Abstract
Objective Although extended-spectrum β-lactamase (ESBL)-producing bacteria are a global threat, as they may cause respiratory infection, the factors associated with the isolation of these bacteria from sputum remain unclear. We therefore explored the factors related to ESBL-producing Klebsiella pneumoniae and Escherichia coli isolated from sputum samples.
Methods This study included consecutive patients admitted to our department from 2010 to 2021 with K. pneumoniae or E. coli isolated from their sputum. The patients were categorized into ESBL-producing and non-ESBL-producing groups, and the factors associated with ESBL-producing bacteria isolation were assessed using a binomial logistic regression analysis.
Results We included 82 patients, and ESBL-producing pathogens were isolated from 23 (28%). The usage rates of cephem [odds ratio (OR) 4.000, 95% confidence interval (CI) 1.402-11.409, p=0.010], quinolone (OR 2.961, 95% CI 1.097-7.996, p=0.032), and macrolide (OR 4.273, 95% CI 1.518-12.028, p=0.006) in the past year were significantly higher in the ESBL-producing group than in the non-ESBL-producing group. The multivariate analysis revealed that the applications of cephem (adjusted OR: 4.130, 95% CI: 1.233-13.830, p=0.021) and macrolide (adjusted OR: 6.365, 95% CI: 1.922-21.077, p=0.002) was independently associated with the isolation of ESBL-producing bacteria.
Conclusion A history of cephem and macrolide use can be considered a risk factor for ESBL-producing bacteria isolation from sputum samples. Physicians need to consider these risk factors when determining antibiotics for the treatment of patients with respiratory infections.
Keywords: Escherichia coli, odds ratio, macrolide, quinolone
Introduction
Globally, the prevalence of infectious diseases caused by extended-spectrum β-lactamase (ESBL)-producing bacteria has been increasing (1). Notably, in Japan, the isolation rate of ESBL-producing Escherichia coli significantly increased from 0.047 per 100 admissions in 2009 to 0.112 per 100 admissions in 2013 (2). To address this global issue, the determination of the risk factors associated with ESBL-producing bacteria and appropriate methods for the use of antibiotics is urged.
Previous studies have investigated the risk factors for ESBL-producing bacteria isolation mainly in bloodstream and urinary tract infections (1,3). A case-control study using data from 254 older patients with E. coli bloodstream infection indicated that prior exposure to cephems and tube placement were independent predictive factors for ESBL-producing E. coli, with adjusted odds ratios (ORs) of 3.782 [95% confidence interval (CI) 1.710-8.365] and 2.572 (95% CI 1.197-5.524) (3). According to a systematic review focusing on ESBL-producing E. coli in urinary tract infections but not respiratory infections (1), the use of penicillin or cephalosporins was an independent factor associated with ESBLs, with ORs ranging between 2.2 (95% CI 1.1-4.5) and 21.4 (95% CI 5.4-85.2). A history of hospitalization and a history of urinary tract infection were also related to ESBL-producing E. coli isolated from urine samples (1).
However, the factors associated with ESBL-producing bacteria isolated from respiratory samples have not been fully investigated. If risk factors vary by infection site, infection control measures for causable infectious diseases are needed. Therefore, the present study assessed the factors associated with ESBL-producing bacteria isolated from respiratory samples.
Materials and Methods
Patients and study design
This is a retrospective cohort study conducted at Oita University Hospital in Oita Prefecture, Japan. Enterobacteria are recognized as the main pathogens producing ESBL (4), and E. coli and Klebsiella pneumoniae account for ＞95% of ESBL-producing bacteria (5). Notably, our institute has no system to determine ESBL-producing bacteria other than E. coli and K. pneumoniae. Therefore, from January 2010 to March 2021, we consecutively enrolled patients with K. pneumoniae or E. coli isolated from sputum who were suspected of having bacterial pneumonia on admission or during hospitalization. These criteria denote that all types of pneumonia, including community-acquired and hospital-acquired pneumonia, were included in the analysis. Patients with ESBL-producing bacteria isolated from bronchoalveolar lavage fluid were excluded from this study because most cases of suspected pneumonia were evaluated using sputum samples. Patients with isolated K. oxytoca were also excluded owing to controversy regarding the pathogen truly causing pneumonia.
