Eur J Clin Microbiol Infect Dis (2004) 23:163–167
DOI 10.1007/s10096-003-1084-2


R. Colodner · W. Rock · B. C...

   The objective of the present study was to investigate                 Results
the risk factors for development of ...
Table 2 Underlying diseases          Disease                  Percentage (no.)                                        ...

from region to region. In addition, some institutions          was identified as an independent risk factor for infec...

   The relationship shown in this study between the use                       cal isolates of Klebsiella pneumoniae. ...
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Betalactamasas en itu y cipro


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Betalactamasas en itu y cipro

  1. 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: 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. 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. 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. 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. 5. 167 The relationship shown in this study between the use cal isolates of Klebsiella pneumoniae. Antimicrob Agents of penicillin and the development of ESBL-producing Chemoter 33:1451–1456 6. Paterson DL, Mulazimoglu L, Casellas JM, Ko WC, Goossens strains is a major concern, since penicillin remains the H, Von Gottberg A, Mohapatra S, Trenholme GM, Klugman drug of choice for treatment of streptococcal pharyngitis. KP, McCormack JG, Yu VL (2000) Epidemiology of cipro- However, penicillin is not known as a selective agent for floxacin resistance and its relationship to extended-spectrum ESBL-producing bacteria, and thus the cause for our beta-lactamase production in Klebsiella pneumoniae isolates causing bacteremia. Clin Infect Dis 30:473–478 finding should be elucidated. 7. Rice LB (1999) Successful interventions for gram-negative Quinolones are also widely used in outpatient treat- resistance to extended-spectrum beta-lactam antibiotics. Phar- ment. The fact that quinolones and cephalosporins were macotheropy 19 (8 Pt 2):120S–128S both identified in our study as independent risk factors for 8. Pena C, Pujol M, Ricart A, Ardanuy C, Ayats J, Linares J, the development of UTI caused by ESBL-producing Garrigosa F, Ariza J, Gudiol F (1997) Risk factors for faecal carriage of Klebsiella pneumoniae producing extended-spec- bacteria is very frustrating: the remaining treatment trum beta-lactamase in the intensive care unit. J Hosp Infect options are very limited. 35:9–16 In conclusion, we identified in this study potential 9. Ho PL, Chan WM, Tsang KW, Wong SS, Young K (2002) independent risks for the development of UTI caused by Extended-spectrum beta-lactamases: frequency, risk factors, and outcomes. Pharmacotherapy 22:14–20 ESBL-producing bacteria in our region: infections due to 10. Mangeney N, Niel P, Paul G, Faubert E, Hue S, Dupeyron C, Klebsiella spp., previous hospitalization, previous antibi- Louarn F, Leluan G (2000) A 5-year epidemiological study of otic treatment (especially with second- and third-gener- extended-spectrum beta-lactamase-producing Klebsiella pneu- ation cephalosporins, penicillins, and quinolones), male moniae isolates in a medium- and long-stay neurological unit. J Appl Microbiol 88:504–511 gender, age over 60 years, and diabetes. The calculated 11. Barrett SP, Savage MA, Rebec MP, Guyot A, Andrews N, positive-predictive value of all these risks factors together Shrimpton SB (1999) Antibiotic sensitivity of bacteria associ- was 66.4% and the negative-predictive value 89.6%. The ated with community-acquired urinary tract infection in Britain. recognition of these risk factors could aid in the identi- J Antimicrob Chem 44:359–365 fication of patients at high risk of harboring ESBL- 12. 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