Community and hospital spread of Escherichia coli producing
CTX-M extended-spectrum b-lactamases in the UK
N. Woodford1*, M. E. Ward1, M. E. Kaufmann2, J. Turton2, E. J. Fagan1, D. James1,
A. P. Johnson1†, R. Pike1, M. Warner1, T. Cheasty3, A. Pearson4, S. Harry5, J. B. Leach6,
A. Loughrey7, J. A. Lowes8, R. E. Warren9and D. M. Livermore1
1Antibiotic Resistance Monitoring and Reference Laboratory,2Laboratory of HealthCare-Associated Infections,
and3Laboratory of Enteric Pathogens, Specialist and Reference Microbiology Division–Colindale, Health
Protection Agency, London;4Communicable Disease Surveillance Centre, Health Protection Agency, London;
5Local and Regional Services, Health Protection Agency, London;6Kingston Hospital NHS Trust, Kingston,
Surrey;7Belfast City Hospital, Belfast;8HPA South-East, Southampton Laboratory, Southampton;
9Shrewsbury and Telford Hospital NHS Trust, Shrewsbury, UK
Received 29 June 2004; returned 6 August 2004; revised 6 August 2004; accepted 10 August 2004
Objectives: During 2003, the Health Protection Agency’s Antibiotic Resistance Monitoring and Refer-
ence Laboratory began to receive isolates of Escherichia coli for confirmation of extended-spectrum
b-lactamase production with a phenotype implying a CTX-M-type b-lactamase, i.e. MICs of cefotaxime
> _8-fold higher than MICs of ceftazidime. Many were referred as being from community patients. We
examined 291 CTX-M-producing isolates from the UK and investigated the genetic basis of their
Methods: PCR was used to detect alleles encoding CTX-M enzymes and to assign these to their
blaCTX-Mphylogenetic groups. Selected alleles were sequenced. Producers were compared by analysis
of banding patterns generated by pulsed-field gel electrophoresis of XbaI-digested genomic DNA.
MICs were determined by an agar dilution method or by Etest.
Results: Of 291 CTX-M-producing E. coli isolates studied from 42 UK centres, 70 (24%) were reportedly
from community patients, many of whom had only limited recent hospital contact. Community isolates
were referred by 12 centres. Two hundred and seventy-nine (95.9%) producers contained genes encod-
ing group 1 CTX-M enzymes and 12 contained blaCTX-M-9-like alleles. An epidemic CTX-M-15-producing
strain was identified, with 110 community and inpatient isolates referred from six centres. Representa-
tives of four other major strains also produced CTX-M-15, as did several sporadic isolates examined.
Most producers were multi-resistant to fluoroquinolones, trimethoprim, tetracycline and aminoglyco-
sides as well as to non-carbapenem b-lactams.
Conclusions: CTX-M-producing E. coli are a rapidly developing problem in the UK, with CTX-M-15
particularly common. The diversity of producers and geographical scatter of referring laboratories
indicates wide dissemination of blaCTX-Mgenes. Because of the public health implications, including
for the treatment of community-acquired urinary tract infections, the spread of these strains—and
CTX-M-15 b-lactamase in particular—merits close monitoring.
Keywords: ESBLs, CTX-M b-lactamases, community infections, molecular epidemiology
*Correspondence address. ARMRL, SRMD–Colindale, Health Protection Agency, 61 Colindale Ave., London NW9 5HT, UK.
Tel: +44-(0)20-8327-7255; Fax: +44-(0)20-8327-6264; E-mail: email@example.com
†Present address. Department of Healthcare-Associated Infection and Antimicrobial Resistance, CDSC,
Health Protection Agency, London, UK
JAC vol.54 no.4 q The British Society for Antimicrobial Chemotherapy 2004; all rights reserved.