The patients were divided into ESBL-producing and non-ESBL-producing groups, and the factors associated with ESBL-producing bacteria isolation were assessed.
The study protocol was approved by the Institutional Ethics Committee of Oita University Hospital (approval number: 2304; approval date: May 31, 2022). Informed consent was waived by the committee because of the retrospective nature of the study.
Data collection and definitions
Patient data upon admission, including the sex, age, body mass index, comorbidities, respiratory status, and feeding status, were collected. The laboratory data included the white blood cell count, neutrophil count, lymphocyte count, C-reactive protein levels, and albumin levels. These are routinely assessed when a patient is admitted to our department. We defined respiratory failure as ＜90% SpO2 without supplemental oxygen inhalation upon admission. Furthermore, the history of antibiotics usage in the past year, including penicillin, cephem, carbapenem, quinolone, and macrolide, was collected from the medical records.
The ESBL expression was screened using CHROMID ESBL agar (bioMérieux, Marcy-l'Étoile, France), a medium designed for the isolation and detection of ESBL, based on a rich nutrient capacity with a mixture of antibiotics for Gram-positive bacteria and yeast inhibition, including cefpodoxime, and confirmed with AmpC/ESBL differential disks (Kanto Chemical, Tokyo, Japan), which was a combination of four individual disks of cefpodoxime, cefpodoxime+ESBL inhibitor, cefpodoxime+AmpC inhibitor, and cefpodoxime+ESBL inhibitor+AmpC inhibitor. Furthermore, these bacteria were tested for antimicrobial susceptibility; the minimum inhibitory concentration was measured using the broth microdilution method based on the Clinical and Laboratory Standards Institute guidelines.
Statistical analyses
Statistical analyses were performed using the IBM SPSS version 24 software program (IBM, Tokyo, Japan). A p value of ＜0.05 was considered statistically significant. Variables among the patients' backgrounds, laboratory data, and presence of respiratory failure with a p value of ＜0.10 in the univariate analysis were included in the multivariate binomial logistic regression analysis.
Results
Factors associated with ESBL-producing bacteria in the univariate analysis
In this study, 82 patients were included; of these, K. pneumoniae and E. coli were isolated within 48 h after admission in 30 patients. Twenty-three isolates (28%) from the 82 patients were found to produce ESBL (Figure). Proportions of patients administered cephem, quinolone, and macrolide in the past year were significantly higher in the ESBL-producing group than in the non-ESBL-producing group, whereas proportions of patients administered other antibiotics were identical between the groups. Among cephalosporins, third-generation drugs were most frequently used, and these were typically administered intravenously (Table 1). No significant differences were observed in the patients' backgrounds except for in the history of antibiotics use between ESBL-producing and non-ESBL-producing groups.
Figure.
Flow chart of included cases.
Table 1.
Clinical Features of ESBL-producing or Non-ESBL-producing K. Pneumoniae or E. Coli..
| ESBL-producing (n=23) | Non-ESBL-producing (n=59) | OR (95% CI) | p value | |
|---|---|---|---|---|
| Female | 5 (22) | 14 (24) | 0.893 (0.280-2.843) | 0.848 |
