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JAC Advance Access originally published online on February 4, 2008
Journal of Antimicrobial Chemotherapy 2008 61(3):498-503; doi:10.1093/jac/dkm538
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Molecular characterization of AmpC-producing Escherichia coli clinical isolates recovered in a French hospital

Hedi Mammeri1,2, François Eb1, Amira Berkani1 and Patrice Nordmann2,*

1 Service de Bactériologie-Hygiène, Centre hospitalier universitaire d’Amiens, Hôpital Nord, Amiens, France 2 Service de Bactériologie-Virologie-Hygiène, Hôpital de Bicêtre, Assistance Publique/Hôpitaux de Paris, Faculté de Médecine Paris-Sud, Université Paris Sud, K.-Bicêtre, France

* Correspondence address. Service de Bactériologie-Virologie, Hôpital de Bicêtre, 78 rue du Général Leclerc, 94275 Le Kremlin-Bicêtre Cedex, France. Tel: +33-1-45-21-36-32; Fax: +33-1-45-21-63-40; E-mail: nordmann.patrice{at}bct.aphp.fr

Received 6 July 2007; returned 28 November 2007; revised 23 September 2007; accepted 12 December 2007


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Objectives: To characterize the AmpC-type β-lactamases produced by Escherichia coli clinical isolates.

Methods: E. coli isolates recovered in a French hospital in 2006 were selected on the basis of a resistance phenotype consistent with increased AmpC production. The presence of genes coding for plasmid-mediated cephalosporinases as well as the existence of mutations in the chromosome-borne ampC genes was studied by PCR and sequencing. Genes for chromosomal cephalosporinases were cloned and the conferred resistance patterns were analysed. The isolates were submitted to phylotyping and genotyping analysis.

Results: Thirty-four out of 2800 E. coli isolates were selected. Sixteen isolates, which overexpressed their chromosomal wild-type cephalosporinases due to mutations into their promoter sequence, were susceptible to extended-spectrum cephalosporins (ECLs). Eighteen isolates, mostly of the commensal phylogenetic group A or B1, had reduced susceptibility to ECLs, due to the production of chromosomal extended-spectrum AmpC (ESAC) β-lactamases, or plasmid-mediated cephalosporinases (CMY-2 and ACC-1), or to combined mechanisms of resistance. Sequence analysis showed that ESAC β-lactamases had amino acid changes in the R2 binding site, among which was a novel structural change corresponding to the duplication of Ile-283 in the H-9 helix. All the E. coli clinical isolates were non-clonally related except for four CMY-2-producing strains.

Conclusions: This work sheds new light on the spread of ESAC β-lactamases in E. coli. It showed that this emerging mechanism of resistance could be as frequent as plasmid-mediated cephalosporinases (0.21% and 0.28% of the E. coli isolates, respectively) and that a phenotypic approach is not able to identify these mechanisms of resistance.

Keywords: cephalosporins , ESAC , CMY , β-lactamase


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Escherichia coli naturally produces a chromosome-encoded AmpC at a very low level due to a weak promoter and the effect of a transcriptional attenuator.1 Spontaneous mutations in the promoter region of the ampC gene in E. coli may induce constitutive overproduction of the AmpC β-lactamase and confer resistance to narrow-spectrum cephalosporins.1,2

Resistance to cephalosporins in E. coli can also be associated with plasmid-mediated AmpC (PMAC) β-lactamases, such as CMY-type or ACC-type enzymes, which confer resistance to extended-spectrum cephalosporins.3 Zwitterionic cephalosporins, such as cefepime and cefpirome, and carbapenems, which penetrate very efficiently through the outer membrane of Gram-negative organisms and are poor substrates for AmpC β-lactamases, remain active in vitro against cephalosporinase overproducers.4

Recently, a novel mechanism of resistance, cephalosporinases with broadened substrate activity, has been reported in several clinical isolates of Enterobacter cloacae, Enterobacter aerogenes, Serratia marcescens and E. coli.5 These extended-spectrum AmpC (ESAC) β-lactamases confer reduced susceptibility to all cephalosporins including cefepime and cefpirome. These enzymes have structural modifications in six regions of the cephalosporinase sequences that are in the vicinity of the active site, the {Omega} loop, the H-2 helix, the H-9 helix, the H-10 helix, the R2 loop and the H-11 helix.5

The objective of the present work was to characterize the AmpC β-lactamases expressed by clinical E. coli isolates that displayed a resistance phenotype consistent with the production of a cephalosporinase, recovered during a 1 year period in a French hospital and to analyse their clonal relationship.