Journal of Antimicrobial Chemotherapy (2004) 54, 735–743
Advance Access publication 3 September 2004
Extended-spectrum b-lactamases (ESBLs) are the major source
of resistance to oxyimino-cephalosporins in Enterobacteriaceae.1
Most ESBLs are mutants of TEM and SHV enzymes, but
CTX-M enzymes are increasingly important.2The CTX-M types
are diverse—with more than 30 alleles divided into five distinct
phylogenetic groups—and have evolved via the genetic escape
and mutation of the chromosomal b-lactamase genes of
Kluyvera spp.2,3CTX-M enzymes predominantly hydrolyse cefo-
taxime and most are only weakly active against ceftazidime,
although some such as CTX-M-15 also have strong activity
against ceftazidime.4CTX-M enzymes have been the predomi-
nant ESBLs in Argentina for >10 years,5but have a growing dis-
tribution and prevalence in many other parts of the world,2,6
including Europe.7,8In the UK, CTX-M-type b-lactamases were
first detected in 2000–2001, with a CTX-M-9-producing isolate
of Klebsiella oxytoca in Leeds;9a nosocomial cluster of Kleb-
siella pneumoniae isolates producing a CTX-M-25-like enzyme
in Birmingham;10and four unrelated CTX-M-15-producing iso-
lates of Escherichia coli from three widely scattered hospitals.11
Most producers of TEM- and SHV-type ESBLs have been
nosocomial isolates, predominantly klebsiellae, although recent
data suggest a significant prevalence in Enterobacter spp.,12
where detection is complicated by the co-presence of AmpC.
Antibiotic Resistance Monitoring and Reference Laboratory
(ARMRL) began to receive isolates of E. coli for confirmation
of ESBL production, with a phenotype implying a CTX-M-type
b-lactamase (see Materials and methods). Of particular concern
was that many isolates were reported to be from patients attend-
ing general practice, with limited or no history of recent hospital
contact. The emergence of ESBL-producing E. coli in the com-
munity is also being seen concurrently elsewhere in Europe and
in Canada.2,13ARMRL investigated the molecular nature of
these isolates and their ESBLs in collaboration with the Labora-
tory of HealthCare-Associated Infections.
Materials and methods
Bacterial isolates and susceptibility testing
For this report, we analysed data for 287 CTX-M-producing E. coli
isolates referred to ARMRL from 42 UK centres in the period
January 2003–March 2004, and for four previously reported isolates
from 2001.11Detailed analysis of histories and outcomes for some
patient groups has been undertaken14and will be reported separately.
MICs were determined by agar dilution or by Etest, and were
interpreted using BSAC breakpoints.15A phenotype consistent with
production of a CTX-M-type b-lactamase was defined by a cefotax-
ime MIC > _8-fold higher than the ceftazidime MIC, with the MICs
of both agents reduced significantly (again > _8-fold) in the presence
of 4mg/L clavulanic acid.
Detection and characterization of blaCTX-Malleles
Isolates with a CTX-M phenotype were screened for blaCTX-M
alleles by PCR, initially with universal primers MA1 and MA2
(amplicon size 554 bp),16and then with primers specific for various
blaCTX-Mgroups.16Cycling conditions were: initial denaturation at
948C for 3min; 35 cycles of 948C for 30s, 558C for 30s and 728C
for 45s; and a final elongation at 728C for 5min (G. Arlet, personal
communication). Linkage of blaCTX-M alleles with ISEcp1-like
elements, which have been implicated in their expression and
mobilization,17–19was sought with primers PROM+ and PRECTX-
M-3B (expected amplicon size approx. 900 bp).4Cycling conditions
were: initial denaturation at 948C for 5min; 30 cycles of 948C for
25s, 528C for 40s and 728C for 50s; and a final elongation at 728C
Both strands of selected amplicons were sequenced using dye-
terminator chemistry on a CEQ8000 analyser (Beckman Coulter,
High Wycombe, UK), either directly or after cloning into pCR2.1
(Invitrogen, Paisley, UK).