| Age (years) | 76 (66-82) | 74 (65-79) | 1.016 (0.977-1.057) | 0.422 |
| Body mass index (kg/m2) | 20.6 (16.9-24.1) | 20.1 (18.2-22.7) | 1.000 (0.870-1.151) | 0.996 |
| Respiratory failure | 11 (48) | 29 (49) | 0.948 (0.362-2.487) | 0.914 |
| Tracheal intubation | 4 (17) | 5 (8) | 2.274 (0.552-9.359) | 0.255 |
| Nasogastric tube | 6 (26) | 6 (10) | 3.118 (0.887-10.953) | 0.076 |
| COPD | 7 (30) | 20 (34) | 0.853 (0.302-2.411) | 0.764 |
| Interstitial pneumonia | 7 (30) | 16 (27) | 1.176 (0.408-3.385) | 0.764 |
| Cardiac diseases | 7 (30) | 21 (36) | 0.792 (0.281-2.230) | 0.658 |
| Diabetes mellitus | 6 (26) | 15 (25) | 1.035 (0.345-3.110) | 0.951 |
| Penicillin usage in the past year | 10 (43) | 24 (41) | 1.122 (0.423-2.972) | 0.817 |
| Cephem usage in the past year | 11 (48) | 11 (19) | 4.000 (1.402-11.409) | 0.010 |
| Oral cephem | 2 | 3 | ||
| Intravenous cephem | 12 | 11 | ||
| 1st-generation cephalosporin | 1 | 2 | ||
| 2nd-generation cephalosporin | 2 | 0 | ||
| 3rd-generation cephalosporin | 9 | 10 | ||
| 4th-generation cephalosporin | 1 | 0 | ||
| Cephamycin | 1 | 2 | ||
| Carbapenem usage in the past year | 9 (39) | 15 (25) | 1.886 (0.679-5.240) | 0.224 |
| Quinolone usage in the past year | 13 (57) | 18 (31) | 2.961 (1.097-7.996) | 0.032 |
| Macrolide usage in the past year | 12 (52) | 12 (20) | 4.273 (1.518-12.028) | 0.006 |
| Erythromycin | 1 | 0 | ||
| Clarithromycin | 10 | 8 | ||
| Azithromycin | 1 | 5 | ||
| Oral or intravenous steroid usage | 12 (52) | 22 (37) | 1.835 (0.693-4.857) | 0.222 |
| Proton pump inhibitor usage | 12 (52) | 35 (59) | 0.748 (0.284-1.972) | 0.557 |
| Hospitalization in the past year | 13 (57) | 35 (59) | 0.891 (0.336-2.362) | 0.817 |
| White blood cells (/μL) | 9,390 (5,460-11,170) | 7,490 (5,820-11,980) | 1.000 (1.000-1.000) | 0.958 |
| Neutrophil (/μL) | 6,942 (4,456-9,509) | 5,776 (3,714-9,707) | 1.000 (1.000-1.000) | 0.775 |
| Lymphocyte (/μL) | 882 (470-1,351) | 941 (653-1,383) | 0.999 (0.999-1.000) | 0.215 |
| C-reactive protein (mg/dL) | 2.86 (1.05-6.83) | 3.40 (0.50-9.59) | 0.956 (0.885-1.032) | 0.247 |
| Albumin (g/dL) | 2.9 (2.4-3.6) | 3.1 (2.5-3.7) | 0.759 (0.384-1.500) | 0.427 |
Data are presented as the number (%) or median (interquartile range).
COPD: chronic obstructive pulmonary disease, OR: odds ratio, CI: confidence interval
Sub-analyses of factors associated with ESBL-producing K. pneumoniae or E. coli in the univariate analysis
Of the 82 patients included in the present study, ESBL-producing K. pneumoniae and E. coli were isolated in 38 and 44 patients, respectively. Among the patients in whom K. pneumoniae was isolated, 8 isolates (21%) were found to produce ESBL. The proportions of patients administered cephem, carbapenem, and macrolide were significantly higher in the ESBL-producing group than in the non-ESBL-producing group (Table 2). In contrast, among the patients in whom E. coli was isolated, 15 isolates (34%) were found to produce ESBL. No significant difference was observed in the patients' background characteristics and laboratory data between the ESBL-producing and non-ESBL-producing groups (Table 3). The proportion of patients administered quinolone tended to be higher in the ESBL-producing group than in the non-ESBL-producing group (p=0.069), whereas proportions of patients administered other antibiotics were identical between the groups.
Table 2.
Clinical Features of ESBL-producing or Non-ESBL-producing K. Pneumoniae.