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Bacterial strains

Clinical isolates were identified using API 20E system (bioMérieux, Marcy-l’Étoile, France). E. coli TOP10 and azide-resistant E. coli J53 were used for transformation and conjugation experiments, respectively.6

Study design

E. coli clinical isolates that were recovered at the Bicêtre hospital (Le K.-Bicêtre, France) in 2006 and that displayed a resistance phenotype consistent with an increased AmpC production on the basis of resistance to amoxicillin and cefalotin, which was not antagonized by clavulanic acid addition, were included in this study. AmpC production was further confirmed using cloxacillin (200 mg/L)-containing plates, which specifically inhibit class C β-lactamases and restore susceptibility to cephalosporins.5 Only non-duplicate isolates were retained in this study.

Molecular typing

The 34 isolates were compared by enterobacterial repetitive intergenic consensus (ERIC) PCR using primer ERIC2.7 The isolates that displayed identical patterns were subsequently genotyped by PFGE analysis.8,9

Phylotyping analysis

The PCR-based phylotyping analysis described by Clermont et al.10 was applied to the clinical isolates included in this study. The method, which uses a combination of two genes (chuA and yjaA) and an anonymous DNA fragment, allows the determination of the main phylogenetic groups of E. coli (these being A, B1, B2 and D).

Plasmid DNA extraction, conjugation and transformation experiments

Plasmid DNA was extracted using the plasmid Midi kit (Qiagen, Courtaboeuf, France). Transfer by conjugation or transformation of β-lactam resistance marker was attempted from ESAC β-lactamase-producing E. coli isolates as described previously.11

Antimicrobial agents and MIC determination

The antibiotic agents and their sources have been described elsewhere.12 MICs were determined by an agar dilution technique on Mueller–Hinton agar (Sanofi-Diagnostics Pasteur, Paris, France) with an inoculum of 104 cfu per spot and were interpreted according to the guidelines of the Clinical and Laboratory Standards Institute.13

Amplification of the ampC genes and sequence analysis

Total DNA was extracted as described previously.12 Genes encoding six phylogenetic groups of acquired AmpC enzymes were sought using multiplex PCR assays.14 The plasmid-borne genes of the blaCMY/LAT lineage were entirely sequenced using primers Prom+ (5'-TGCTCTGTGGATAACTTGC-3'), PreCMY-2b (5'-TGCGCATGGGATTTTCCTTG-3') and the primer pair, CITMR and CITMF, used in the multiplex PCR described previously.14

PCR amplifications of ampC genes were performed with primers Int-B2 (5'-TTCCTGATGATCGTTCTGCC-3') and Int-HN (5'-AAAAGCGGAGAAAAGGTCCG-3'), yielding a 1315 bp amplification product that contained the entire ampC gene of E. coli, including its own promoter sequence. Sequence analyses were performed with PAUP version 3.1.1 and software available at the internet web sites www.ncbi.nlm.nih.gov and http://www.ebi.ac.uk/clustalw/.

Cloning of β-lactamase genes

Amplification with primers Int-B1 (5'-TTTTGTATGGAACCAGACC-3') and Int-HN of ampC genes from E. coli ECB9 to E. coli ECB33 and E. coli BER gave PCR products of 1120 bp containing only the coding regions without their own promoter. These PCR products were cloned into pCR-BluntII-Topo (Invitrogen), and the recombinant plasmids were subsequently transformed into E. coli strain TOP10 as described previously.6

Nucleotide sequence accession numbers

The nucleotide sequence of blaAmpC genes of E. coli ECB33 has been deposited in EMBL nucleotide sequence database under accession no. EF661829.