After determining the genetic context of blaCTX-M-15 in three
representatives of epidemic strain A (see below), all isolates were
screened with primers 50-GCG GTA AAT CGT GGA GTG AT-30
and 50-ATT CGG CAA GTT TTT GCT GT-30, which were designed
to amplify a 400 bp fragment spanning the link between IS26 and
blaCTX-M-15. Cycling conditions were the same as those for primers
Pulsed-field gel electrophoresis (PFGE) and serotyping
Isolates were compared by PFGE of XbaI-digested genomic DNA, as
described previously,20on a CHEF DRII apparatus (Bio-Rad Labora-
tories, Hemel Hempstead, UK). A linear ramp of 5–35s was used
and gels [1.2% (w/v) agarose in 0.5?Tris/borate/EDTA buffer] were
run for 30h at 6V/cm at 128C. Banding patterns were analysed using
Belgium) and strains were defined as having PFGE profiles with
> _85% similarity (UPGMA, Dice coefficient). E. coli strain TN17, a
CTX-M-15 producer from Paris that has an IS26 element linked to its
blaCTX-M-15gene,21was included as a comparator.
In addition, all isolates were confirmed biochemically as E. coli
and serotyped using the internationally accepted serotyping scheme
based on the agglutination reactions of heat-stable lipopolysacchar-
ide somatic or ‘O’ antigen with polyclonal rabbit antisera.22The
scheme comprises somatic antigens O1–O173. Strains that could
not be serogrouped using the scheme were classed as unidentifiable
and designated ‘O ?’.
Transfer of blaCTX-Min vitro
Transfer of cefotaxime resistance by conjugation from 10 CTX-M-
producing donor isolates was attempted in broth and on agar plates,
using E. coli J62-2 (RifR) (NCTC 50170) as the recipient. The
donors were the first 10 isolates subjected to blaCTX-Msequencing.
Transconjugants were selected on nutrient agar containing cefotax-
ime (10mg/L) and rifampicin (50mg/L).
GenBank accession numbers
Sequences relevant to this work have been deposited in GenBank
under accession numbers AY462238 (strain A), AY463958 and
Detection of blaCTX-Malleles
All 291 isolates, from 42 centres, with a CTX-M phenotype con-
tained blaCTX-Malleles, as demonstrated by PCR amplicons with
the universal primers used. Of these, 279 (95.9%) yielded
products with group 1-specific primers and with primers PROM+
and PRECTX-M-3B, indicating linkage of an allele encoding a
group 1 CTX-M enzyme with an ISEcp1-like element. One hun-
dred and sixty-nine isolates yielded products of the expected size
N. Woodford et al.
(approx. 900 bp) with PROM+/PRECTX-M-3B, but the remain-
ing 110 isolates gave amplicons of approx. 1.9kb.
Twelve of 291 (4.1%) CTX-M-producing isolates, referred
from nine centres, did not yield products with primers PROM+/
PRECTX-M-3B. Amplification with group-specific primers indi-
cated the presence of blaCTX-M-9-like alleles.
PFGE analysis, serotyping and identification of an epidemic
CTX-M-producing E. coli strain
PFGE banding patterns were obtained for 287 of the 291 CTX-M-
producing E. coli isolates; DNA from four producers consistently
autodigested and no banding patterns were obtained. The 287 iso-
lates represented multiple strains (Figure 1), among which several
clusters of related isolates (> _85% similarity) were observed.
Most notable among the clusters were 110 isolates, from six
centres, that represented a single epidemic strain, designated
A. Most of these isolates were referred by centres 1 (in the West
Midlands), 2 (on the south coast of England) and 41 (in Northern
Ireland), although single isolates were referred from two hospi-
tals in London and two isolates from another Midlands centre
(Table 1). Isolates of strain A were from urine (59), blood (15),
faecal screens (13), sputa (2), wounds (1) and of unknown
Figure 1. Dendrogram to illustrate the relatedness of 287 CTX-M-producing E. coli isolates from UK centres. Major strains (n=188 isolates), defined by
PFGE profiles with > _85% similarity (UPGMA, Dice; black vertical line), are indicated (see text for details). Each gradation on the scale represents a 5%
difference in similarity. Banding patterns were not obtained from four isolates due to DNA autodigestion.