| ESBL-producing (n=8) | Non-ESBL-producing (n=30) | OR (95% CI) | p value | |
|---|---|---|---|---|
| Female | 1 (13) | 7 (23) | 0.469 (0.049-4.497) | 0.512 |
| Age (years) | 77 (65-85) | 74 (60-81) | 1.036 (0.970-1.107) | 0.294 |
| Body mass index (kg/m2) | 21.9 (18.4-25.3) | 20.4 (17.1-22.5) | 1.065 (0.863-1.314) | 0.558 |
| Respiratory failure | 7 (88) | 16 (53) | 6.125 (0.669-56.095) | 0.109 |
| Tracheal intubation | 2 (25) | 3 (10) | 3.000 (0.408-22.077) | 0.281 |
| Nasogastric tube | 3 (38) | 4 (13) | 3.900 (0.660-23.052) | 0.133 |
| COPD | 2 (25) | 9 (30) | 0.778 (0.131-4.615) | 0.782 |
| Interstitial pneumonia | 5 (63) | 9 (30) | 3.889 (0.762-19.858) | 0.103 |
| Cardiac diseases | 3 (38) | 13 (43) | 0.785 (0.158-3.899) | 0.767 |
| Diabetes mellitus | 2 (25) | 7 (23) | 1.095 (0.179-6.694) | 0.922 |
| Penicillin usage in the past year | 4 (50) | 15 (50) | 1.000 (0.210-4.758) | 1.000 |
| Cephem usage in the past year | 6 (75) | 5 (17) | 15.000 (2.321-96.961) | 0.004 |
| Oral cephem | 1 | 0 | ||
| Intravenous cephem | 7 | 6 | ||
| 1st-generation cephalosporin | 1 | 0 | ||
| 2nd-generation cephalosporin | 1 | 0 | ||
| 3rd-generation cephalosporin | 5 | 5 | ||
| 4th-generation cephalosporin | 1 | 0 | ||
| Cephamycin | 0 | 1 | ||
| Carbapenem usage in the past year | 6 (75) | 8 (27) | 8.250 (1.373-49.574) | 0.021 |
| Quinolone usage in the past year | 4 (50) | 9 (30) | 2.333 (0.475-11.451) | 0.297 |
| Macrolide usage in the past year | 7 (88) | 7 (23) | 23.000 (2.401-220.335) | 0.007 |
| Erythromycin | 0 | 0 | ||
| Clarithromycin | 6 | 4 | ||
| Azithromycin | 1 | 4 | ||
| Oral or intravenous steroid usage | 5 (63) | 15 (50) | 1.667 (0.336-8.258) | 0.532 |
| Proton pump inhibitor usage | 6 (75) | 21 (70) | 1.286 (0.217-7.629) | 0.782 |
| Hospitalization in the past year | 4 (50) | 14 (47) | 1.143 (0.240-5.441) | 0.867 |
| White blood cells (/μL) | 10,105 (4,275-15,523) | 7,530 (5,048-10,600) | 1.000 (1.000-1.000) | 0.290 |
| Neutrophil (/μL) | 8,448 (3,290-14,309) | 5,532 (3,589-9,199) | 1.000 (1.000-1.000) | 0.206 |
| Lymphocyte (/μL) | 898 (444-1,199) | 788 (556-1587) | 1.000 (0.998-1.001) | 0.448 |
| C-reactive protein (mg/dL) | 2.89 (0.95-5.99) | 3.31 (0.46-9.07) | 0.972 (0.870-1.086) | 0.617 |
| Albumin (g/dL) | 2.8 (2.3-3.0) | 3.0 (2.4-3.6) | 0.471 (0.115-1.930) | 0.296 |
Data are presented as the number (%) or median (interquartile range).
COPD: chronic obstructive pulmonary disease, OR: odds ratio, CI: confidence interval
Table 3.
Clinical Features of ESBL-producing or Non-ESBL-producing E. Coli..
| ESBL-producing (n=15) | Non-ESBL-producing (n=29) | OR (95% CI) | p value | |
|---|---|---|---|---|
| Female | 4 (27) | 7 (24) | 1.143 (0.275-4.756) | 0.854 |
| Age (years) | 76 (66-80) | 74 (68-79) | 0.999 (0.947-1.054) | 0.979 |
| Body mass index (kg/m2) | 19.8 (16.3-23.5) | 20.0 (18.5-22.8) | 0.967 (0.799-1.171) | 0.730 |
| Respiratory failure | 4 (27) | 13 (45) | 0.448 (0.115-1.741) | 0.246 |
| Tracheal intubation | 2 (13) | 2 (7) | 2.077 (0.262-16.437) | 0.489 |
| Nasogastric tube | 3 (20) | 2 (7) | 3.375 (0.498-22.884) | 0.213 |
| COPD | 5 (33) | 11 (38) | 0.818 (0.221-3.031) | 0.764 |
| Interstitial pneumonia | 2 (13) | 7 (24) | 0.484 (0.087-2.685) | 0.406 |
| Cardiac diseases | 4 (27) | 8 (28) | 0.955 (0.234-3.888) | 0.948 |
| Diabetes mellitus | 4 (27) | 8 (28) | 0.955 (0.234-3.888) | 0.948 |
| Penicillin usage in the past year | 6 (40) | 9 (31) | 1.481 (0.404-5.428) | 0.553 |
| Cephem usage in the past year | 5 (33) | 6 (21) | 1.917 (0.473-7.772) | 0.362 |
| Oral cephem | 1 | 3 | ||
| Intravenous cephem | 5 | 5 | ||
| 1st-generation cephalosporin | 0 | 2 | ||
