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Journal of Clinical Microbiology, August 2008, p. 2796-2799, Vol. 46, No. 8
0095-1137/08/$08.00+0     doi:10.1128/JCM.01008-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

High Rate of Intestinal Colonization with Extended-Spectrum-β-Lactamase-Producing Organisms in Household Contacts of Infected Community Patients{triangledown}

Aránzazu Valverde,1,2 Fabio Grill,3 Teresa M. Coque,1,2 Vicente Pintado,3 Fernando Baquero,1,2 Rafael Cantón,1,2* and Javier Cobo3

Servicio de Microbiología,1 CIBER en Epidemiología y Salud Pública (CIBERESP),2 Servicio de Enfermedades Infecciosas, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain3

Received 27 May 2008/ Accepted 6 June 2008


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ABSTRACT
 
Fecal carriage of extended-spectrum-β-lactamase (ESBL)-producing organisms was detected in 70% of index cases of patients (n = 40) with community-acquired infections due to ESBL producers and reached 16.7% in household contacts (n = 54). A total of 66% of ESBL-producing organisms from index cases were indistinguishable from isolates from household contacts by pulsed-field gel electrophoresis. Patients with community infections and members of their households represent a reservoir for ESBL producers, increasing dispersal of resistance in healthy people.


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TEXT
 
Rates of colonization by extended-spectrum-β-lactamase (ESBL)-producing organisms have increased dramatically worldwide (2, 22). This change has been associated with efficient dispersion of specific clones and plasmids harboring blaESBL genes (5, 6, 20). In addition, coresistance to non-β-lactam antibiotics may have fueled the persistence of ESBL-producing isolates, as has been demonstrated in studies of intensive care units (17, 19, 23). A threatening epidemiological problem is the dissemination of ESBL-producing organisms to healthy people in the community, which might depend on the frequency of ESBL fecal carriage as well as on the presence of ESBL-producing organisms in the food chain (15, 18, 30).

In a previous study, we demonstrated that nearly 12% of hospitalized patients might carry ESBL-producing isolates in the intestinal compartment (32). This colonization has been associated with a high risk for developing an infection due to ESBL producers (23, 25). This has scarcely been investigated in studies of community patients and, to an even lesser extent, in studies of healthy subjects (24, 32). Moreover, there is little information about the pathways of intestinal colonization. This has been investigated in studies of hospitalized patients and recently in studies of outpatients involved in food-borne outbreaks (9, 15). In the present study, we analyzed fecal carriage of ESBL-producing organisms in a group of patients with community-acquired infections (CAIs) due to these organisms and the corresponding status of the people living with them (household contacts).

From April 2004 to June 2005, a total of 299 patients presented in our institution with an infection or colonization process due to an ESBL-producing organism. Fifty-six percent were outpatients, of whom 95% had a urinary tract infection. Forty clinical samples from 40 patients (index cases [ICs]) with CAIs (37 urinary tract infections, 2 cases of bacteremia, and 1 soft tissue infection) due to an ESBL-producing Escherichia coli (n = 39) or Klebsiella pneumoniae (n = 1) strain and fecal samples (1 per IC) were studied. Only IC patients who positively agreed to participate in the study and submitted fecal samples were enrolled. Thirty-four of the 40 IC patients (mean age, 63.6 years; range, 2 to 96 years) were females. In addition, 54 fecal samples from 54 household contacts of 29 IC patients recovered within 2 weeks of IC enrollment were also studied. The number of household contacts for each IC patient ranged from only one to seven (mean, two per household per patient). The ethical committee approved the study, and signed informed consents were obtained.

Fecal samples were screened for ESBL producers as previously described (32). Bacterial identification was performed by standard methods and CLSI microdilution (4) to determine susceptibility patterns. ESBL characterization was performed by PCR and sequencing (6, 32, 33). Population structure data were established by pulsed-field gel electrophoresis (PFGE) (32). In addition, phylogenetic groups among E. coli isolates were identified by multiplex PCR (3).

Twenty-eight out of 40 IC patients (70%; 95% confidence interval [CI], 53.4 to 83.4) and 9 out of 54 household contacts (16.7%; 95% CI, 6.7 to 26.1) presented fecal carriage of ESBL-producing E. coli strains (Fig. 1). Moreover, 9 IC patients out of 29 had at least one colonized household contact (31.0%; 95% CI, 14.2 to 47.9). This figure increased (42.1%; 95% CI, 19.9 to 64.3) in the subset of household contacts of IC patients with fecal carriage (8 of 19). In contrast, only one household contact (1 of 10) (10%; 95% CI, 0 to 28.6) within the subset of those from households with IC patients with negative fecal carriage results presented an intestinal colonization of an ESBL-producing E. coli strain (Fig. 1).


Figure 1
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  		FIG. 1. IC patients with fecal carriage of ESBL-producing organisms and their corresponding household contacts. Index case, patient with ESBL-producing-organism infection; index case carriage (+), patient with ESBL-producing-organism infection and ESBL-positive fecal culture; household contacts carriage (+), household contacts with ESBL-producing-organism infection and ESBL-positive fecal culture.