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AmpC producer detection

Thirty-four out of 2800 E. coli isolates that were recovered at the Bicêtre hospital in 2006 met the selection criteria and were included in this study. These isolates were retained because their resistance phenotype was consistent with AmpC β-lactamase production. They were resistant to narrow-spectrum cephalosporins; this resistance was not antagonized by clavulanic acid, whereas the susceptibility to these compounds was restored using cloxacillin-containing plates. Twenty-four isolates were recovered from urine samples, 1 from blood culture and 9 from purulent exudates.

Detection of plasmid-mediated cephalosporinase genes

Plasmid-mediated ampC genes were detected in eight E. coli isolates, ECB1 to ECB8 (Table 1). A multiplex PCR gave rise to a 350 bp amplicon from isolate ECB1, which was in agreement with the presence of a gene of the blaACC lineage. Sequencing of the entire gene showed 100% identity with the blaACC-1 gene. Multiplex PCR for detection of PMAC β-lactamase genes yielded an amplicon whose size (760 bp) was consistent with the presence of a gene of the blaCMY/LAT lineage from isolates ECB2 to ECB8. PCR mapping using primers Prom+ and PreCMY2b, which are complementary to the flanking regions of other blaCMY-2-like genes, yielded amplification products of ~1.7 kb from isolates ECB2 to ECB8, suggesting that in all of them the blaCMY gene was located downstream of ISEcp1. Sequencing of the entire gene revealed the presence of an identical allele, which encoded the β-lactamase CMY-2. All the E. coli isolates producing PMAC β-lactamases belonged to phylogenetic group B1 (Table 1).


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  		Table 1. Molecular features of E. coli clinical isolates included in this study

 
Analysis of the chromosome-borne β-lactam resistance determinants

Sequence analysis of the chromosomal ampC genes revealed mutations in the promoter regions of 26 isolates, ECB9 to ECB33 and E. coli BER (Table 1), which created promoters that more closely resembled the E. coli consensus promoter.1 Mutations that created an alternative displaced promoter only occurred in E. coli isolates of the group A or B1 (Table 1). Changes included C->T mutation at position –42, which changed CTGACA to TTGACA to create a novel –35 box, and a G->A transition at position –18, which changed TGTCGT to TATCGT to create a novel –10 box.1 The alternative –35 and –10 sequences were separated by 17 bp. The mutations in the ampC promoter region at positions –11, –32 or the insertion of one or two nucleotides between the –35 and –10 boxes, which have already been described in previous studies,1,2,15 were more frequently identified in isolates of the group B2 or D (Table 1).

The analysis of the deduced amino acid sequences of the chromosome-borne cephalosporinases revealed that AmpC ECB29 to AmpC ECB33 and AmpC BER that were produced by isolates ECB29 to ECB33 and E. coli BER, respectively, and presented structural modifications in the H-9 helix or in the R2 loop [Table 1 and Figure S1; Figure S1 is available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/)]. The amino acid replacement H296P, which occurred in AmpC ECB29, AmpC ECB30 and AmpC ECB31, and the S287N replacement, which occurred in AmpC ECB32, have been already reported.6 The insertion of two residues inside the H-10 helix, which occurred in AmpC BER, was recently characterized,16 whereas AmpC ECB33 presented the peculiarity of a single amino acid insertion in the H-9 helix due to the duplication of Ile-283. This is the first report of an insertion inside the H-9 helix as a source of extended-spectrum hydrolysis.

Transferability and genetic support of the blaAmpC genes from isolates ECB9 to ECB33 and E. coli BER

Plasmid-mediated ampC genes were transferred by conjugation to E. coli J53 from clinical isolates ECB1 to ECB8. Conjugation and transformation experiments were also performed to determine whether the cephalosporin resistance marker could be transferred from E. coli ECB9 to ECB33 and E. coli BER. Despite multiple attempts, this resistance marker could not be transferred, thus indicating a chromosomal location of the ampC genes as very likely in those isolates.

Susceptibility testing of E. coli clinical isolates

The MIC values for E. coli clinical isolates are presented in Table 2.


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  		Table 2. MIC (mg/L) values of several β-lactams for E. coli clinical isolates

 
The E. coli clinical isolates ECB9 to ECB16, ECB18 to ECB23, ECB27 and ECB28 remained fully susceptible to extended-spectrum cephalosporins (ESCs), whereas E. coli clinical isolates ECB1 to ECB8, ECB17, ECB24 to ECB26, ECB29 to ECB33 and E. coli BER presented a reduced susceptibility to ESCs and to aztreonam (Table 2). No difference between MICs of imipenem and ertapenem was noticed.

