL. For a comprehensive picture of the penetration and globalization of CTX-M-type enzymes occurred during the past two decades the reader may refer to the

Diagnostic issues

Diagnosis of CTX-M-producers may be relevant to molecular epidemiology and infection control. While CTX-M production can be suspected in ESBL producers that exhibit certain resistance profiles (see above), molecular analysis is needed to confirm the presence of a CTX-M-type determinant. Diversity of blaCTX-M genes complicates molecular detection, and various strategies have been proposed, based on multiplex PCR (Woodford et al., 2006, Naas et al., 2007, Pitout et al., 2007, Dallenne et al., 2010

Conclusions

The rapid and extensive dissemination of CTX-M-type ESBLs in clinical and veterinary settings, but also among commensal bacteria of humans and animals and in the environment, is one of the most successful histories of microbial drug resistance observed in the antibiotic era. This success likely depend on the combination of various factors including efficient capture and dispersal of blaCTX-M gene by mobile genetic elements, association of these elements with highly successful bacterial clones,

Acknowledgements

Research on antibiotic resistance mechanisms in the Laboratories of the Authors has been funded by Grants from the European Commission (TROCAR contractHEALTH-F3-2008-223031; TEMPOtest-QC contract HEALTH-2009-241742; EvoTAR contract LSHM-2011-282004), and from the Italian Ministry of University and Research (PRIN 2009, protocol no. 200929YFMK_004).

References (163)

  • J. Delmas et al.

    Structural insights into substrate recognition and product expulsion in CTX-M enzymes

    J. Mol. Biol.

    (2010)
  • C. Ewers et al.

    Extended-spectrum β-lactamase-producing and AmpC-producing Escherichia coli from livestock and companion animals, and their putative impact on public health: a global perspective

    Clin. Microbiol. Infect.

    (2012)
  • J.L. Gomez-Garces et al.

    Osteomyelitis associated to CTX-M-15-producing Aeromonas hydrophila: first description in the literature

    Diagn. Microbiol. Infect. Dis.

    (2011)
  • P.L. Ho et al.

    Dissemination of pHK01-like incompatibility group IncFII plasmids encoding CTX-M-14 in Escherichia coli from human and animal sources

    Vet. Microbiol.

    (2012)
  • K.L. Hopkins et al.

    Novel plasmid-mediated CTX-M-8 subgroup extended-spectrum β-lactamase (CTX-M-40) isolated in the UK

    Int. J. Antimicrob. Agents

    (2006)
  • S. Kimura et al.

    Predictive analysis of ceftazidime hydrolysis in CTX-M-type β-lactamase family members with a mutational substitution at position 167

    Int. J. Antimicrob. Agents

    (2007)
  • M.Y. Lee et al.

    High prevalence of CTX-M-15-producing Klebsiella pneumoniae isolates in Asian countries: diverse clones and clonal dissemination

    Int. J. Antimicrob. Agents

    (2011)
  • W.U. Lo et al.

    Fecal carriage of CTXM type extended-spectrum β-lactamase-producing organisms by children and their household contacts

    J. Infect.

    (2010)
  • U.O. Luvsansharav et al.

    Prevalence of fecal carriage of extended-spectrum β-lactamase-producing Enterobacteriaceae among healthy adult people in Japan

    J. Infect. Chemother.

    (2011)
  • V. Manageiro et al.

    Genetic diversity and clonal evolution of carbapenem-resistant Acinetobacter baumannii isolates from Portugal and the dissemination of ST118

    Int. J. Antimicrob. Agents

    (2012)
  • J. Oteo et al.

    Extended-spectrum β-lactamase-producing Escherichia coli in Spain belong to a large variety of multilocus sequence typing types, including ST10 complex/A, ST23 complex/A and ST131/B2

    Int. J. Antimicrob. Agents

    (2009)
  • M. Adler et al.

    Influence of acquired β-lactamases on the evolution of spontaneous carbapenem resistance in Escherichia coli

    J. Antimicrob. Chemother.

    (2013)
  • N. al Naiemi et al.

    A CTX-M extended-spectrum β-lactamase in Pseudomonas aeruginosa and Stenotrophomonas maltophilia

    J. Med. Microbiol.

    (2006)
  • A. Baraniak et al.

    Countrywide spread of CTX-M-3 extended-spectrum β-lactamase-producing microorganisms of the family Enterobacteriaceae in Poland

    Antimicrob. Agents Chemother.

    (2002)
  • A. Bartoloni et al.

    Relentless increase of resistance to fluoroquinolones and expanded-spectrum cephalosporins in Escherichia coli: 20 years of surveillance in resource-limited settings from Latin America

    Clin. Microbiol. Infect.

    (2012)
  • A. Bauernfeind et al.

    A new plasmidic cefotaximase in a clinical isolate of Escherichia coli

    Infection

    (1990)
  • A. Bauernfeind et al.