CTX-M-producing E. coli in the UK
Four other substantial clusters of isolates were noted. These
were designated: strain B, with 13 isolates from four centres;
strain C (with subtypes C and C’), with 29 isolates from nine
centres; strain D, with 21 isolates from a single centre; and strain
E (with subtypes E and E’), with 15 isolates from seven centres
Overall, 188 of 291 CTX-M producers (64.6%) belonged to
one of these five major strains, which were related at 78% simi-
larity (Figure 1). Fifty-six tested isolates of the five major strains
all serotyped as O25. The remaining isolates represented numer-
ous PFGE patterns and serotypes, although some small groups of
related isolates were observed (Figure 1 and Table 1). The four
CTX-M-15-producing E. coli isolates reported previously from
the UK11were unrelated to the major strains described here.
Among those laboratories referring >10 isolates, laboratory
1 was affected primarily by isolates of strains A and D
(91/114 isolates), laboratory 2 solely by strain A (26/26 iso-
lates), laboratory 41 by strains A and C/C’ (23/26 isolates) and
laboratory 4 partly by strains C/C’ and E/E’ (12/31 isolates).
In contrast, laboratory 43 referred diverse CTX-M-producers
with 16 different PFGE-defined strains among 18 referred iso-
lates (Table 1).
E. coli strain TN17, a CTX-M-15 producer from France,21
was distinct from all major and other UK CTX-M-producing
strains (data not shown).
blaCTX-MPCR in relation to PFGE
Twenty-five group 1 alleles were sequenced. Representatives of
each of the five major strains (A–E) identified by PFGE
produced CTX-M-15 b-lactamase. In 20 isolates from 17
centres, including representatives of strains B, C/C’, D and E/E’,
blaCTX-M-15 was linked directly to an upstream ISEcp1-like
element (e.g. GenBank AY463958). In contrast, all isolates
belonging to epidemic strain A yielded approx. 1.9kb amplicons
with primers PROM+/PRECTX-M-3B. In the three isolates of
strain A sequenced, from different centres, an IS26 element was
found within the terminal inverted repeat of the ISEcpI-like
element upstream of blaCTX-M-15(Figure 2), thus separating the
blaCTX-M-15 allele from its usual promoter. One of the three
sequenced representatives of strain A possessed a T ! C poly-
morphism in the spacer region between ISEcp1 and blaCTX-M-15
(GenBank AY462238; Figure 2).
The IS26 element in strain A was flanked by 8 bp direct
repeats of ISEcp1 DNA, consistent with target site duplication
following a transposition event (Figure 2). Based on this
arrangement, a PCR assay was designed to amplify a 400 bp
fragment spanning the link between IS26 and blaCTX-M-15. Mem-
bers of strain A yielded amplicons of the expected size and most
other producers failed to yield amplicons, but four isolates
from centre 1, which were related by PFGE, gave products of
Table 1. Details of CTX-M-producing E. coli isolates from 42 UK centres, including instances of possible community
1 W Mids114 17 A (70), B (3), C/C’ (1),
D (21), E/E’ (3)
C/C’ (9), E/E’ (3)
A (10), C/C’ (13)
A (1), B (1)
C/C’ (1), E/E’ (1)
C/C’ (1), E/E’ (1)
C/C’ (4), E/E’ (2)
aReferring laboratory code numbers exceed 42 because the presented data were extracted from a larger database.
bStrains were defined as isolates with PFGE banding patterns showing > _85% similarity. No PFGE profiles were obtained for 4/291
isolates due to DNA autodigestion.
cIsolates considered by the referring laboratory to have been community-derived.
N. Woodford et al.
approx. 800 bp. Sequencing of a representative isolate again
revealed IS26 inserted within the ISEcp1-like element but, in
this strain, the insertion was located upstream of the blaCTX-M
promoter (and the PROM+ primer; GenBank AY536259).
A single PFGE-distinct isolate containing a group 1 allele and
selected for sequencing produced CTX-M-3, which differs from
CTX-M-15 by a single amino acid, Asp-240 ! Gly.4
All 12 producers of CTX-M-9-like enzymes had distinct
PFGE banding patterns, including in those instances when more
than one such isolate was received from a centre.
