JAC Advance Access originally published online on May 16, 2008
Journal of Antimicrobial Chemotherapy 2008 62(2):289-295; doi:10.1093/jac/dkn182
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Original research |
Dissemination of the CTX-M-25 family β-lactamases among Klebsiella pneumoniae, Escherichia coli and Enterobacter cloacae and identification of the novel enzyme CTX-M-41 in Proteus mirabilis in Israel
Division of Epidemiology, Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
* Corresponding author. Tel: +972-3-692-5644; Fax: +972-3-697-4966; E-mail: shiri_nv{at}tasmc.health.gov.il
Received 10 January 2008; returned 26 February 2008; revised 26 March 2008; accepted 1 April 2008
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Abstract |
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Objectives: The CTX-M-25 family of β-lactamases is a closely related family of enzymes found rarely in the world. We aimed to describe the occurrence and to understand the dissemination of this extended-spectrum β-lactamase family among Enterobacteriaceae strains in our hospital.
Methods: Fifty-four CTX-M-producing Enterobacteriaceae strains collected from 2000 to 2005 were screened for blaCTX-M-25 genes by PCR and sequencing. Genetic relatedness was analysed by PFGE. Antibiotic susceptibilities were determined by VITEK-2. Plasmids encoding blaCTX-M-25-type genes were isolated, transformed and analysed by Southern blot using a blaCTX-M-25 probe. Chromosomal location of blaCTX-M-25-type was studied by I-CeuI restriction analysis. The blaCTX-M-25 genetic environment was characterized by PCR mapping and partial sequencing.
Results: Ten out of 54 CTX-M-producing isolates (18.5%) carried blaCTX-M-25 genes, including Klebsiella pneumoniae (n = 4), Escherichia coli (n = 3), Enterobacter cloacae (n = 1) and Proteus mirabilis (n = 2). Isolates were genetically unrelated. Four β-lactamases were found: CTX-M-25, CTX-M-26, CTX-M-39 and CTX-M-41, a new member of the family (accession no. DQ023162 [GenBank] ) that differed from CTX-M-25 in three amino acids, Ala80Val, Val106Ile and Ile126Ser. blaCTX-M-25-type genes were plasmid-mediated in all genera but P. mirabilis, organized in a class I integron and located downstream of an ISEcp1 element. The genes were encoded on different plasmids with varying degree of similarities. Several antibiotic-resistant determinants conferring resistance to trimethoprim and aminoglycosides existed on the same integron.
Conclusions: blaCTX-M-25 exists in Israel in different enteric species. Spread of these enzymes within and between species is due to transfer of plasmids with common regions and by dissemination of determinants encoding these genes. CTX-M-41, a novel member of this family, was identified in the chromosome of P. mirabilis.
Keywords: plasmids , spread , integrons
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Introduction |
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CTX-M-type extended-spectrum β-lactamases (ESBLs) are currently the most widespread ESBL family worldwide.1–3 These β-lactamases have been classified into five phylogenetic families on the basis of their amino acid identities: CTX-M-1, CTX-M-2, CTX-M-8, CTX-M-9 and CTX-M-25.3 The CTX-M-25 family includes CTX-M-25, which was reported in a single Escherichia coli strain from Canada in 2000, and CTX-M-26, which was described in a Klebsiella pneumoniae outbreak strain from the UK in 2002.4 These two enzymes share 99% amino acid identity and differ in only three amino acids. The genes encoding these ESBLs were identified on large plasmids and were located downstream of ISEcp1, the most common insertion sequence of the CTX-M-type enzymes.1,2
In a previous study performed in our institution, a 1200-bed tertiary-care teaching hospital, comprising 45 wards, with almost 100 000 admissions annually, we found 80 ESBL-producing isolates of 400 unique-patient isolates screened.5 Fifty-four of these isolates carried blaCTX-M-type genes (67.5%): 44 isolates carried blaCTX-M-2-type genes and 10 isolates carried blaCTX-M-25-type genes. Sequencing of these blaCTX-M-25-type genes revealed a new CTX-M-25-related enzyme, CTX-M-39, in Enterobacter and in E. coli.6,7 CTX-M-39 revealed 99% homology with CTX-M-26, with a substitution of arginine for glutamine at position 225. The goals of this study were to elucidate the elevated occurrence of these rarely occurring CTX-M-25 family enzymes in various clinical isolates of Enterobacteriaceae, including K. pneumoniae, E. coli, Enterobacter cloacae and Proteus mirabilis, and to understand the mechanism of dissemination of this ESBL family among these bacteria. The possibilities of clonal spread and horizontal transfer of plasmid carrying the blaCTX-M-25-related gene or transfer of the intact gene were examined.
