JAC Advance Access originally published online on May 30, 2006
Journal of Antimicrobial Chemotherapy 2006 58(2):320-326; doi:10.1093/jac/dkl217
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Prevalence and mechanisms of cephalosporin resistance in Enterobacteriaceae in London and South-East England
1 Healthcare-Associated Infection and Antimicrobial Resistance Department, Health Protection Agency Centre for Infections 61 Colindale Avenue, London NW9 5EQ, UK 2 Antibiotic Resistance Monitoring and Reference Laboratory, Health Protection Agency Centre for Infections 61 Colindale Avenue, London NW9 5EQ, UK
*Corresponding author. Tel: +44-208-327-7217; Fax: +44-208-205-9185; E-mail: nicola.potz{at}HPA.org.uk
Received 20 January 2006; returned 13 March 2006; revised 5 May 2006; accepted 8 May 2006
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Abstract |
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Objectives: To investigate the molecular epidemiology of Enterobacteriaceae producing extended-spectrum ß-lactamases (ESBLs) in London and South-East England.
Methods: A prospective study involving 16 hospital microbiology laboratories in London and South-East England was undertaken over a 12 week period. Each laboratory submitted up to 100 consecutive cephalosporin-resistant Enterobacteriaceae isolates judged clinically significant by microbiology staff. Centralized testing was undertaken to confirm organism identification and cephalosporin resistance and to analyse resistance mechanisms.
Results: The predominant mechanism of cephalosporin resistance in isolates from both hospital and community settings was the production of CTX-M-type ESBLs, with CTX-M-producing Escherichia coli as the most numerous resistant organism overall. Other major mechanisms of cephalosporin resistance included production of non-CTX-M ESBLs and AmpC ß-lactamases. Most ESBL (both CTX-M and non-CTX-M) producers were multiply resistant to non-ß-lactam antibiotics, including trimethoprim, ciprofloxacin and gentamicin.
Conclusions: CTX-M enzymes, which were unrecorded in the UK prior to 2000, have become the major mechanism of cephalosporin resistance in Enterobacteriaceae in South-East England. E. coli has overtaken Klebsiella and Enterobacter spp. to become the major host for ESBLs. Due to the multiple antibiotic resistance exhibited by many ESBL-producers, these changes have major implications for antimicrobial therapy.
Keywords: ESBLs , CTX-M enzymes , E. coli
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Introduction |
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Oxyimino-cephalosporins are the ‘workhorse’ antibiotics in many UK hospitals and are widely used in the therapy of urinary, respiratory and intra-abdominal infections. Inevitably, this usage exerts a great selection pressure for resistance which, among bacteria of the family Enterobacteriaceae, most often arises via hyperproduction of chromosomal ‘AmpC’ ß-lactamases in Enterobacter spp. and Citrobacter freundii or by the acquisition of transferable extended-spectrum ß-lactamases (ESBLs).1
Until 2003, most ESBL-positive bacteria referred to the Health Protection Agency's Centre for Infections were Klebsiella spp. with mutant forms of the long-known TEM and SHV penicillinases. These mutations modify the enzyme's active site, allowing attack on the cephalosporins, which are stable to the classical penicillinases. The producers were almost exclusively nosocomial, often from specialist units.2–4
Since 2003, in contrast, multidrug-resistant ESBL-producing Escherichia coli (especially) and Klebsiella pneumoniae have been repeatedly confirmed in non-hospitalized patients, both in the UK and elsewhere in Europe.5,6 Many of these have CTX-M rather than mutant TEM or SHV ESBLs. CTX-M enzymes represent a distinct class of ESBLs, which arose by gene escape from a medically unimportant genus, Kluyvera.7 Molecular typing reveals that some E. coli isolates with CTX-M enzymes belong to widely disseminated clones, whereas others are diverse.5,8 In either case, most producer isolates are multiresistant not only to ß-lactams but also to quinolones, trimethoprim, tetracyclines and most aminoglycosides. This complicates therapy, sometimes necessitating hospitalization of patients for infections that would otherwise have been managed with oral antibiotics in the community.
The molecular epidemiology, incidence and clinical features of these organisms have not been adequately studied before in the UK and were investigated here for London and South-East England.
