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Betalactamasas en itu y cipro
1. Eur J Clin Microbiol Infect Dis (2004) 23:163–167
DOI 10.1007/s10096-003-1084-2
ARTICLE
R. Colodner · W. Rock · B. Chazan · N. Keller ·
N. Guy · W. Sakran · R. Raz
Risk Factors for the Development of Extended-Spectrum
Beta-Lactamase-Producing Bacteria in Nonhospitalized Patients
Published online: 19 February 2004
Springer-Verlag 2004
Abstract Although the risk factors for acquiring infec- 5.51), male gender (OR=2.47, 95%CI, 1.22–5.01), Kleb-
tion by extended-spectrum beta-lactamase (ESBL)-pro- siella pneumoniae infection (OR=2.31, 95%CI, 1.17–
ducing bacteria have been investigated in hospitalized 4.54), previous use of third-generation cephalosporins
patients, such risk factors have not been defined in the (P=0.014, OR=15.8, 95%CI, 1.7–143), previous use of
community setting. In this study, clinical data from a total second-generation cephalosporins (P0.0001, OR=10.1,
of 311 nonhospitalized patients with community-acquired 95%CI, 4.2–24), previous use of quinolones (P=0.001,
urinary tract infection (128 with ESBL-positive strains OR=4.1, 95%CI, 1.8–9.0), and previous use of penicillin
and 183 with ESBL-negative strains) were obtained. (P=0.003, OR=4.0, 95%CI, 1.6–9.0).
According to a multivariate analysis, the following were
identified as independent risk factors: previous hospital-
ization in the past 3 months (OR=8.95, 95%CI, 3.77– Introduction
21.25), antibiotic treatment in the past 3 months (OR=
3.23, 95%CI, 1.76–5.91), age over 60 years (OR=2.65, Extended-spectrum beta-lactamases (ESBLs) are a het-
95%CI, 1.45–4.83), diabetes (OR=2.57, 95%CI, 1.20– erogeneous group of enzymes responsible for resistance
against extended-spectrum beta-lactam antibiotics [1].
R. Colodner ()) The first reports of ESBLs came from Europe [2, 3] and
Clinical Microbiology Laboratory, were followed very quickly by reports in the USA [4, 5].
Ha’Emek Medical Center, This type of antimicrobial resistance has been recognized
18101 Afula, Israel worldwide in the last 20 years.
e-mail: colodner_ra@clalit.org.il ESBL-producing bacteria often show cross-resistance
Tel.: +972-4649-4480
to other groups of antibiotics, like fluoroquinolones. The
Fax: +972-4649-5428
close relationship between ESBL production and cipro-
B. Chazan · W. Sakran · R. Raz floxacin resistance is particularly worrisome because it
Infectious Diseases Unit, narrows the range of alternative therapy for isolates
Ha’Emek Medical Center, harboring both mechanisms at the same time. Such
18101 Afula, Israel clinical isolates have already been reported [6].
N. Keller One of the pillars of infection control is the knowledge
Sheba Medical Center, obtained from surveillance studies. Among the data
Tel Hashomer, Israel obtained from such studies performed in hospitalized
ESBL-harboring patients, specific risk factors included
B. Chazan · N. Guy
Department of Family Medicine,
length of hospital stay, severity of illness, time in the ICU,
Ha’Emek Medical Center, intubation and mechanical ventilation, urinary or arterial
18101 Afula, Israel catheterization, previous exposure to antibiotics [7, 8] and
urinary tract infection (UTI) [9, 10].
W. Sakran There is little data about the incidence of community-
Pediatric B Ward,
acquired infections caused by ESBL-producing bacteria
Ha’Emek Medical Center,
18101 Afula, Israel [11]. In a recent pilot surveillance study, we demonstrated
the presence of ESBL-producing strains causing commu-
W. Rock · W. Sakran · R. Raz nity-acquired UTIs in our region [12]. This data must be
The Rappaport Faculty of Medicine, confirmed in a larger study.
The Technion,
Haifa, Israel
2. 164
The objective of the present study was to investigate Results
the risk factors for development of ESBL-producing
bacteria in nonhospitalized patients and the role of these Of a total of 311 cultures, 128 grew ESBL-producing
factors in the spread of this relatively new mechanism of bacteria and were included in the ESBL-producing group.
bacterial resistance in our region. Of these, 74 (57.8%) were Escherichia coli and 54
(42.2%) Klebsiella spp. Another 183 grew ESBL-negative
organisms and were included in the ESBL-negative
Materials and Methods group: 149 were Escherichia coli (81.4%) and 34
(18.6%) Klebsiella spp. The mean age of the study group,
Nonhospitalized patients with community-acquired UTI due to 61.5 years (range, 1–92), was significantly higher than
Escherichia coli or Klebsiella spp. were included in the study. that of the control group, 46.4 years (range, 0.2–92). The
Urine cultures growing more than 104 colony-forming units (cfu)
per milliliter were considered positive, according to the urine length of antibiotic treatment in the last 3 months was also
culture protocol in use at the Ha’Emek Medical Center, a significantly higher in the ESBL-producing group (mean
modification of the protocol recommended in the Cumitech 2B values, 21.6 days vs. 12.3 days for ESBL-producing and
manual [13]. ESBL-negative groups, respectively).