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Bacterial strains
Of 54 isolates belonging to the Enterobacteriaceae group collected at random in our institution in 2000–05, which were found to carry a blaCTX-M-25-related gene, 10 were included in this study.5 The isolates belonged to the following species: K. pneumoniae (n = 4), E. coli (n = 3), Enterobacter spp. (n = 1) and P. mirabilis (n = 2). Bacterial identification was performed by the VITEK-2 (bioMérieux, Hazelwood, MO, USA). Susceptibility testing was performed using the VITEK-2 AST GN09 card (bioMérieux) and using Etest (AB Biodisk, Solna, Sweden). An ESBL-producing phenotype was determined based on the ESBL confirmatory disc diffusion assay recommended in the CLSI guidelines,8 using the clavulanic acid combination disc method (Oxoid, Hampshire, England, UK) with both cefotaxime and ceftazidime.9
Pulsed-field gel electrophoresis
Clonal relatedness within each species was determined by PFGE. DNA preparation and cleavage was performed using 20 U of SpeI endonuclease (New England Biolabs, Beverly, MA, USA) for E. coli, K. pneumoniae and E. cloacae isolates, and using SmaI (New England Biolabs) for P. mirablils strains. Electrophoresis was performed in a 1% agarose gel (BMA Products, Rockland, ME, USA) prepared and run in 0.5x Tris/borate/EDTA buffer on a CHEF-DR III apparatus (Bio-Rad Laboratories, Ltd, Rishon LeZion, Israel). For SpeI digests, the initial switch time was 3 s, the final switch time was 20 s and the run time was 23 h at 6 V/cm at 14°C. For SmaI digests, the initial switch time was 5 s, the final switch time was 20 s and the run time was 24 h. Gels were stained in ethidium bromide, de-stained in distilled water and photographed using a Bio-Rad GelDoc 2000 camera (Bio-Rad Laboratories). PFGE DNA patterns were compared between isolates belonging to the same genera.
Detection of blaCTX-M, blaCTX-M-25-family and other β-lactamase genes by PCR, cloning and sequencing
The presence of blaCTX-M and, specifically, of blaCTX-M-25-family ESBLs in all the studied isolates was determined by PCR and sequencing. The specific primers that were used for different blaCTX-M-type gene detection are summarized in Table 1. The presence of other β-lactamase genes was determined using previously described primers.6,16 Bacterial cell lysates were used as DNA templates, and PCR conditions were as described previously.6 PCR products were cloned into pGEM-T Easy Vector System and transformed into E. coli JM109 (Promega), after which inserts were bi-directionally sequenced, analysed and compared via the National Center for Biotechnology Information (NCBI) web site. Isolates that carried blaCTX-M-25-type ESBLs were chosen for further characterization.
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Conjugation experiments
Transconjugation experiments were performed by filter mating with five strains representing each of the CTX-M-producing genera (E. cloacae 1018, K. pneumoniae 1016, E. coli 1430 and two P. mirabilis strains 1270 and 1336). E. coli HB101 was used as a recipient strain. Transconjugants were selected on Luria-Bertani (LB) agar plates containing streptomycin (500 mg/L) and ceftriaxone (16 mg/L).
CTX-M-25-type plasmid analysis, transformation and Southern blot hybridization
Plasmid DNA from all blaCTX-M-25-type carrying isolates was isolated using a NucleoBond PC 100 kit (Macherey-Nagel, Germany) according to the manufacturer's instructions. The DNA preparations were electrophoresed on 1% agarose gels. BAC-Tracker supercoiled DNA ladder (Epicentre, Madison, WI, USA) was used as a size marker for blaCTX-M-25-type carrying plasmids. Transformation experiments were carried out by electroporation of plasmid DNA to E. coli strain GeneHogs (Invitrogen, UK) using an Electroporator 2510 (Eppendorf, Hamburg, Germany). Transformant colonies were selected on LB agar plates containing ampicillin (100 mg/L). For Southern blot analysis, plasmid DNA from donor strains and transformants were digested with ApaI (does not recognize CTX-M-type genes) and EcoRV (recognizes CTX-M-type genes at nucleotide 744) endonucleases (New England Biolabs), electrophoresed, transferred to a Hybond N+ membrane (Amersham Biosciences) and cross-linked with UV light. A blaCTX-M-25 gene radioactively labelled with random primer DNA-labelling mixture (Biological Industries, Beit Haemek, Israel) was used as a probe.