Functional characterization of chromosome-borne AmpC β-lactamases

The functional properties of chromosomal cephalosporinases, which were overexpressed due to mutations in the promoter regions, were investigated by cloning the coding regions into the plasmid vector TOPO-Blunt followed by expression in E. coli TOP10. MIC values were determined for each clone and are presented in Table 3. Clones expressing AmpC ECB8 to AmpC ECB28 presented similar patterns of resistance and remained fully susceptible to ESCs, thus indicating that these enzymes were narrow-spectrum cephalosporinases. E. coli recombinant clones producing AmpC ECB29 to AmpC ECB33 and AmpC BER were resistant to ceftazidime and presented reduced susceptibility to other ESCs, such as cefotaxime and cefepime, and to aztreonam, thus indicating that they were ESAC β-lactamases. The recombinant clones remained fully susceptible to imipenem and ertapenem without reliable difference between the MICs of these two compounds.


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  		Table 3. MIC (mg/L) values of several β-lactams for E. coli recombinant clones expressing wild-type AmpCs or ESAC β-lactamases

 
Genotyping analysis of AmpC-producing isolates

Genotyping by random amplification of polymorphic DNA showed that isolates were non-clonally related except E. coli ECB5, ECB6, ECB7 and ECB8, which presented identical amplification patterns (data not shown). Analysis of the XbaI-digested DNA fragments by PFGE confirmed this clonal relationship (data not shown).


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AmpC-producing E. coli isolates constitute a relevant epidemiological threat in hospitals.17 This work sheds new light on the prevalence of E. coli clinical isolates that produced variant cephalosporinases with a broadened hydrolysis spectrum. The ESAC β-lactamases have likely evolved from wild-type cephalosporinases by structural modifications in peculiar secondary structures, i.e. the H-9 helix and the R2 loop containing the H-10 helix, which are both involved in the binding of ESCs.18 These structural changes have been reported in previous studies, except for the amino acid duplication in the helix H-9, which is reported here for the first time.6,16

Clinical isolates which overproduced a chromosomal wild-type cephalosporinase due to mutations in the ampC promoter region remained fully susceptible to ESCs (MICs ≤4 mg/L), although discrepancies, which could be attributed to the promoter strength, were noticed. According to MIC values, the –32 (T->A) and –42 (C->T) substitutions and the insertion of 1 bp between the –35 and the –10 boxes led to a higher level of expression than the –11 (C->T) substitution or a 2 bp insertion. These phenotypic variations were in agreement with the molecular results recently obtained by Tracz et al.19 using RT–PCR.

Almost all the chromosomal AmpC-overexpressing isolates of group A or B1 had the –42 (C->T) transition in their ampC promoter region whereas this mutation was never observed in the ampC promoter of group B2 or D.6 Moreover, this substitution was always associated with a G->A transversion at position –18, thus giving rise to an alternative displaced strong promoter.1 It is noteworthy that the adenine at position –18 had already been described without the –42 (C->T) mutation in several AmpC-non-overexpressing isolates.20 Therefore, it seems that the nucleotide variability at position –18 relies on a natural polymorphism which could match with the phylogenetic groups, thus providing a selective advantage to the isolates of groups A and B1. Further studies are necessary to confirm this hypothesis.

As indicated above, the wild-type chromosomal AmpC-producing isolates were fully susceptible to ESCs, except E. coli ECB17, ECB24, ECB25 and ECB26. However, the corresponding recombinant clones of these clinical isolates were all fully susceptible to ESCs, thus indicating that an additional non-enzymatic mechanism of resistance, such as loss of outer membrane porins,21 was likely to be involved in those clinical isolates.