In addition to extended-spectrum cephalosporins, most CTX-M
producers were resistant to ciprofloxacin (MICs>8mg/L) and
trimethoprim (MICs>2mg/L). All remained susceptible to
carbapenems, and the MICs of mecillinam were also low
(geometric mean MIC 1.5mg/L). However, susceptibility to ami-
noglycosides and b-lactamase inhibitor combinations was vari-
able between and within strains, but with resistance frequent
(Tables 2 and 3).
When compared with other producers of group 1 CTX-M
enzymes, isolates of epidemic strain A were less resistant to
cefotaxime (geometric mean MIC 37.3mg/L versus 81.3mg/L),
ceftazidime (geometric mean MIC 2.9mg/L versus 30.4mg/L),
241.2mg/L) and cefalexin (geometric mean MIC 49.7mg/L
versus 256mg/L), and were markedly more susceptible to gen-
tamicin (geometric mean MIC 1.1mg/L versus 17.6mg/L).
Producers of CTX-M-9-like enzymes were also less resistant
(Table 2). All tested isolates belonging to epidemic strain A
were resistant to ciprofloxacin and trimethoprim, but remained
susceptible to nitrofurantoin (MICs 8mg/L) and fosfomycin
(MICs< _2mg/L), as also did most isolates belonging to other
strains (Table 3). Limited studies with co-trimoxazole and tetra-
cycline suggested that resistance to these agents was frequent
among CTX-M producers (data not shown).
Community-associated CTX-M-producing E. coli
Seventy (24%) CTX-M-producing isolates, mainly from urine
specimens (52/65 with a stated origin), were considered by 12
referring centres to have been derived from samples obtained
from patients in the community, although we cannot exclude the
possibility that prior hospital contact had not been indicated to
the laboratory that referred isolates to ARMRL. These isolates
had diverse PFGE banding patterns, but representatives of each
major strain were referred from community patients: 25 isolates
belonged to epidemic strain A; one to strain B; 10 to strain
C/C’; five to strain D; and four to strain E/E’. Among commu-
nity-acquired CTX-M-producers, 67 produced group 1 enzymes
and three produced CTX-M-9-like enzymes. The community iso-
lates were as multi-resistant as hospital isolates.
Transfer of blaCTX-Min vitro
Transfer of CTX-M production was not achieved from 10 poten-
tial donor isolates tested, including representatives of strains A,
B, D and E.