Characteristics of ESBL-producing isolates from IC patients and their corresponding household contacts are shown in Table 1 and Table 2. Seventy-two percent (21 of 29) of IC patients harbored E. coli clinical strains with the same PFGE type as those from their fecal samples. Moreover, PFGE analysis revealed indistinguishable patterns among ESBL-producing E. coli isolates from IC patients (clinical sample or fecal sample) and their corresponding household contacts for 66% (6 of 9) of the isolates.


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  		TABLE 1. Characteristics of ESBL-producing isolates from clinical and fecal samples of ICs with no household contacts


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  		TABLE 2. Characteristics of ESBL-producing E. coli isolates from all samples of ICs and fecal samples from ESBL-positive household contacts

Overall, ESBL characterization revealed a predominance of CTX-M-14 (57%) and SHV-12 (18.6%), the emergence of ESBLs belonging to the CTX-M-1 group (7.1%), and a small representation of TEM (5.7%) enzymes. This distribution is in agreement with the epidemiological situation of ESBL-producing strains from the community at the time of enrollment in our study (2, 27, 31). It is of note that two IC patients and two household contacts were colonized with two different ESBL-producing strains.

The present report demonstrates a high (70%) rate of intestinal colonization of patients with CAI due to ESBL-producing organisms. The presence of these pathogens in the bowel is considered to be a risk factor for infections with these bacteria (28). Moreover, it can explain the high rates of isolation of ESBL-producing organisms in certain anatomic locations (i.e., abdominal and urinary tract infections) compared to the rates seen in others where there is not a clear indication of the presence of endogenous microbiota (28). It is of note that our 70% figure is similar to that seen with hospitalized patients under high antimicrobial selective pressure (17, 23). Around 50% of our patients received antimicrobial treatment (18 patients) or medical assistance outside of the hospital setting (22 patients) at least 2 months before incurring ESBL infections; those conditions have been defined as risk factors for colonization with these pathogens (28).

An important finding was the high (16.7%) rate of intestinal colonization in members of households of patients suffering CAI with ESBL-producing organisms. This figure is higher than that previously found by our group in the same geographic area (3.7%; P = 0.004 [chi-square test]) and in other countries (range, 1.7% to 13.1%) for healthy individuals (13, 21, 26, 32). This value was even higher (42.1%) in the subset of household contacts of IC patients with fecal carriage. Despite a potential limitation of our study due to the small sample size, these results revealed the importance of intestinal colonization as a reservoir for transmission of resistant bacteria and its potential role as a trafficker of antibiotic resistance genes (14, 29). This has been studied in the nosocomial setting, for which it is generally assumed that for every patient with a clinically significant infection with an ESBL-producing organism, at least one other patient with intestinal colonization by an ESBL producer is present in the same unit (9, 17, 22). Data from the community remain scarce. It has been shown that methicillin-resistant Staphylococcus aureus or vancomycin-resistant enterococci may be acquired from different family members (1, 10, 11), and there is no available information concerning ESBL pathogens that contradicts this suspicion.

Patient-to-patient transmission of ESBL-producing K. pneumoniae strains in the nosocomial setting has been demonstrated previously (7, 17, 23). In the community, this phenomenon can occur with E. coli as well (6, 8, 9, 16). In our study, up to 66% of isolates from IC patients and their corresponding household members had indistinguishable PFGE patterns. Epidemic plasmid distribution might be responsible for this situation. This possibility was studied using different CTX-M-14-producing clones (A. Valverde, R. Cantón, and T. M. Coque, unpublished data). We cannot rule out a common source, as we did not investigate the presence of ESBL-producing organisms in food or domestic pets. Both have been involved in the spread of these pathogens and their corresponding blaESBL genes (12, 15, 30).

In summary, high rates of intestinal colonization with ESBL-producing organisms of community patients infected with these strains was observed. Household contacts of these patients had rates of intestinal colonization with ESBL-producing organisms that were higher than those seen with outpatients and the general population (32). These results highlight the fact that community patients and their household contacts represent a clear reservoir for these organisms and the corresponding blaESBL genes. This fact increases the risk of dissemination of such organisms to healthy people and facilitates the acquisition of resistance mechanisms by susceptible bacteria.


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ACKNOWLEDGMENTS
 
A.V. is supported by CIBERESP (Network Center for Biomedical Research in Epidemiology and Public Health) of Instituto Carlos III, Ministerio de Sanidad y Consumo of Spain. F.G. was supported by Red Española de Investigación en Patología Infecciosa (REIPI-ISCIII-C03/14) of Instituto Carlos III, Ministerio de Sanidad y Consumo of Spain. This study was partially supported by research grants from the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III (PI040162), DeReMicrobiana Project of the Madrid Autonomous Community, and the European Commission (LSHM-CT-2003-503335).

We thank Azucena Rollán for her excellent technical work.


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FOOTNOTES
 
* Corresponding author. Mailing address: Servicio de Microbiología, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain. Phone: 34913368330. Fax: 34913368809. E-mail: rcanton.hrc{at}salud.madrid.org Back

{triangledown} Published ahead of print on 18 June 2008. Back


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Journal of Clinical Microbiology, August 2008, p. 2796-2799, Vol. 46, No. 8
0095-1137/08/$08.00+0     doi:10.1128/JCM.01008-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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