JAC Advance Access originally published online on February 21, 2006
Journal of Antimicrobial Chemotherapy 2006 57(4):780-783; doi:10.1093/jac/dkl035
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Risk factors for community-onset urinary tract infections due to Escherichia coli harbouring extended-spectrum ß-lactamases
1 Department of Internal Medicine, Infectious Diseases Unit, Hospital Mútua de Terrassa, Barcelona, Spain; 2 Service of Microbiology, Hospital Mútua de Terrassa, Barcelona, Spain; 3 Intensive Care Unit, Hospital Mútua de Terrassa, Barcelona, Spain; 4 Department of Microbiology, Hospital Clínic, University of Barcelona, Spain
* Corresponding author. Tel: +34-93-7365050 ext. 3931; Fax: +34-93-7365037; E-mail: esthercalbo{at}hotmail.com
Received 7 October 2005; returned 6 November 2005; revised 13 January 2006; accepted 25 January 2006
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Abstract |
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Objectives: Extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli have been increasingly recognized in the community. The aim of this study was to determine the prevalence, types of ESBLs and risk factors for community-onset ESBL-producing E. coli in urinary tract infections (UTIs).
Methods: Adults with community-onset UTIs due to ESBL-producing E. coli (cases) and non-ESBL-producing E. coli (controls) were identified through records of the clinical microbiology laboratory of the hospital. Two different periods were studied: from January 2000 to January 2001 and from October to December 2003. Controls were matched in a 3:1 ratio to case patients according to age, sex, date of isolation and residence in a long-term care facility. Potential risk factors were recorded. Isoelectric focusing as well as PCR and DNA sequencing were used to characterize the blaTEM, blaSHV and blaCTX-M genes. A possible clonal relationship among the strains was determined by repetitive extragenic palindromic sequence PCR.
Results: The prevalence of infection due to ESBL-producing E. coli increased from 0.47% in 2000 to 1.7% in 2003 (P < 0.001). Community-onset ESBL-producing E. coli infection shifted from 50% in the first period to 79.5% in 2003 (P < 0.001). Nineteen cases and 55 matched controls of community-onset ESBL-producing E. coli UTI were included. ESBL-producing E. coli strains were clonally unrelated. On univariate analysis, genitourinary pathology (P < 0.03), previous bacterial infection (P = 0.01), intravenous antibiotic treatment (P = 0.01), hospitalization in the previous 12 months (P = 0.04) and previous exposure to oral second-generation cephalosporins (P < 0.05) were associated with community-onset infection due to ESBL-producing E. coli. In our regression model, only previous exposure to second-generation cephalosporins was strongly associated with E. coli harbouring ESBLs (OR, 21.42; CI 95%, 5.38–85.22; P < 0.05). In the first period, only TEM- and SHV-derived ESBLs were identified. The enzymes were characterized as members of the TEM group (60%), SHV group (16%) and CTX-M group (24%).
Conclusions: We detected a marked increase in infections due to ESBL-producing E. coli, especially in the community, in the periods studied. Only previous exposure to the oxyimino cephalosporin cefuroxime, and not to ciprofloxacin, aminoglycosides or third-generation cephalosporins, was predictive of an ESBL-producing E. coli community-onset infection in our area. The emergence of the CTX-M type of ß-lactamase in E. coli follows closely the spread of ESBLs in community isolates.
Keywords: ESBLs , UTIs , CTX-M ß-lactamases , cefuroxime , multiresistant E. coli
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Introduction |
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Gram-negative microorganisms producing extended-spectrum ß-lactamases (ESBLs) were recognized in the early 1980s, shortly after the introduction of the oxyimino ß-lactam agents. ESBLs are enzymes most commonly derived from TEM or SHV parents, but the prevalence of CTX-M types has increased dramatically since 1995 in most parts of the world.1 All confer resistance to amino and ureido penicillins, oxyimino cephalosporins and monobactams, but not to 7-
-substituted ß-lactams. The ESBL strains are increasingly associated with resistance to other non-related antimicrobials and pose significant therapeutic challenges.2 Typically, the isolation of ESBLs has occurred in the hospital setting, but this organism has begun to disseminate in the community.3,4
The increasing prevalence of ESBL-producing Escherichia coli prompted our interest to investigate risk factors for ESBL-producing E. coli in patients with community-onset urinary tract infections (UTIs). The aim of the present study was to determine the prevalence, type and risk factors for ESBL-producing E. coli in community-onset UTIs in our area.