In order to find the study group patients, all isolates from urine
cultures positive for gram-negative bacteria and received in a In addition, as shown in Table 1, patients in the study
period of 2 years in the microbiology laboratory of Ha’Emek group apparently stayed in the hospital for a longer period
Medical Center were identified to the species level. Strains were (6.28 days vs. 3.75 days). However, this difference was
then tested for antimicrobial susceptibility and were also screened not significant (P=0.201), due to a non-Gaussian distri-
for ESBL production using Microscan Gram-Negative Combo bution (the median was 5 days for both groups). Of the
Urine panels Type 2 (Dade-Behring, USA) and a Microscan
Walkaway 96 apparatus. The presumptive presence of ESBL was total 311 patients, 71 were male and 240 were female.
determined using the Microscan DMS software and the Microscan However, the ESBL-producing group included a signif-
ESBL algorithm. icantly higher number of males (P0.0001). Table 1 also
Once a strain was suspected as an ESBL producer, ESBL shows the prevalence of three other risk factors for both
production was confirmed using two ESBL E test strips (AB
Biodisk, Sweden) containing ceftazidime and cefotaxime with and groups: previous hospitalization, gender, and age over 60
without clavulanate, according to the manufacturer’s recommen- years. When the prevalence rates were compared between
dations. A strain was defined as an ESBL producer when the the two groups, all three factors showed very significant
minimal inhibitory concentration (MIC) in the presence of clavu- differences (P0.0001). Fifty-seven patients in the study
lanic acid was at least eight times lower than the MIC without
clavulanic acid [14]. group were previously hospitalized within the period of 3
Patients with urine cultures that grew ESBL-negative Escher- months prior to development of ESBL-positive UTI,
ichia coli or Klebsiella spp. strains that were consecutively received compared to only eight patients in the control group.
in the laboratory were included in the control group. The list of underlying diseases in both groups is
Every patient’s treating physician filled out a questionnaire that presented in Table 2. Of all diseases recorded, only for
included the following information: age, gender, underlying dis-
eases (diabetes, cardiovascular diseases, gastrointestinal diseases, gastrointestinal and ear-nose-throat diseases were signif-
genitourinary diseases, recurrent UTIs, neurological diseases, ear- icant differences between both groups not observed.
nose-throat diseases, malignancies), use of antibiotics in the past 3 Statistical significance of differences between groups was
months, duration of treatment and class of antibiotic used, previous more remarkable for diabetes, cardiovascular, genitouri-
hospitalization in the past 3 months, and duration of any hospital-
ization within the past 3 months. nary, and neurological diseases.
The same table shows the number of underlying
diseases as a predictor of ESBL production. As shown in
Statistical Analysis the table, the predictive value for the production of ESBL
Data analysis was performed using the Pearson chi-square test; increased together with the number of underlying diseases
Fisher’s exact test was used for small numbers. For antibiotic (positive predictive value, 38.2%, 53.4%, and 65.5% for
treatment comparisons, the Mann-Whitney test was used. A 1, 2, and 3 diseases respectively)
multivariate analysis was performed for all significant unilateral A total of 177 patients received antibiotics in the past 3
variables, with results presented as odd ratios with 95% confidence months. Table 3 shows the use of different antibiotic
intervals.