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Materials and methods |
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Collection of bacteria
A total of 16 hospital microbiology laboratories participated, 8 in London and 8 elsewhere in South-East England (see Acknowledgements). These served urban and rural areas and were attached to hospitals of various sizes. Each laboratory was asked to test all clinically significant isolates of Enterobacteriaceae against either cefpodoxime or both cefotaxime and ceftazidime by their routine method and to submit isolates resistant to any of these agents to the Antibiotic Resistance Monitoring and Reference Laboratory (ARMRL). In addition, those laboratories using CLSI (formerly NCCLS) methods were asked to submit all Enterobacteriaceae giving zones smaller than the ESBL screening criteria, not only those found resistant. Laboratories using automated (Vitek or Phoenix) systems sent isolates indicated by the expert system to have an ESBL and any found resistant to cefpodoxime, ceftazidime or cefotaxime. Repeat isolates from the same patient within 30 days were excluded.
Participating laboratories identified isolates using their routine methods; the provisional identification of ‘coliform’ was considered acceptable for referred specimens. The study commenced on 1 August 2004 for a 12 week period. A maximum of 100 submissions was allowed per laboratory. For each isolate submitted, patient demographic and microbiology laboratory information were collected. Any isolate submitted without this information was excluded. Data detailing the number of Enterobacteriaceae isolates tested in each laboratory during the study period were collected and sub-divided by specimen type and organism where possible.
Central testing
Isolates received by ARMRL were identified to the species level using Chromogenic UTI agar (Oxoid, Basingstoke, UK) to distinguish E. coli and using API20E strips (bioMérieux, Marcy l'Étoile, France) to identify non-E. coli isolates. Antibiotic susceptibility was assessed by determination of MICs by the British Society for Antimicrobial Chemotherapy (BSAC) method.9 For those agents where breakpoints are only available for urinary isolates, only urinary isolates were analysed. For agents with differing breakpoints for urinary and non-urinary isolates, the two groups were analysed separately using the appropriate breakpoints. Cephalosporins were tested with and without 4 mg/L clavulanic acid, and isolates where clavulanate reduced the cephalosporin MIC 
8-fold were inferred to have ESBLs, except in the case of those Klebsiella oxytoca isolates with resistance profiles that otherwise implied hyperproduction of K1 enzyme.10,11 All isolates interpreted as being ESBL-producers underwent a PCR for blaCTX-M groups.12 AmpC-production was inferred by interpretive reading using identification and MIC data10 and by the detection of plasmid-mediated genes using a multiplex PCR.13 Outer membrane proteins were examined by SDS–PAGE14 for a number of isolates where, based on their antibiogram, impermeability was suspected to contribute to resistance.
Statistical methods
2 Tests to assess associations between pairs of categorical variables were calculated using STATA v8.2. Patients with unrecorded age or sex were excluded from tests for associations with these factors. Isolates were categorized as either community-associated (those referred by GPs or from Accident and Emergency Departments) or hospital-associated (in-patient and out-patient isolates). Specimen type categories used for analyses were blood, urine and other.
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Results |
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Cephalosporin-resistance mechanisms
Of 1253 isolates submitted to the ARMRL as cephalosporin resistant, 1122 (89.5%) were confirmed as resistant by MIC determination to at least one of cefpodoxime, cefotaxime or ceftazidime. Of these, 51.2% were E. coli, 21.7% Klebsiella spp. and 17.9% Enterobacter spp. (Table 1) along with smaller proportions of Citrobacter, Hafnia, Morganella, Pantoea, Proteus and Serratia spp. The remaining 131 isolates failed to grow, were contaminated on arrival, were not Enterobacteriaceae or were not confirmed as resistant to any oxyimino-cephalosporin.
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Cephalosporin resistance was attributed to the following mechanisms, singularly or in combination: (i) production of a CTX-M-type ESBL, based on positive cephalosporin/clavulanate synergy tests and a PCR product with universal primers for blaCTX-M; (ii) production of a non-CTX-M ESBL, based on positive synergy tests but no PCR product with primers for blaCTX-M; (iii) production of AmpC ß-lactamase, based on resistance to cefoxitin, cefotaxime and ceftazidime, but not cefepime and cefpirome, without cephalosporin/clavulanate synergy; and (iv) other resistance mechanisms. Almost half the isolates confirmed as cephalosporin resistant (502, 44.7%) produced CTX-M ESBLs, compared with 149 (13.3%) that had other ESBLs and 190 (16.9%) with high-level AmpC ß-lactamase. Two hundred and eighty-three isolates (25.2%) had mechanisms other than ESBL or AmpC enzymes. These mostly (n = 273) comprised isolates with borderline resistance (i.e. MICs one or two dilutions above the breakpoint) to only one or two cephalosporins (most often cefpodoxime), but also included 11 K. oxytoca and Proteus vulgaris inferred to hyperproduce their chromosomal ß-lactamases.