Location of blaCTX-M-25-type genes
Chromosomal location of blaCTX-M-25-type genes was confirmed by I-CeuI digestion (New England Biolabs) followed by PFGE electrophoresis and hybridization with radioactive-labelled probes of 16S and blaCTX-M-25 genes. P. mirabilis ATCC strain 25933 lacking blaCTX-M-25 was used as a control strain. Separation of DNA fragments was performed as described previously.17 Saccharomyces cerevisiae chromosomal DNA (Bio-Rad) was used as a size marker.
Genetic environment of blaCTX-M genes
The genetic organization of the blaCTX-M-25 gene environment was examined in all the blaCTX-M-25-carrying isolates by PCRs using specific primers (Table 1) and partial sequencing. PCR mapping analysis was performed on plasmid preparations of transformed strains, except for E. coli 1466, whose mapping was performed on plasmid DNA isolated from the clinical strain, and for P. mirabilis strains, whose mapping was performed on chromosomal DNA. The insertion sequence forward primer ISEcp1 with the blaCTX-M-25 reverse primer was used to amplify the CTX-M-25 upstream region. Specific primers Int1D and Int1U were used to detect the presence of integrase 1 gene. Primers qacE
1F and sul1R were used for identification of blaCTX-M-25 genes downstream region. Primers 5'CS and 3'CS were used for identifying the presence of additional resistant determinants in the integron.
Nucleotide sequence accession number
The nucleotide sequence data for CTX-M-41 have been submitted to the GenBank nucleotide sequence database under accession no. DQ023162.
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Detection of CTX-M-25 β-lactamase family among CTX-M-producing Enterobacteriaceae
DNA derived from 10 isolates of the 54 CTX-M-producing Enterobacteriaceae isolates was amplified by CTX-M-25 primers (Table 1) and comprised the subject of this study (Table 2). Sequence analysis revealed four different enzymes: CTX-M-25, CTX-M-26, CTX-M-39 reported previously in E. cloacae from Israel6 and a new member of this family identified in this study in P. mirabilis designated CTX-M-41, according to the Lahey clinic nomenclature (http://www.lahey.org/Studies/). Sequencing of the novel blaCTX-M-41 gene revealed three point mutations when compared with the blaCTX-M-25 gene: C239T, G316A and T377G, resulting in the amino acid substitutions Ala80Val, Val106Ile and Ile126Ser. Analysis of a deduced amino acid sequence of CTX-M-41 using ClustalW through the EMBL-EBI site (http://www.ebi.ac.uk/) showed an identity of 99% with both CTX-M-25 (accession no. AF518567 [GenBank] )18 and CTX-M-26 (accession no. AY455830 [GenBank] ).4 Of the four members of the CTX-M-25 family, CTX-M-39 was the most prevalent enzyme (6 of 10 strains). Among all species, K. pneumoniae isolates possessed three different variants of this ESBL family (Table 2). In addition to the CTX-M-25 family, two Klebsiella isolates (1268 and 1320) and one E. coli isolate (1466) also carried other ESBLs such as SHV-14, SHV-27 and CTX-M-2, respectively (Table 2).
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Apparent susceptibilities to various cephalosporins and to aztreonam varied between isolates, even among those carrying the same CTX-M enzyme. Most (8 of 10) strains were resistant to trimethoprim/sulfamethoxazole. Co-resistance to quinolones and gentamicin also varied. All isolates were susceptible to imipenem and amikacin, except for E. coli 1430, which was amikacin intermediate (Table 3).
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Dissemination of the CTX-M-25 family
Genotyping. The 10 bacterial strains that carried blaCTX-M-25 were isolated from 10 patients who were hospitalized in six different wards in the hospital and did not exhibit any apparent epidemiological relation. Seven of the 10 bacterial strains were isolated from wounds, 2 from peritoneal fluid and 1 from blood. The clonal relatedness of isolates belonging to each genus, assessed by PFGE, showed a different DNA pattern, indicating non-clonal transmission of the CTX-M-25-type-producing strains.