classes by patients in both groups. When the groups were
Table 1 Demographic and clinical characteristics of the patients included in the study
Characteristic ESBL-positive group (n=128) ESBL-negative group (n=183) P value
Mean age in years €SD (range) 61.5€22.9 (1–92) 46.4€24.9 (0.2–92) 0.0001
Percent infected with E. coli 57.8 (n=74) 81.4 (n=149) 0.0001
Percent infected with Klebsiella spp. 42.2 (n=54) 18.6 (n=34) 0.0001
Mean duration of hospitalization in days €SD (range) 6.28€5.4 (1–32) 3.75€1.75 (1–5) 0.201
Mean duration of antibiotic treatment in days €SD (range) 21.6€5.4 (2–90) 12.3€17.2 (1–90) 0.0001
Percent hospitalized in the last 3 months 44.5 (n=57) 4.4 (n=8) 0.0001
Percent male gender 35.9 (n=46) 13.7 (n=25) 0.0001
Percent aged 60 years 69.5 (n=89) 35.2 (n=64) 0.0001
3. 165
Table 2 Underlying diseases Disease Percentage (no.) P value PPV (%)
by univariate analysis
ESBL-positive group ESBL-negative group
Diabetes 33.6 (43) 9.8 (18) 0.0001
Cardiovascular 43.0 (55) 13.7 (25) 0.0001
Gastrointestinal 18.0 (23) 12.0 (22) 0.1
Genitourinary 35.9 (46) 16.4 (30) 0.0001
Recurrent UTI 57.0 (73) 42.1 (77) 0.006
Neurological 30.5 (39) 11.5 (21) 0.0001
Ear-nose-throat 4.7 (6) 4.4 (8) 0.55
Malignancies 14.1 (18) 4.4 (8) 0.002
1 underlying disease 22.7 (29) 25.8 (47) 0.0001 38.2
2 underlying diseases 24.2 (31) 14.8 (27) 0.0001 53.4
3 underlying diseases 44.5 (57) 16.5 (30) 0.0001 65.5
PPV, positive predictive value
Table 3 Univariate analysis of Antibiotic class Percent (no.) P value
the use of antibiotics in the past
3 months ESBL-positive group ESBL-negative group
Any antibiotic 78 (100) 42 (77) 0.0001
1st-generation cephalosporins 3.9 (5) 8.7 (16) 0.094
2nd-generation cephalosporins 39.1 (50) 5.5 (10) 0.0001
3rd-generation cephalosporins 5.5 (7) 0.5 (1) 0.009
Macrolides 5.5 (7) 3.8 (7) 0.49
Penicillin 23.4 (30) 7.1 (13) 0.0001
Quinolones 30.5 (39) 8.7 (16) 0.0001
TMP-SMX 3.9 (5) 5.5 (10) 0.53
Nitrofurantoin 15.6 (20) 10.4 (19) 0.17
Aminoglycosides 2.3 (3) 0 (0) 0.069
TMP-SMX, trimethoprim-sulfamethoxazole
Table 4 Multivariate analysis Risk factor P value Odds ratio 95%CI
of all risk factors, ranked by
logistic regression Lower Upper
Treatment with 2nd-generation cephalosporins 0.0001 15.8 1.7 143.0
Treatment with 3rd-generation cephalosporins 0.009 10.1 4.2 24.0
Hospitalization in the last 3 months 0.0001 8.95 3.77 21.25
Treatment with quinolones 0.0001 4.1 1.8 9.0
Treatment with penicillin 0.0001 4.0 1.6 9.0
Antibiotic treatment in the last 3 months 0.0001 3.23 1.76 5.91
Age 60 years 0.0001 2.65 1.45 4.83
Diabetes 0.0001 2.57 1.20 5.51
Male gender 0.0001 2.47 1.22 5.01
Infection with Klebsiella spp. 0.0001 2.31 1.17 4.54
compared, very significant differences were observed in with Klebsiella spp. The calculated positive predictive
the use of penicillin, second-generation cephalosporins, value of all those risks together was 66.4% and the
and quinolones (P0.0001 for all). Lesser but still negative-predictive value 89.6%. Regarding previous
significant differences were observed with third-genera- antibiotic treatment, second- and third-generation cepha-
tion cephalosporins. However, it should be noted that only losporins, quinolones, and penicillin were also identified
eight patients received this antibiotic class in the past 3 as independent risk factors.
months. Finally, no significant differences were observed
with the use of first-generation cephalosporins, macro-
lides, nitrofurantoin, and trimethoprim-sulfamethoxazole. Discussion
Table 4 shows the results of a multivariate analysis of
all significant risk factors for the development of ESBL- Most patients with community-acquired bacterial infec-
producing strains. The following were identified as tions are treated empirically. Thus, when treatment
independent risk factors: previous hospitalization in the protocols are designed, the prevalence of ESBLs among
past 3 months, antibiotic treatment in the past 3 months, clinical isolates must be taken into consideration. Yet,
age over 60 years, diabetes, male gender, and infection such prevalence rates vary from country to country and
4. 166
from region to region. In addition, some institutions was identified as an independent risk factor for infection
serving regions with low levels of ESBL may not find it with ESBL-producing strains.
cost-effective to test for this resistance mechanism on a Hospitalization has been widely reported as a major
routine basis. All these reasons make the definition of risk cause of the development of infection by ESBL-produc-
factors for the development of ESBL-producing bacteria ing bacteria, and this was corroborated in our study:
at the community level a major concern. previous hospitalization in the past 3 months was iden-
Unfortunately, the data concerning risk factors for the tified as the strongest independent risk factor in the
development of infection by ESBL-producing bacteria logistic regression analysis. However, our findings sug-
among outpatients is very scarce. Recently, Borer et al. gest that patients can also develop infection with ESBL-
[15] conducted a study in southern Israel in which the producing strains in the community: 71 (55.5%) patients
prevalence and clinical features of community-acquired in the ESBL-positive group were not hospitalized in the
bacteremia involving ESBL-producing Enterobacteri- past 3 months.