Of the 574 E. coli, 292 (50.9%) had CTX-M enzymes and 88 (15.3%) had other ESBLs (Table 1); most others (153, 26.7%) had only borderline cephalosporin resistance but 41 hyperproduced AmpC enzymes, either probably chromosomal (28) or known acquired types with genes detected in a multiplex PCR (13). Of 243 cephalosporin-resistant klebsiellae, 199 (81.9%) had CTX-M enzymes and 27 (11.1%) other ESBLs. Two had an acquired AmpC enzyme along with a non-CTX-M ESBL and eight (3.3%) showed only borderline cephalosporin resistance. Nine (3.7%) were K. oxytoca with a phenotype indicating a hyperproduced chromosomal K1 ß-lactamase. CTX-M enzymes were much less common in Enterobacter spp. and Citrobacter spp., accounting for 4.0% (8/201) and 4.1% (2/49) of cephalosporin resistance, respectively, with most cephalosporin resistance due to hyperproduced AmpC enzymes (46.3% and 57.1%, respectively) or non-CTX-M ESBLs (12.9% in Enterobacter spp. and 6.1% in Citrobacter spp). Two enterobacters had both a hyperproduced AmpC enzyme and a non-CTX-M ESBL. Borderline cephalosporin resistance, generally affecting cefpodoxime but not cefotaxime and ceftazidime, was seen in 74 (36.8%) Enterobacter spp. and 16 (32.7%) Citrobacter spp.
Prevalence of cephalosporin resistance
Since only cephalosporin-resistant Enterobacteriaceae were collected and different sites used different laboratory and testing systems the calculation of denominators was complicated. Only 4 of 16 laboratories identified all Enterobacteriaceae isolates to the species level and these comprised the minority using automated Phoenix or Vitek systems. Based on these laboratories alone, it was estimated that 2.5% of all E. coli were cephalosporin resistant and that 1.1% had CTX-M enzymes (Table 2). Cephalosporin-resistance rates for Klebsiella and Enterobacter spp. were 9.7% and 15.7%, respectively, with CTX-M and other ESBLs present in 7.6% of the Klebsiella spp. and derepressed AmpC in only 6.7% of Enterobacter spp.
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Twelve laboratories provided data on specimen type for all Enterobacteriaceae isolates (often identified only as ‘coliforms’) tested during the collection period, but the only two specimen types consistently categorized by all laboratories were urine and blood. Of 18 685 urinary isolates tested during the study period, 305 (1.6%) produced CTX-M enzymes, 109 (0.6%) had other ESBLs and 72 (0.4%) hyperproduced AmpC enzymes. The rate of cephalosporin resistance was significantly higher (P = 0.001) amongst the 567 blood isolates tested, at 5.8%; rates for individual mechanisms among blood isolates were 3.4% (CTX-M enzymes), 0.7% (other ESBLs) and 0.7% (hyperproduced AmpC enzymes).
All 16 laboratories participating in the study submitted isolates of E. coli and K. pneumoniae with CTX-M ESBLs, and the proportion of CTX-M-producers among all Enterobacteriaceae tested varied from 0.6% to 4.3% among the 12 laboratories with known testing denominators (Figure 1); the corresponding range for non-CTX-M ESBLs was 0.1% to 2.7%. There was no relationship between prevalence rates for CTX-M and non-CTX-M ESBLs.