ESBLs belonging to the CTX-M family were first reported in
the UK in 2003, with the isolates having been collected in
Subsequently, CTX-M-producing strains of
E. coli have emerged as a rapidly developing problem. As of
July 2004, ARMRL had received almost 500 isolates from >70
centres located in all nine of the English Government Office
Regions, as well as in Wales, Scotland and Northern Ireland. In
many instances, referred isolates represent only a proportion of
isolates from these centres, and were referred as examples of the
strains. In this study, describing the first 291 E. coli producers
referred to us, most isolates (95.9%) produced enzymes in
phylogenetic group 1, particularly CTX-M-15, although a few
isolates (4.1%) that produced CTX-M-9-like enzymes were also
found. Since 2003, we have also detected CTX-M-15 in UK
isolates of K. pneumoniae and Proteus mirabilis, and CTX-M-9
in an isolate of Enterobacter (N. Woodford, M. E. Ward,
E. J. Fagan & D. M. Livermore, unpublished data).
CTX-M-15 was first reported in 2001 in E. coli, K. pneumo-
niae and Enterobacter aerogenes from India,17but has now been
widely reported, including from Bulgaria, Canada, France,
Italy, Japan, Poland, Romania, Russia and Turkey.2,6It is
Figure 2. Schematic representation of the arrangment of IS elements upstream of the blaCTX-M-15allele in epidemic E. coli strain A showing the presence of
an IS26 element between the structural gene and its usual promoter (located within terminal inverted repeat of an ISEcp1-like element).17,18
CTX-M-producing E. coli in the UK
Table 2. Susceptibilities of CTX-M-producing E. coli from the UK to b-lactams, alone and in combination with b-lactamase inhibitors
RADLEX MEC PIPTZPIPMMEM
no. isolates tested 61
other major strainsa
no. isolates tested 55
no. isolates tested 57
0.125–0.5 32–256 0.5–2
No. isolates tested
16–256 0.06–0.25 1–32
AMP, ampicillin; AMC, co-amoxiclav; CTX, cefotaxime; CAZ, ceftazidime; CLA, clavulanic acid; CPD, cefpodoxime; RAD, cefradine; LEX, cefalexin; MEC, mecillinam; PIP, piperacillin; TZP,
piperacillin/tazobactam; IPM, imipenem; MEM, meropenem.
aDefined by PFGE (see text and Figure 1)
N. Woodford et al.
closely-related to CTX-M-3, differing by a single amino acid
substitution (Asp-240 ! Gly). CTX-M-3 has been reported from
many countries, including Poland, France, Japan, Taiwan,
Greece and China.2The same Asp-240 ! Gly substitution
occurs in other CTX-M enzymes, such as CTX-M-16, -25, -27,
-28, -29, -30 and -32, and, where kinetic data are available, has
been associated with increased catalytic activity against ceftazi-
dime.4,6,17,23,24In this study, the expression of phenotypic ceftazi-
dime resistance—previously recommended as a single screen for
ESBLs—may have biased detection in diagnostic laboratories,
and referral for reference testing, in favour of those CTX-M
enzymes, such as CTX-M-15, that are most active against cefta-
zidime. Despite this, the MICs of cephalosporins for isolates of
strain A, an epidemic CTX-M-15-producing E. coli strain with
>100 individual patient isolates from six UK centres, were con-
sistently lower than for other CTX-M-15 producers, and many
isolates would be considered susceptible to ceftazidime by
BSAC criteria (MICs< _2mg/L).15As emphasized in several
recent guidance updates,10,11,25initial laboratory screens for
ESBL-producing Enterobacteriaceae should be undertaken using
both cefotaxime and ceftazidime or, if a single indicator is pre-
ferred, using cefpodoxime; resistance to cefotaxime and cefpo-
doxime was clear in all producers.
The blaCTX-M-15allele is located on plasmids and is associ-
ated with an upstream copy of an ISEcp1-like element;17similar
genetic arrangements have been reported for several other
blaCTX-Malleles.2,18,19Indeed, the ?35 and ?10 promoter regions
necessary for expression of these alleles are located within the
30end of the ISEcp1-like insertion sequences.16–18We have not
yet investigated comprehensively whether the blaCTX-Malleles
in the numerous isolates reported here are plasmid-mediated
(though transfer was not detected in the few representative iso-
lates where conjugation was studied), but those encoding group
1 enzymes were all associated with an upstream ISEcp1-like
element. Interestingly, isolates of strain A had an IS26 element
within the terminal inverted repeat of their ISEcp1-like element.
It seems likely that separation by IS26 of blaCTX-M-15from its
usual promoter was responsible for the lower cephalosporin
MICs for strain A, as this organization may diminish transcrip-
tion efficiency. However, it is unclear why the MICs of b-lacta-
mase inhibitor combinations were not also lower for strain A as
these should also reflect enzyme quantity. Further molecular
studies are planned to identify the functional promoter of
blaCTX-M-15in this strain, to measure directly enzyme expression
and to determine the reasons for the strain’s susceptibility to
The presence of an IS26 element served, alongside the PFGE
banding pattern, as a useful molecular marker for isolates
belonging to epidemic strain A, and an ‘IS26-blaCTX-M link’
PCR assay was developed to allow rapid screening. Using this
assay, we also identified four isolates, from a single centre,
belonging to a second strain in which a copy of IS26 had
inserted further upstream of blaCTX-M-15. This insertion sequence
has also been associated with blaCTX-Malleles in E. coli isolates
from Paris, France.16,21Nevertheless, PFGE confirmed that a
representative of these French strains, TN17, which also pro-
duces CTX-M-15,21was unrelated to any CTX-M-producing
strain from the UK. Thus, although the presence of the IS26-
blaCTX-Mlink was a useful additional criterion for characterizing
strain A,such linkagedoes
In addition to epidemic strain A, four other major CTX-
M-15-producing strains were defined in this study on the basis
of their PFGE banding patterns. Representative isolates of all
major strains belonged to the same serotype, O25, and may have
common ancestry. It is interesting that the five major strains
appeared more closely related to each other (78% similarity)
than to many of the other producers. Although strain D was only
Table 3. Susceptibilities of CTX-M-producing E. coli from the UK to non-b-lactam antibiotics
Enzyme produced/strain CIPAMKGENTMPNIT FOF
no. isolates tested
other major strainsa
no. isolates tested
no. isolates tested
No. isolates tested
CIP, ciprofloxacin; AMK, amikacin; GEN, gentamicin; TMP, trimethoprim; NIT, nitrofurantoin; FOF, fosfomycin.