Location of the CTX-M-25-family genes, CTX-M-25-family-encoding plasmid analysis and transfer experiments
The location of blaCTX-M-25 was determined in order to understand the occurrence of this gene family in various clones and in four different species (Klebsiella, E. coli, E. cloacae and P. mirabilis).
blaCTX-M-25-encoding plasmids were isolated from all isolates, except for the two P. mirabilis isolates, suggesting a chromosomal origin of blaCTX-M-25 and blaCTX-M-41 in this genus. An attempt to transfer blaCTX-M-25 by transconjugation of five of the blaCTX-M-25-producing strains was unsuccessful. In the case of Proteus, I-CeuI endonuclease digestion was used with two blaCTX-M-25-type genes carrying P. mirabilis isolates and a control strain. The analysis generated fragments ranging from 2.2 Mb to a fragment smaller than 2.25 kb. The rRNA probe hybridized with all fragments of all three strains except fragments 2.2 and 1.6 Mb, whereas the blaCTX-M-25 probe hybridized only with the 2.2 Mb fragment of P. mirabilis isolate 1270 and with 785 kb fragment of isolate 1336 further supporting the chromosomal location of these genes in P. mirabilis (data not shown).
Transformation of plasmid DNA carrying blaCTX-M-25-type-family genes (verified by PCR and subsequent sequencing) into a susceptible E. coli GeneHogs recipient strain was successful in seven isolates (four K. pneumoniae, two E. coli and one E. cloacae). Plasmid DNA containing blaCTX-M-39 of E. coli 1466 was isolated but was non-transformable on repeated transformation attempts and therefore not studied further.
Transformants showed antibiotic susceptibility patterns similar to those of their donors upon acquisition of the plasmids. The MICs of ceftriaxone and ceftazidime were similar among donors and transformants, with the exception of E. coli 1393 transformant, in which acquisition of the blaCTX-M-39 plasmid conferred resistance to ampicillin and piperacillin, and increased the MIC of ceftriaxone from <1 to 8 mg/L and of gentamicin from <1 to 2 mg/L (Table 3).
The size of all blaCTX-M-25-type-carrying plasmids was estimated to be 
165 kb (data not shown). Restriction analysis of plasmid DNA from all transformed strains using ApaI and EcoRV endonucleases showed different restriction profiles with varying degree of similarities (see Figure 1a for EcoRV restriction). Southern analysis revealed an identical hybridization profile in two pairs of transformed isolates originating from K. pneumoniae strains 1032 and 1320, and from E. coli 1430 and K. pneumoniae 1016. The other two transformants from K. pneumoniae isolates (1268 and 1016) showed a different hybridization pattern. The transformant of E. cloacae 1018 showed a unique pattern (Figure 1b).
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PCR analysis of transformed plasmids showed that TEM-1 co-transferred with the CTX-25-family gene in all of the isolates, whereas SHV-1, SHV-14 and SHV-27 did not (Table 2).
Genetic environment of the blaCTX-M-25 family
Since CTX-M-type enzymes are associated with ISEcp1-like insertion sequences and class I integrons, the genetic organization of the blaCTX-M-25 gene's environment was studied in all 10 isolates, including the two P. mirabilis strains in which this gene was chromosomally encoded and the E. coli isolate 1466 that failed to transform. blaCTX-M-25 genes in all isolates were located on a class I integron. The integron included int1, the gene encoding for integrase 1, qacE1, the truncated form of qacE gene that confers resistance to quaternary ammonium compounds,19 sul1, which confers resistance to sulphonamides20 and one of the CTX-M-25-family genes. ISEcp1, the most common insertion sequence of genes encoding CTX-M enzymes,2 was located 126–128 bp upstream of the start codon of the CTX-M-25-type gene. The resistance elements located between 5'CS and 3'CS conserved segments varied among the different isolates (Figure 2). PCR mapping and partial sequencing of this region in seven selected isolates (three K. pneumonia strains, two E. coli strains, one E. cloacae strain and one P. mirabilis strain) revealed the presence of different resistance determinants. Dihydrofolate reductase (dhfr type VII), which confers resistance to trimethoprim,21,22 was the most common resistant determinant present in four strains (K. pneumonia 1032 and 1320, E. coli 1393 and E. cloacae 1018). Aminoglycoside adenyltransferase (aadA1), which confers resistance to streptomycin and spectinomycin,23 was found in K. pneumoniae 1016 and E. coli 1430. The aac(6')-Ib gene encoding an aminoglycoside 6'-N-acetyltransferase that confers resistance to amikacin, kanamycin and tobramycin24 and the blaOXA-2 gene were found in the P. mirabilis isolate 1270 (Figure 2).