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Multiresistance among cephalosporin-resistant isolates
Most Enterobacteriaceae with CTX-M or non-CTX-M ESBLs were also resistant to ciprofloxacin, trimethoprim and gentamicin (Table 3). Nitrofurantoin remained active against many of the ESBL-producing E. coli but not Klebsiella spp. Mecillinam appeared active against many ESBL-producers of both genera but its MICs are prone to inoculum effects and its value against infections due to ESBL-producers is undetermined.15 Enterobacteriaceae with a derepressed AmpC were less often resistant to non-ß-lactam antibiotics than were ESBL-producers, probably because hyperproduction of AmpC is often a consequence of chromosomal mutation, at least in Enterobacter and Citrobacter spp., rather than the presence of a multiresistance plasmid.
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None of the 1122 isolates with confirmed cephalosporin resistance was resistant to the carbapenems imipenem and meropenem but a few required ertapenem MICs of
4 mg/L. Specifically, six AmpC-producing Enterobacter spp., one E. coli with an ESBL and two K. pneumoniae with ESBLs required ertapenem MICs of 4 to >16 mg/L. Examination revealed that these isolates had lost outer membrane proteins in the range typical for porins (31–45 kDa),14 implying permeability lesions (not shown). Descriptive epidemiology of source patients
Among 1116 cephalosporin-resistant isolates for which the sex of the source patient was available, 36.0% (402) were from males. This proportion did not significantly change with the mechanism of resistance (Table 4). The mean patient age was 67.1 years (range <1–100), with 72.1% of patients aged over 60 years, again varying insignificantly with the resistance mechanism.
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Table 5 shows the distribution of isolates submitted by the participating laboratories, grouped by hospital- or community-association. Almost half (49.4%) of the cephalosporin resistance in hospital-associated isolates was due to CTX-M enzymes. CTX-M enzymes were also the dominant cephalosporin-resistance mechanism in community-based isolates, but to a significantly lesser degree (37.9%, P < 0.001). Prevalence rates of cephalosporin resistance due to non-CTX-M ESBLs were similar in both environments (13.3% and 13.2%, respectively). If borderline resistance without defined mechanisms was discounted, the proportions of cephalosporin-resistant isolates with CTX-M enzymes rose to 59.8% and 57.7% among hospital-associated and community-based isolates, respectively.
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Until at least 2001, ESBLs in the UK were mostly found in nosocomial Klebsiella spp. and were virtually all TEM and SHV mutants. However, CTX-M ESBLs were first detected in the UK in 2000 and their spread has been gathering pace since then, both in the hospital and community settings.4,5,16 This work, the first prospective study of ESBLs in clinically significant Enterobacteriaceae in the UK, confirms their now wide distribution and dominance among cephalosporin-resistance mechanisms amongst the Enterobacteriaceae. Over 65% of cephalosporin-resistant E. coli harboured ESBLs, and CTX-M ESBLs outnumbered non-CTX ESBLs by more than 10:3 in this species. These proportions were even higher among Klebsiella spp. at 93% and 7:1, respectively.
ESBLs, while historically restricted to hospital-associated isolates, were shown here to now occur in significant numbers among isolates from the community, defined here as those submitted by GPs or by A&E departments. The primary source of such isolates remains uncertain, with both hospital exposure and food being possible candidates. Recent studies from both the UK8 and Spain6 point to growing gut carriage of ESBL-producing Enterobacteriaceae outside of hospitals. Carriage by food animals has also been noted, though it appears uncommon in the UK and has not been shown to involve the particular CTX-M-producing E. coli clones that are most prevalent in humans.17
For all mechanisms of cephalosporin resistance, the mean age of patients was >60 years and most were females. Similar age and sex distributions for patients with ESBL-producing bacteria have been seen in case–control studies investigating ESBL production in E. coli and Klebsiella spp. in non-hospitalized patients,18,19 and a patient age of over 60 years was shown to be an independent risk factor for infection by ESBL-producing bacteria.18,19