    A new plasmidic cefotaximase from patients infected with Salmonella typhimurium

    Infection

    (1992)
  • R. Ben-Ami et al.

    Influx of extended-spectrum β-lactamase-producing enterobacteriaceae into the hospital

    Clin. Infect. Dis.

    (2006)
  • R. Ben Sallem et al.

    Prevalence and characterisation of extended-spectrum β-lactamase (ESBL)-producing Escherichia coli isolates in healthy volunteers in Tunisia

    Eur. J. Clin. Microbiol. Infect. Dis.

    (2012)
  • R. Bonnet

    Growing group of extended-spectrum β-lactamases: the CTX-M enzymes

    Antimicrob. Agents Chemother.

    (2004)
  • E. Calbo et al.

    Foodborne nosocomial outbreak of SHV1 and CTX-M-15-producing Klebsiella pneumoniae: epidemiology and control

    Clin. Infect. Dis.

    (2011)
  • R. Canton et al.

    CTX-M enzymes: origin and diffusion

    Front. Microbiol.

    (2012)
  • A. Carattoli

    Resistance plasmid families in Enterobacteriaceae

    Antimicrob. Agents Chemother.

    (2009)
  • G. Celenza et al.

    Spread of blaCTX-M-type and blaPER-2β-lactamase genes in clinical isolates from Bolivian hospitals

    J. Antimicrob. Chemother.

    (2006)
  • M.C. Cergole-Novella et al.

    First description of blaCTX-M-14- and blaCTX-M-15-producing Escherichia coli isolates in Brazil

    Microb. Drug Resist.

    (2010)
  • V.P. Chaubey et al.

    Clinical outcome of empiric antimicrobial therapy of bacteremia due to extended-spectrum β-lactamase producing Escherichia coli and Klebsiella pneumoniae

    BMC Res. Notes

    (2010)
  • S. Chen et al.

    High prevalence of KPC-2-type carbapenemase coupled with CTX-M-type extended-spectrum β-lactamases in carbapenem-resistant Klebsiella pneumoniae in a teaching hospital in China

    Antimicrob. Agents Chemother.

    (2011)
  • Y. Chen et al.

    The acylation mechanism of CTX-M β-lactamase at 0.88 Å resolution

    J. Am. Chem. Soc.

    (2007)
  • C. Chouchani et al.

    Occurrence of IMP-8, IMP-10, and IMP-13 metallo-β-lactamases located on class 1 integrons and other extended-spectrum β-lactamases in bacterial isolates from Tunisian rivers

    Scand. J. Infect. Dis.

    (2012)
  • H.C. Chung et al.

    Bacteremia caused by extended-spectrum-β-lactamase-producing Escherichia coli sequence type ST131 and non-ST131 clones: comparison of demographic data, clinical features, and mortality

    Antimicrob. Agents Chemother.

    (2012)
  • T.M. Coque et al.

    Dissemination of clonally related Escherichia coli strains expressing extended-spectrum β-lactamase CTX-M-15

    Emerg. Infect. Dis.

    (2008)
  • P. Cornejo-Juarez et al.

    Molecular analysis and risk factors for Escherichia coli producing extended-spectrum β-lactamase bloodstream infection in hematological malignancies

    PLoS One

    (2012)
  • J.L. Cottell et al.

    Complete sequence and molecular epidemiology of IncK epidemic plasmid encoding blaCTX-M-14

    Emerg. Infect. Dis.

    (2011)
  • A. Cullik et al.

    A novel IS26 structure surrounds blaCTX-M genes in different plasmids from German clinical Escherichia coli isolates

    J. Med. Microbiol.

    (2010)
  • G. Cuzon et al.

    Outbreak of OXA-48-positive carbapenem-resistant Klebsiella pneumoniae isolates in France

    Antimicrob. Agents Chemother.

    (2011)
  • C. Dallenne et al.

    Development of a set of multiplex PCR assays for the detection of genes encoding important β-lactamases in Enterobacteriaceae

    J. Antimicrob. Chemother.

    (2010)
  • I. Damjanova et al.

    Expansion and countrywide dissemination of ST11, ST15 and ST147 ciprofloxacin-resistant CTX-M-15-type β-lactamase-producing Klebsiella pneumoniae epidemic clones in Hungary in 2005 – the new ‘MRSAs’?

    J. Antimicrob. Chemother.

    (2008)
  • J.W. Decousser et al.

    Characterization of a chromosomally encoded extended-spectrum class A β-lactamase from Kluyvera cryocrescens

    Antimicrob. Agents Chemother.

    (2001)
  • J. Delmas et al.

    Prediction of the evolution of ceftazidime resistance in extended-spectrum β-lactamase CTX-M-9

    Antimicrob. Agents Chemother.

    (2006)
  • H. Dhanji et al.

    Isolation of fluoroquinolone-resistant O25b:H4-ST131 Escherichia coli with CTX-M-14 extended-spectrum β-lactamase from UK river water

    J. Antimicrob. Chemother.

    (2011)
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