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Materials and methods |
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Hospital Mutua de Terrassa is an acute care teaching hospital serving a population of
300 000 habitants, with 24 000 admissions per year. All E. coli isolated from any sample in the years 2000 and 2003 were included for the prevalence study. All cases of ESBL-producing E. coli in which a community-onset UTI was suspected were reviewed.
A case–control study was designed to identify risk factors associated with community-onset UTIs due to ESBL-producing E. coli. Consecutive patients with community-onset UTIs due to ESBL-producing E. coli from two different periods were studied: from January 2000 to January 2001 and from October to December 2003.
A case was a patient seen in the emergency department or in one of the primary care centres with a UTI, defined by the presence of symptoms related to the urinary tract, pyuria (
10 leucocytes per high-power field), a positive urine culture (105 cfu/mL) of ESBL-producing E. coli and without history of hospital admission within the preceding month. Controls were patients with community-onset UTIs due to non-ESBL-producing E. coli. They were matched in a 3:1 ratio to case patients according to age, sex, place of residence and date of isolation.
We recorded the presence of urinary tract abnormalities, immunosuppression, comorbidities based on Charlson score,5 previous antibiotic treatment (1 standard dose in >24 h) and any interaction with the healthcare system in the previous year.
E. coli isolation and identification were performed following standard methods. Susceptibility testing was performed with the VITEK 2 system (bioMerieux, Hazelwood, MO, USA). ESBL production was detected by double-disc synergy test (NCCLS) and with the Etest (AB Biodisk, Sweden) for ceftazidime and ceftazidime-clavulanate. We considered ESBL-producing E. coli multiresistant if they were resistant to more than two classes of other antimicrobials (quinolones, trimethoprim/sulfamethoxazole or aminoglycosides).
ESBL-producing E. coli strains were further studied to characterize the ß-lactamases. Isoelectric focusing (IEF) was performed to identify isoelectric points of the ß-lactamases. Specific PCR amplification and DNA sequencing of the PCR products were used to determine whether the blaTEM, blaSHV and blaCTX-M genes were present and to characterize the type of ß-lactamase belonging to each family. The primers used have been described previously.6,7 Possible clonal relationship among the strains was determined by repetitive extragenic palindromic sequence PCR.
Statistical analysis
Potential risk factors for ESBL-producing E. coli UTI were identified by univariate analysis. The 
2 or Fisher's exact test was used for categorical variables; the significance was 0.05. Significant variables in the univariate analysis were further tested by means of logistic regression using the forward conditional method. The final model included confounding variables significant at a two-tailed P value of <0.05. The SPSS (version 11.5) software package was used for analysis.
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Results |
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The prevalence of infection due to ESBL-producing E. coli in our area increased from 0.47% in 2000 (17 of 3617 isolates from any type of infection) to 1.7% in 2003 (44 of 2600) (P < 0.001). In 2000, 50% of ESBL-producing E. coli were community-onset cases versus 79.5% in 2003 (P < 0.001; OR, 4; CI 95%, 2–8). Finally, 48 (79%) of the 61 ESBL-producing E. coli isolates were of urinary origin; 19 of these were from patients with community-onset UTIs. The latter were selected for the case–control study.
Case–control study
A total of 19 cases of community-onset UTIs due to ESBL-producing E. coli and 57 matched controls with a community-onset UTI due to non-ESBL-producing E. coli were studied; two controls had to be excluded because of a mismatch. Six out of 19 (31.5%) ESBL-producing E. coli produced two different ESBLs. Therefore, there were 25 different ESBLs. A TEM type was detected in 15 isolates (six TEM-104, three TEM-70, two TEM-54, two TEM-117, one TEM-10 and one TEM-1-D), a CTX-M type in six isolates (two CTX-M-9, three CTX-M-toho2 and one CTX-M-1) and a SHV type in four isolates (one SHV-12, one SHV-56, one SHV2a and one SHV-5a). All CTX-M type ESBLs were recovered during 2003. The 19 ESBL-producing E. coli strains studied were not clonally related.
Patient characteristics, epidemiological data and all variables found to be associated with ESBL-producing E. coli in univariate analysis are shown in Table 1.