ESBL-producing Enterobacteriaceae were seen in greater proportions in blood than urine. This may reflect inadequate treatment of those urinary tract infections where an ESBL-producer is present, leading to an ‘overspill’ bacteraemia. A BSAC study of blood pathogens in the UK in 2002 reported ESBLs in 3.2% of E. coli and 5.0% of Klebsiella spp.20 By 2004 these figures had increased to 6.0% and 18.3%, respectively.21 Differences in the rates observed here may be due to the smaller numbers of isolates collected in the BSAC study or because it covers the whole of the British Isles, not just South-East England. No comparable UK data are published on the proportion of urinary Enterobacteriaceae isolates harbouring ESBLs, though one abstract relating to Leeds22 reported 258/2246 urinary isolates (11.5%) resistant to cefpodoxime, with 83 (3.7%) having ESBLs. There has also been an increase in ciprofloxacin resistance in recent years in E. coli, Klebsiella and Enterobacter spp., with a dramatic increase in E. coli in particular since 2000 from just over 4% in that year to almost 16% in 2004.23,24
E. coli has also proved to be a surprisingly frequent host for AmpC-mediated resistance, accounting for over a fifth of the isolates with high-level AmpC activity in this study. At least one-third of these isolates had plasmid-coded AmpC genes of types originating from C. freundii (data not shown),13 but the majority apparently had non-plasmidic AmpC activity probably arising via overproduction of chromosomal enzymes. Predictably, AmpC hyperproduction was commonest in Enterobacter spp., where it arises readily by a simple high frequency mutation.1
Multiresistance was common among the organisms with ESBLs, regardless of species and enzyme type. This association is well recognized and is partly because ESBLs are mostly encoded by multiresistance plasmids. Treatment with any of several antibiotics might therefore select for organisms with ESBLs. Recent studies on infections with ESBL-producers outside of hospitals identify prior treatment with cephalosporins, quinolones and penicillins as risk factors, along with recent hospitalization.25 Inadequate initial antimicrobial therapy is strongly associated with multidrug resistance and is an independent risk factor for mortality in severe infections due to ESBL-producing E. coli and Klebsiella spp.26 While resistance to multiple antibiotics limits the therapeutic options for infections with ESBL-producing organisms, none of the isolates in the present study was resistant to imipenem or meropenem and very few were resistant to ertapenem. It is therefore comforting to observe the continuing efficacy of the carbapenems against these problematic isolates, though it is disturbing that the changing nature of resistance in E. coli (especially) will force more front-line use of these agents.
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N. A. C. P. received funds from Merck, Sharp & Dohme to present some of these data at the 15th ECCMID, Copenhagen, 2005. D. M. L. and A. P. J. have received research grants and/or speaking honoraria from manufacturers of carbapenem agents. D. M. L. has shares, inter alia, in GlaxoSmithKline and AstraZeneca.
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Acknowledgements |
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We thank members of the Steering Group (G. Duckworth, HCAI & AMR Dept., HPA, London; G. Fraser, HPA London; E. Haworth, HPA South-East), Andre Charlett for his advice on statistical analysis and Sokei Harry for his input into the early stages of the study. We also express our thanks and appreciation to the following colleagues at participating laboratories, without whom this study would not have been possible:
Ashford (Kent) Microbiology Laboratory: M. Baker, G. Calver; Epsom Hospital: S. Chambers, P. Jackson, R. Prosser; Frimley Park Hospital, Camberley: R. Sharkey; Harold Wood Hospital: R. Reeve; Hillingdon Hospital: P. Kumari; Kingston Hospital: J. Leach, S. Patel; Milton Keynes General Hospital: D. Bardell; Northwick Park Hospital, Harrow: A. O'Connor, R. Wall; Royal Free Hospital, London: I. Balakrishnan, A. Ghafur; Royal Hampshire County Hospital, Winchester: M. Dryden, M. Grover, S. Lowden; Queen Elizabeth Hospital, Woolwich: M. Millett, G. Vosper; St Peter's Hospital, Chertsey: S. Baillie; St Thomas Hospital, London: G. French, K. Shannon; Southampton HPA Laboratory: H. Humphrey; University College Hospital, London: C. Palmer, N. Shetty; Worthing Hospital: H. Plumb. This study was partly sponsored by Merck, Sharp & Dohme (US & UK).
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16 Health Protection Agency. Infections with Organisms Carrying Extended-Spectrum ß-Lactamases in the Community: First Report CDR Wkly 2003; 13(32). http://www.hpa.org.uk/cdr/PDFfiles/2003/cdr3203.pdf (28 March 2006, date last accessed).
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21 Reynolds R, Hope R, Colman M, et al. Rising ESBL production and ciprofloxacin resistance in invasive Enterobacteriaceae in the UK and Ireland. Abstracts of the Forty-fifth Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, 2006(American Society for Microbiology, Washington, DC, USA) Abstract C2-778, p. 117.
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