This study identified the prevalence of plasmid-mediated cephalosporinases of the CMY/LAT-type lineage among the PMAC-producing E. coli isolates in our hospital. CMY-2 originated from the chromosomal AmpC of Citrobacter freundii and is now widely distributed throughout the world probably due to the spread of conjugative plasmids of the IncA/C type.2,3,20–28 Moreover, in several settings, this plasmid-borne resistance marker has been disseminated by epidemics of particular clones.23,24

This study revealed that the phenotypic approach failed to differentiate AmpC-type β-lactamases. Most of the CMY-2- and ESAC-producing isolates identified here had increased resistance to cefoxitin and ceftazidime. Moreover, several ESAC-producing isolates, such as E. coli BER, shared with ACC-producing E. coli isolates, such as E. coli ECB1, the peculiarity of being susceptible to cefoxitin whereas they had reduced susceptibility to ceftazidime and even cefepime. Thus, cefoxitin, ceftazidime and cefepime could not constitute good markers to differentiate between these different mechanisms of resistance to cephalosporins in E. coli.

In conclusion, the prevalence of ESAC and PMAC β-lactamases, 0.21% and 0.28%, respectively, was identical in E. coli clinical isolates from our hospital. Only molecular methods, such as PCR, are able to differentiate chromosomal and plasmid-mediated resistance to ESCs, the latter only being transferable among Enterobacteriaceae.


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This work was funded by a grant from the Ministère de l’Education Nationale et de la Recherche (UPRES-EA3539), Université Paris XI, France, and mostly by a grant from the European Community (LSHM-CT-2005-018705).


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None to declare.


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Figure S1 is available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/).


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1 Caroff N, Espaze E, Gautreau D, et al. Analysis of the effects of –42 and –32 ampC promoter mutations in clinical isolates of Escherichia coli hyperproducing ampC. J Antimicrob Chemother (2000) 45:783–8.[Abstract/Free Full Text]

2 Mulvey MR, Bryce E, Boyd DA, et al. Molecular characterization of cefoxitin-resistant Escherichia coli from Canadian hospitals. Antimicrob Agents Chemother (2005) 49:358–65.[Abstract/Free Full Text]

3 Philippon A, Arlet G, Jacoby GA. Plasmid-determined AmpC-type β-lactamases. Antimicrob Agents Chemother (2002) 46:1–11.[Free Full Text]

4 Hancock RE, Bellido F. Antibacterial in vitro activity of fourth generation cephalosporins. J Chemother (1996) 8(Suppl 2):31–6.[Web of Science][Medline]

5 Nordmann P, Mammeri H. Extended-spectrum cephalosporinases: structure, detection, and epidemiology. Future Microbiol (2007) 2:297–307.[CrossRef][Medline]

6 Mammeri H, Poirel L, Fortineau N, et al. Naturally occurring extended-spectrum cephalosporinases in Escherichia coli. Antimicrob Agents Chemother (2006) 50:2573–6.[Abstract/Free Full Text]

7 Versalovic J, Koeuth T, Lupski JR. Distribution of repetitive DNA sequences in eubacteria and application to fingerprinting of bacterial genomes. Nucleic Acids Res (1991) 19:6823–31.[Abstract/Free Full Text]

8 Neuwirth C, Siebor E, Lopez J, et al. Outbreak of TEM-24-producing Enterobacter aerogenes in an intensive care unit and dissemination of the extended-spectrum β-lactamase to other members of the family Enterobacteriaceae. J Clin Microbiol (1996) 34:76–9.[Abstract]

9 Tenover FC, Arbeit RD, Goering RV, et al. Interpreting chromosomal DNA restriction patterns produced by pulsed-field gel electrophoresis: criteria for bacterial strain typing. J Clin Microbiol (1995) 33:2233–9.[Web of Science][Medline]

10 Clermont O, Bonacorsi S, Bingen E. Rapid and simple determination of the Escherichia coli phylogenetic group. Appl Environ Microbiol (2000) 66:4555–8.[Abstract/Free Full Text]

11 Mammeri H, Nazic H, Naas T, et al. AmpC β-lactamase in an Escherichia coli clinical isolate confers resistance to expanded-spectrum cephalosporins. Antimicrob Agents Chemother (2004) 48:4050–3.[Abstract/Free Full Text]

12 Bellais S, Aubert D, Naas T, et al. Molecular and biochemical heterogeneity of class B carbapenem-hydrolyzing β-lactamases in Chryseobacterium meningosepticum. Antimicrob Agents Chemother (2000) 44:1878–86.[Abstract/Free Full Text]

13 Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing: Fifteenth Informational Supplement M100-S15 (2005) Wayne, PA, USA: CLSI.