| 2nd-generation cephalosporin | 1 | 0 | ||
| 3rd-generation cephalosporin | 4 | 5 | ||
| 4th-generation cephalosporin | 0 | 0 | ||
| Cephamycin | 1 | 1 | ||
| Carbapenem usage in the past year | 3 (20) | 7 (24) | 0.786 (0.171-3.609) | 0.757 |
| Quinolone usage in the past year | 9 (60) | 9 (31) | 3.333 (0.910-12.212) | 0.069 |
| Macrolide usage in the past year | 5 (33) | 5 (17) | 2.400 (0.567-10.155) | 0.234 |
| Erythromycin | 1 | 0 | ||
| Clarithromycin | 4 | 4 | ||
| Azithromycin | 0 | 1 | ||
| Oral or intravenous steroid usage | 7 (47) | 7 (24) | 2.750 (0.732-10.333) | 0.134 |
| Proton pump inhibitor usage | 6 (40) | 14 (48) | 0.714 (0.202-2.528) | 0.602 |
| Hospitalization in the past year | 9 (60) | 21 (72) | 0.571 (0.153-2.129) | 0.404 |
| White blood cells (/μL) | 9,390 (5,460-10,570) | 7,490 (5,880-13,840) | 1.000 (1.000-1.000) | 0.390 |
| Neutrophil (/μL) | 6,942 (4,456-8,665) | 6,578 (3,907-11,627) | 1.000 (1.000-1.000) | 0.467 |
| Lymphocyte (/μL) | 868 (470-1,364) | 1,009 (832-1,330) | 0.999 (0.998-1.001) | 0.287 |
| C-reactive protein (mg/dL) | 2.86 (1.16-7.68) | 3.40 (0.57-9.91) | 0.941 (0.845-1.048) | 0.266 |
| Albumin (g/dL) | 3.1 (2.4-3.8) | 3.2 (2.6-3.8) | 0.838 (0.371-1.895) | 0.672 |
Data are presented as the number (%) or median (interquartile range).
COPD: chronic obstructive pulmonary disease, OR: odds ratio, CI: confidence interval
Factors associated with ESBL-producing bacteria in the multivariate analysis
Based on the results of the univariate analysis, the use of cephem, quinolone, and macrolide in the past year and the presence of a nasogastric tube were included in the multivariate analysis. Due to the small number of patients, a multivariate analysis for each strain was not conducted. The results indicated that the applications of cephems and macrolides were independently associated with ESBL-producing bacteria isolation, whereas the use of quinolone and the presence of a nasogastric tube were not (Table 4).
Table 4.
Results of a Multivariate Analysis of the Risk Factors for ESBL-producing K. pneumoniae or E. coli.
| Risk factor | OR | 95% CI | p value |
|---|---|---|---|
| Nasogastric tube | 2.804 | 0.647-12.150 | 0.168 |
| Cephem usage in the past year | 4.130 | 1.233-13.830 | 0.021 |
| Quinolone usage in the past year | 2.549 | 0.806-8.063 | 0.111 |
| Macrolide usage in the past year | 6.365 | 1.922-21.077 | 0.002 |
OR: odds ratio, CI: confidence interval
Discussion
The present study revealed that the use of cephems and macrolides was independently associated with ESBL-producing bacteria isolation. This study included a number of elderly patients, with a median age of 74 years old. Advanced age can contribute to the growth of enterobacteria in the oral cavity (6), probably because elderly people are likely to suffer from gastroesophageal reflex disease resulting from age-related deterioration or surgical operation in these sites.
Although a number of studies previously assessed the risk factors associated with ESBL-producing bacteria in bloodstream or urinary tract infections, those focusing on respiratory infections did not present conclusive results. We summarized the risk factors for ESBL-producing bacteria in bloodstream (Table 5) (3,7-24) and urinary tract infections (Table 6) (25-39). In contrast, only 1 case-control study using the data of 130 patients with hospital-acquired pneumonia demonstrated that cephalosporin usage (OR 3.473) and nasogastric tube feeding (OR 2.488) were independently associated with ESBL-producing K. pneumoniae isolation (40). However, the present study included only patients with K. pneumoniae isolation.
