Spread of multiresistance and extended-spectrum ß-lactamases amongst urinary Escherichia coli in Oxford, UK

David H. Wyllie1,*, Emma Baxter2, Marcus Morgan2 and Ian C. J. W. Bowler2

1 Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford, UK; 2 Department of Microbiology, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK


* Corresponding author. Tel: +44-1865-221226; Fax: +44-1865-764192; E-mail: david.wyllie{at}ndcls.ox.ac.uk

Keywords: E. coli , epidemiology , ESBLs , ciprofloxacin

Sir,

Escherichia coli is the commonest trigger for urinary tract infection, and is an important cause of bacteraemia. In the UK, two worrying trends in E. coli antimicrobial resistance have been described recently: the increase in ciprofloxacin resistance in bloodstream isolates,1 and the isolation in multiple areas of the UK of strains of E. coli expressing a recently emerged strain of ß-lactamase, designated CTX-M.2 The emergence of CTX-M enzymes, which can be missed by the laboratory tests formerly employed, prompted new laboratory guidelines that stress the role of the cephalosporin cefpodoxime when screening for CTX-M.3

Between 1998 and the end of 2004, the microbiology laboratory in the John Radcliffe Hospital reported lactose-fermenting, indole-positive Gram-negative bacilli growing on CLED agar as E. coli, with first line susceptibility testing by disc diffusion using DST agar (Oxoid) and cefradine, amoxicillin, co-amoxiclav, nitrofurantoin, ciprofloxacin and trimethoprim as first-line sensitivities.

We analysed trends in urinary resistance not by studying the proportions of individual antibiotic resistance but by a graphical method designed to recognize emerging resistance patterns (‘antibiograms’). A score is given to each antibiogram of n antibiotics, and the scores plotted against time. The antibiogram score is the sum of scores assigned to individual susceptibility results, where each antibiotic resistance scores 2i, and i varies from 0, for the most commonly resistant antibiotic, to n-1 for the antibiotic least commonly resistant in the isolates of interest. The result is an integer between 0 and 2n-1, with high values for uncommon resistance patterns. This method, applied to our first-line urine sensitivities, assigned resistant isolates scores of 1 for trimethoprim, 2 for amoxicillin, 4 for cefradine, 8 for nitrofurantoin, 16 for co-amoxiclav and 32 for ciprofloxacin. Increasing numbers of isolates resistant to amoxicillin, trimethoprim and ciprofloxacin appeared from early 2002 onwards; some isolates also appeared that were resistant to co-amoxiclav and cefradine in vitro (see Figure 1a). We analysed the group of organisms with trimethoprim, amoxicillin and ciprofloxacin resistance, referred to as multidrug-resistant E. coli (MDR-EC) further.



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Figure 1. (a) Dot-plot showing antibiotic susceptibility scores against time. For reasons of clarity, a random 25% of the E. coli isolates is plotted. (b) The proportion of hospital (filled diamonds) and general practice (open squares)-derived isolates that are multidrug-resistant (MDR). (c and d) Both refer to urines obtained in hospital, and show the proportion of E. coli that were multidrug-resistant, stratified by age (c) and by prior hospital exposure (d).

 
Among 80 248 samples, 56 985 were sent by general practitioners, the rest being of hospital origin. The proportion of MDR-EC increased exponentially in both hospital and GP samples (Figure 1b). Analysis of inpatient E. coli isolates showed that MDR-EC rates varied with age (Figure 1c; {chi}2 testing heterogeneity between age groups = 34.2, 3 df, P < 0.001) and with hospital exposure ({chi}2 testing heterogeneity between age groups = 344, 3 df, P < 0.001, Figure 1d). Among inpatients, MDR-EC isolation was not significantly associated with sex ({chi}2 0.27, 1 df, P = 0.60), or with the sample being taken in the first 2 days of admission (community acquisition) compared with being taken after 2 or more days as an inpatient (hospital acquisition) ({chi}2 0.34, 1 df, P = 0.56). Multivariate logistic regression showed later years in the study and duration of hospital stay, but not sex or age, to be independent risk factors for multiresistance (not shown).

A prospective series of 30 consecutive isolates reported by the laboratory as MDR-EC between 1 and 31 January 2005 were analysed in more detail. All were identified as E. coli by API 20E (BioMérieux), and all were confirmed resistant to amoxicillin, trimethoprim and ciprofloxacin on retesting as described by the British Society for Antimicrobial Chemotherapy (http://www.bsac.org.uk). Seventeen out of 30 (57%) isolates contained ESBL activity, as judged by the cefpodoxime/clavulanic acid synergy test.3

Our data show a sustained, exponential increase in the incidence of urinary MDR-EC strains is occurring in Oxfordshire. Many of these strains have ESBLs. Isolates are being obtained in general practice and from the hospital. Prolonged hospital stay is a risk factor. The outbreak in our region was not detected clinically, rather, it was identified using a simple graphical method for monitoring antimicrobial susceptibility patterns, a technique that may have general applicability. We believe that systematic analysis of the type we describe will confirm a widespread UK outbreak in units in which, like ours, this was unsuspected.

Further work is required to determine additional risk factors for, and clinical outcome of, infections with this class of organism, which has also been isolated in France and the USA, where they comprise several different lineages.4,5

Transparency declarations

We have no conflicts to declare.

Acknowledgements

I.B. initiated the study of ESBL prevalence in Oxford, and reviewed the results and paper. D.W. studied secular antibiotic resistance patterns, designed the study and wrote the paper. E.B. and M.M. performed the sequential study of E. coli isolates. The study received no specific funding.

References

1. Livermore DM, Nichols T, Lamagni TL et al. Ciprofloxacin-resistant Escherichia coli from bacteraemias in England; increasingly prevalent and mostly from men. J Antimicrob Chemother 2003; 52: 1040–2.[Abstract/Free Full Text]

2. Woodford N, Ward ME, Kaufmann ME et al. Community and hospital spread of Escherichia coli producing CTX-M extended-spectrum ß-lactamases in the UK. J Antimicrob Chemother 2004; 54: 735–43.[Abstract/Free Full Text]

3. Livermore DM, Woodford N. Laboratory detection and reporting of bacteria with extended spectrum ß-lactamases. Health Protection Agency, 2004.

4. Branger C, Zamfir O, Geoffroy S et al. Genetic background of Escherichia coli and extended-spectrum ß-lactamase type. Emerg Infect Dis 2005; 11: 54–61.[ISI][Medline]

5. Johnson JR, Kuskowski MA, Gajewski A et al. Virulence characteristics and phylogenetic background of multidrug-resistant and antimicrobial-susceptible clinical isolates of Escherichia coli from across the United States, 2000–2001. J Infect Dis 2004; 190: 1739–44.[CrossRef][ISI][Medline]





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