14 Perez-Perez FJ, Hanson ND. Detection of plasmid-mediated AmpC β-lactamase genes in clinical isolate by using multiplex PCR. J Clin Microbiol (2002) 40:2153–62.[Abstract/Free Full Text]

15 Corvec S, Caroff N, Espaze E, et al. –11 mutation in the ampC promoter increasing resistance to β-lactams in a clinical Escherichia coli strain. Antimicrob Agents Chemother (2002) 46:3265–7.[Abstract/Free Full Text]

16 Mammeri H, Poirel L, Nordmann P. Extension of the hydrolysis spectrum of AmpC β-lactamase of Escherichia coli due to amino acid insertion in the H-10 helix. J Antimicrob Chemother (2007) 60:490–4.[Abstract/Free Full Text]

17 Potz N, Hope R, Warner M, et al. Prevalence and mechanisms of cephalosporin resistance in Enterobacteriaceae in London and South-East England. J Antimicrob Chemother (2006) 58:320–6.[Abstract/Free Full Text]

18 Kim JY, Jung HI, An YJ, et al. Structural basis for the extended substrate spectrum of CMY-10, a plasmid-encoded class C β-lactamase. Mol Microbiol (2006) 60:907–16.[CrossRef][Web of Science][Medline]

19 Tracz DM, Boyd DA, Hizon R, et al. ampC gene overexpression in promoter mutants of cefoxitin-resistant Escherichia coli clinical isolates. FEMS Microbiol Lett (2007) 270:265–71.[CrossRef][Web of Science][Medline]

20 Brinas L, Lantero M, de Diego I, et al. Mechanisms of resistance to expanded-spectrum cephalosporins in Escherichia coli isolates recovered in a spanish hospital. J Antimicrob Chemother (2005) 56:1107–10.[Abstract/Free Full Text]

21 Martínez-Martínez L, Pascual A, Hernández-Allés S, et al. Role of β-lactamases and porins in activities of carbapenems and cephalosporins against Klebsiella pneumoniae. Antimicrob Agents Chemother (1999) 43:1669–73.[Abstract/Free Full Text]

22 Eckert C, Gautier V, Arlet G. DNA sequence analysis of the genetic environment of various blaCTX-M genes. J Antimicrob Chemother (2006) 57:14–23.[Abstract/Free Full Text]

23 Woodford N, Reddy S, Fagan EJ, et al. Wide geographic spread of diverse acquired AmpC β-lactamases among Escherichia coli and Klebsiella spp. in the UK and Ireland. J Antimicrob Chemother (2007) 59:102–5.[Abstract/Free Full Text]

24 D’Andrea MM, Nucleo E, Luzzaro F, et al. CMY-16, a novel acquired AmpC-type β-lactamase of the CMY/LAT lineage in multifocal monophyletic isolates of Proteus mirabilis from northern Italy. Antimicrob Agents Chemother (2006) 50:618–24.[Abstract/Free Full Text]

25 Deshpande LM, Jones RN, Fritsche TR, et al. Occurrence of plasmidic AmpC type β-lactamase-mediated resistance in Escherichia coli: report from the SENTRY antimicrobial surveillance program (North America, 2004). Int J Antimicrob Agents (2006) 28:578–81.[CrossRef][Web of Science][Medline]

26 Literacka E, Empel J, Baraniak A, et al. Four variants of the Citrobacter freundii AmpC-type cephalosporinases, including novel enzymes CMY-14 and CMY-15, in a Proteus mirabilis clone widespread in Poland. Antimicrob Agents Chemother (2004) 48:4136–43.[Abstract/Free Full Text]

27 Su L-H, Chen H-L, Chia J-H, et al. Distribution of a transposon-like element carrying blaCMY-2 among Salmonella and other Enterobacteriaceae. J Antimicrob Chemother (2006) 57:424–9.[Abstract/Free Full Text]

28 Hopkins KL, Liebana E, Villa L, et al. Replicon typing of plasmids carrying CTX-M or CMY β-lactamases circulating among Salmonella and Escherichia coli isolates. Antimicrob Agents Chemother (2006) 50:3203–6.[Abstract/Free Full Text]


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