aDefined by PFGE (see text and Figure 1).
CTX-M-producing E. coli in the UK
referred from one centre, the other major strains were referred
from multiple locations. A cluster of cases involving an O25
ESBL-producing strain of E. coli was recently reported in the
Our data indicate that CTX-M-producing E. coli have become
widely scattered throughout the UK, and that the underlying epi-
demiology is complex; it involves not only the spread of
epidemic and other major strains between centres, but also
instances of intra-hospital spread of minor strains and, poten-
tially, horizontal transfer of plasmids or integrons carrying
blaCTX-Malleles. Some of the centres that referred large numbers
of isolates were affected largely by one or more of the major
strains, whereas others, particularly around London, referred
more diverse isolates.
The recognition of CTX-M-producing community strains is a
cause of concern in many other countries besides the UK.2,13In
the current analysis, almost one quarter of UK isolates were
derived from samples received from the community. Commu-
nity-derived isolates included CTX-M-15 producers belonging to
all of the major strains, including epidemic strain A, and produ-
cers of CTX-M-9-like enzymes. CTX-M-9-related enzymes have
also been reported recently in non-hospitalized patients in Spain,
although, here too, many patients had recent hospital contact.27
Clearly the epidemiology of CTX-M enzymes in the UK, as
elsewhere, is very different from that of TEM- and SHV-derived
ESBLs; specifically, CTX-M enzymes are not limited mainly to
nosocomial klebsiellae, and their potential for spread beyond the
The occurrence of CTX-M enzymes in the community pre-
sents treatment problems. Among oral agents licensed for treat-
ment of urinary tract infection (UTI), only nitrofurantoin and
fosfomycin were generally active and neither is ideal. Nitrofur-
antoin is unsuitable for empirical use, being inactive against
Proteeae; while fosfomycin is not marketed in the UK. Other
oral treatment options that may deserve investigation—at least
in UTI—include mecillinam, which was surprisingly active
in vitro, and simultaneous administration of co-amoxiclav and
a third-generation cephalosporin. For more severe infections,
carbapenems appear to be the only rational choice, with their
empirical use being considered in settings and locales where
CTX-M producers appear likely, e.g. in a patient with a
community-acquired bacteraemia following a poorly-responsive
In summary, because of the significant public health impli-
cations, including for the treatment of community-acquired urin-
ary tract infections, the spread of CTX-M producers in general,
and of epidemic and non-epidemic strains with CTX-M-15 in
particular, merits close monitoring.
We are grateful to our many colleagues in clinical microbiology
laboratories throughout the UK who refer E. coli isolates for
confirmation of ESBL production. Thanks also to Dr Guillaume
Arlet (Laboratoire de Bacte ´riologie, Universite ´ Paris) for provid-
ing strain TN17. Work by D. M. L. and N. W. on emerging
b-lactamases is supported, in part, by the EU/FP6-funded
COBRA project (6-PCRD LSHM-CT-2003–503–335). Part of
this work was presented at the 14th ECCMID (Prague, May
2004; poster P 758).
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3. Poirel, L., Kampfer, P. & Nordmann, P. (2002). Chromosome-
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