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Discussion |
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The CTX-M group has become the most widespread ESBL family but the CTX-M-25 family, the most recently reported CTX-M subgroup, is still rare in the world. We describe the high occurrence of this β-lactamase family and examine their mode of dissemination between K. pneumoniae, E. coli, E. cloacae and P. mirabilis. We describe a new member of the CTX-M-25 family, CTX-M-41, in P. mirabilis and we report for the first time the occurrence of this ESBL family in E. cloacae. Other CTX-M-type β-lactamases such as CTX-M-1, CTX-M-2 or CTX-M-9 were described previously in these two genera.25–29 Phylogenetically, CTX-M-41, found in this study in P. mirabilis, is the closest enzyme to CTX-M-25, reported initially in E. coli from Canada. CTX-M-39, found in this study in K. pneumoniae, E. coli and E. cloacae, is closer to CTX-M-26, reported initially in K. pneumoniae from the UK.
Of the CTX-M-25 family, CTX-M-39 was the most common β-lactamase, identified in 6 of 10 isolates and in 3 different genera (Table 2). The presence of four different members of the CTX-M-25 family β-lactamases in four different species in our hospital is intriguing and we attempted to reveal their mode of dissemination.
There were no epidemiological relationships between the isolates, and PFGE confirmed that the isolates belonged to different clones within each genus ruling out the possibility of clonal spread. blaCTX-M-25 genes were found to be encoded on different large plasmids with varied degrees of similarities except in P. mirabilis where blaCTX-M-41 and blaCTX-M-25 were found to be chromosomally encoded.
The presence of blaCTX-M-25-family genes among different species encoded in different plasmids and located even in the chromosome suggests an integron-based dissemination. Indeed, blaCTX-M-25-family genes were found to be located in a class I integron associated with the ISEcp1 insertion sequence adjacent to the gene which presumably acts as a key factor in the dispersion of these genes, as was reported previously.30 This mode of spread may explain the existence of the same gene in several plasmids, such as in the case of blaCTX-M-39 carried on five different plasmids of which some were highly similar, for example, plasmids of E. coli 1430 and K. pneumoniae 1016, and others that were highly different, such as plasmids of K. pneumoniae 1032 and E. cloacae 1018 (Figure 1).
In spite of the presence of different plasmids each encoding a different enzyme as in the case of K. pneumoniae 1032 (encoding CTX-M-39) and 1320 (encoding CTX-M-26), a similar hybridization pattern was obtained with the blaCTX-M-25-labelled probe (Figure 1b) suggesting the presence of similar fragments.
The apparent differences between plasmids carrying the same ESBL gene but exhibiting variability in the genetic environment of these genes (Figure 2) have been documented before, in the case of blaCTX-M-9 in genetically unrelated E. coli strains31 and in the structure of other blaCTX-M genes.2,32 blaTEM was found to be present on the same plasmids carrying the blaCTX-M-25-family genes, as was also reported in other blaCTX-M genes.31
The origin of the CTX-M-25 family is yet undetermined. Other CTX-M-type enzymes seem to have descended from chromosomal β-lactamases of Kluyvera spp.2 The enzyme that was found to be most closely related to the CTX-M-25 family is KLUG-1 from Kluyvera georgiana, the progenitor of CTX-M-8,33 which is the closest enzyme to the CTX-M-25 subgroup34 but is considered as a different subgroup.3 CTX-M-25 and CTX-M-26, respectively, show 89.4% and 89.7% identities with KLUG-1, which similar to CTX-M-39 and CTX-M-41, respectively, show 90% and 89% identities to KLUG-1. These high similarities indicate that these four enzymes probably originate from the same but a different progenitor gene, yet to be identified.
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This work was supported by a grant from the Public Committee for the Designation of Estate Funds Ministry of Justice State of Israel.
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None to declare.
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Acknowledgements |
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The study was presented in part at the Forty-fifth Interscience Conference on Antimicrobial Agents Chemotherapy, Washington, DC, 2005. The author thank Mrs Esther Eshkol for her assistance in editing the manuscript.
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References |
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