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Multivariate analysis included all significant risk factors found in univariate analysis. Only previous exposure to oral cefuroxime was strongly associated with ESBL-producing E. coli (P < 0.05; OR, 21.42; CI 95%, 5.38–85.22).
The antibiotic susceptibility patterns of E. coli from cases and controls are shown in Table 2. ESBL-producing E. coli exhibited much higher resistance to all antimicrobials tested. More than 70% of these strains were multidrug-resistant.
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Discussion |
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We have witnessed a recent 3-fold increase in community-onset UTIs due to ESBL-producing E. coli in our area. Our findings are in keeping with other recent reports,8 highlighting the rapid spread of these strains in the community.
Only previous cefuroxime use was strongly associated with ESBL-producing E. coli community-onset UTIs (OR, 21.42; CI 95%, 5.38–85.22). Very similar findings have been reported by Colodner et al.4 in ESBL-producing bacteria in non-hospitalized patients, where exposure to second-generation cephalosporins was an important risk factor for the occurrence of these organisms (OR, 10.1; CI 95%, 4.2–24). Cefuroxime may select for ESBL-producing E. coli from the existing gastrointestinal flora when a patient is exposed to this agent. Recent data from Spain indicate that the prevalence of faecal ESBL-producing E. coli has increased >5-fold in the past decade. Up to 5.5% of faecal E. coli isolates in faeces of healthy volunteers were found to harbour ESBLs.9
We did not find any relation between exposure to other antimicrobials and ESBL-producing E. coli UTI. Previous use of third-generation cephalosporins has been widely reported as a risk factor for ESBL-producing isolates.2 The lack of correlation in our study between the use of third-generation cephalosporins, ciprofloxacin or trimethoprim/sulfamethoxazole and ESBL-producing E. coli UTI could be easily explained by the very infrequent exposure to these agents in our population.
Strikingly, in multivariate analysis neither comorbidity nor previous contacts with the healthcare system were risk factors for ESBL-producing E. coli UTI. Traditionally, outbreaks of third-generation cephalosporin-resistant Gram-negative bacilli have been seen in high-risk areas and attributed mostly to in-hospital person-to-person spread for the epidemic strains and/or third-generation cephalosporin use. In contrast to this experience, recent studies suggest that infections due to ESBL-producing E. coli in non-hospitalized patients might be emerging.3,4 In this context, it is noteworthy that in a recent nationwide study of ESBL-producing organisms in Spain, more than 50% of the ESBL-producing E. coli isolates were thought to have a community origin.10 In our study, the lack of clonal relationship between ESBL-producing E. coli strains argues in favour of its community origin.
It is of interest that in our area CTX-M enzymes were first detected in 2003 and that they appeared to replace the older TEM- and SHV-derived types. The number of reports of E. coli producing CTX-M at the community level causing disease or as colonizers is increasing.9 It is becoming clear that the epidemiology of CTX-M enzymes is different from that of TEM- and SHV-derived ESBLs.
The majority of our ESBL-producing E. coli strains were multiresistant. Specifically, most were resistant to quinolones and trimethoprim/sulfamethoxazole. This associated resistance to other classes of antimicrobials is especially problematic in urinary isolates and underscores the therapeutic challenge that they represent.
Our analysis is retrospective and has limitations; the small sample size might mean that other, less prevalent risk factors for ESBL-producing E. coli infections could go undetected. However, the strictly matched design for the two groups makes it easier to balance all confounding factors. Plasmid analysis was not performed. Finally, our study was conducted in an urban teaching institution with a very large outpatient population, and the results cannot be extrapolated to other settings.
Despite the above limitations, our study has shown the remarkable increase in the incidence of ESBL-producing E. coli and that previous exposure to oral cefuroxime is clearly linked to the isolation of ESBL-producing E. coli causing UTI in the outpatient population of our area. CTX-M enzymes first detected in 2003 appear to have replaced older types of ESBLs and to have become the predominant enzymes among ESBL-producing E. coli. When treatment protocols are designed, the prevalence of ESBLs among clinical isolates must be taken into consideration and, on this basis, a rational choice of empirical antibiotic therapy can be recommended.
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J. G. has received grants from Bayer, GSK, Wyeth-Lederle and Sanofi-Aventis.
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References |
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