aceae were evaluated. In their study, age, hospitalization The length of hospitalization proved to be irrelevant in
in an intensive care unit, urinary catheterization, and bed- our study. On the contrary, Bisson et al. [17] reported that
ridden conditions were significant risk factors for ESBL duration of hospitalization was the only independent risk
production [15]. Their report was the first to describe factor for colonization with ESBL-producing Escherichia
community-acquired Enterobacteriaceae bacteremia in- coli or Klebsiella spp. However, their study analyzed data
volving ESBL-producing strains in Israel, and their from a small number of patients (n=13), 8 (62%) of whom
findings suggest that ESBL producers have already begun were admitted from another healthcare facility.
to disseminate in our community. However, the small In our study, a total of 177 patients received antibiotic
number of ESBL-positive patients (only 6) makes con- treatment during the 3-month period prior to UTI with an
clusions very problematic in terms of statistical validity. ESBL-producing strain. Patients in the ESBL-positive
In our study, we analyzed data from a much greater group were treated with antibiotics for a longer period of
number of patients: 128 with community-acquired UTI time compared to the ESBL-negative group. Moreover,
who developed infections due to ESBL-producing uro- antibiotic use in the past 3 months was identified as a
pathogens, compared to 183 infected with non-ESBL- major independent risk factor for the development of
producing bacteria. infection by ESBL-producing bacteria, ranked second
Klebsiella spp. remain the predominant organisms after previous hospitalization. When antibiotic classes
harboring ESBL worldwide. In our study, the percentage used in pretreatment were analyzed, macrolides, trimeth-
of Klebsiella spp. within the ESBL-positive group oprim-sulfamethoxazole, nitrofurantoin, and aminoglyco-
(42.2%) was significantly higher (P0.0001) than in the sides proved not to be statistically relevant as risk factors.
control group (18.6%). In addition, as shown in Table 4, Regarding trimethoprim-sulfamethoxazole, our findings
UTI with Klebsiella spp. was identified as an independent differ from those of Wiener et al. [18], who found use of
risk factor for the development of infection by ESBL- this drug to be an independent risk factor. These findings
producing bacteria. are encouraging, since the first three drugs are widely
Age was another significant risk factor. As shown in used at the community level. In addition, nitrofurantoin is
Table 1, patients in the ESBL-producing group were the first-choice drug in the treatment of community-
much older. In a multivariate analysis, age over 60 years acquired UTI and, as we have shown in the past,
was found to be an independent risk factor for infection resistance rates are still very low in our region [12].
by ESBL-producing bacteria. In addition, we found a Surprisingly, treatment with first-generation cephalos-
significant increase (P0.0001) in the number of males, porins did not show any risk for developing an infection
from 13.7% in the ESBL-negative group to 35.9% in the by ESBL-producing bacteria, since other cephalosporins
ESBL-producing group, and male gender was identified and even penicillins were found to be statistically
as another independent risk factor in the multivariate relevant. As shown in Table 3, significant differences
analysis. The main reason for this gender effect may be were found when the use of second- and third-generation
that elderly males develop complicated UTI more fre- cephalosporins, penicillin, and quinolones in both patient
quently than elderly women [16]. Another possible groups were compared, and these four antibiotics classes
explanation may be the increased number of underlying were found to be independent risk factors in the multi-
diseases among the males in our study, which was in itself variate analysis.
another significant risk factor. The selective pressure of third-generation cephalos-
Among the underlying diseases recorded, diabetes, porins for selection of ESBL-producing mutants has been
heart diseases, genitourinary, neurological diseases, re- widely described. Moreover, reduction in their use and
current UTI, and malignancies were significantly more barrier precautions markedly reduced the incidence of
frequent in the ESBL-positive group, and the risk of colonization and infection [19]. In our study, few patients
developing infection with ESBL-producing strains in- received antibiotics from this class in the past 3 months,
creased with the increasing number of underlying diseases because third-generation cephalosporins are not used
(2 or more). However, when a logistic regression analysis much at the community clinic level. However, oral
of all underlying diseases was performed, only diabetes second-generation cephalosporins like cefuroxime axetil
are widely used in outpatient treatment.
5. 167
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of penicillin and the development of ESBL-producing Chemoter 33:1451–1456
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Acknowledgements The authors thank Idit Lavie for performing Society for Microbiology Press, Washington DC
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