Table 5.
Summary of Major Risk Factors for Extended-spectrum-β Lactamaseproducing Bacteria in Bloodstream Infection.
| Risk factors | References |
|---|---|
| Recent hospitalization | (7) (8) (9) (10) (11) |
| Central venous catheterization | (12) (13) |
| Usage of antibiotic administration regardless of types | (7) (8) (11) (14) (15) (16) (17) (18) |
| β-lactam use | (10) (12) |
| Fluoroquinolone use | (7) (19) (20) |
| Cephalosporin use | (8) (9) (12) (16) (20) (21) (22) (23) (24) |
| Urinary catheterization | (16) (17) (18) |
| Urological disorder | (3) (9) (19) (21) (22) |
| Biliary tract disorder | (3) (9) |
Table 6.
Summary of Major Risk Factors for Extended-spectrum-β Lactamase-producing Bacteria in Urinary Tract Infection.
| Risk factors | References |
|---|---|
| Recent hospitalization | (25) (26) (27) (28) (29) |
| Usage of antibiotic administration regardless of types | (25) (29) (30) (31) (32) (33) |
| β-lactam use | (34) (35) (36) |
| Fluoroquinolone use | (32) (35) |
| Cephalosporin use | (34) (37) |
| Repeated urinary tract infection | (26) (34) (36) (38) |
| Urinary catheterization | (25) (34) |
| Urological disorder | (25) (28) (31) (39) |
The results of the current univariate analysis showed that cephems, carbapenems, and macrolides were more frequently administered in the ESBL-producing K. pneumoniae group than in the non-ESBL-producing K. pneumoniae group. The use of cephem containing β-lactam rings is bacteriologically reasonable as a risk factor for inducing ESBLs. Furthermore, cephems are often prescribed as an oral medicine. The fact that the blood concentration of patients orally administered with cephems does not sufficiently increase may contribute to the development of antibiotic resistance (41). However, most of the cephems used in the present study were administered intravenously, suggesting that not only oral prescription but also intravenous administration of cephem can pose a risk for ESBLs.
Carbapenems are unlikely to have a direct role in the development of ESBLs because ESBL-producing bacteria are killed by carbapenems (42). They are usually administered intravenously during hospitalization, which may increase the risk of antimicrobial resistance transmission. Furthermore, carbapenems might have been used when suspecting the existence of some resistant bacteria. In such cases, a variety of antibiotics, including cephems, may have already been administered a year before the administration of carbapenem, which may be a confounding factor between carbapenem usage and ESBL-producing bacteria. Similarly, macrolides are occasionally used as immunomudulatory agents for chronic respiratory tract inflammations, including diffuse panbronchiolitis and chronic obstructive pulmonary disease (43). These patients are at high risk for frequent bacterial infections and may be administered other antibiotics that may induce the production of ESBLs.
The proportion of patients administered quinolone tended to be higher in the ESBL-producing group than in the non-ESBL-producing E. coli group, but quinolones are not likely to directly produce ESBLs. Of note, approximately 70% of ESBL-producing E. coli are commonly resistant to quinolones (44). In the present study, 11 of 15 (73%) cases of ESBL-producing E. coli were resistant to quinolones. A nationwide surveillance study reported that 77.8% of simple urinary tract infections are caused by E. coli, whereas only 3.4% are caused by K. pneumoniae (44). The use of cephems for urinary tract infections is similar to that of quinolones, which might be a confounding factor between quinolone usage and ESBL-producing E. coli. Thus, the use of quinolone may lead to the survival of E. coli with both quinolone and ESBL resistance. In fact, the multivariate analysis revealed that the use of quinolone was not significant in the present study. These clinical backgrounds regarding which class of antibiotics is preferred for individual types of infection (e.g. urinary tract infections) may explain the difference in risk factors for ESBLs between K. pneumoniae and E. coli.
The strength of this study is that it determined the factors associated with ESBL-producing K. pneumoniae and E. coli isolated from respiratory samples. The results were consistent with those in previous studies focusing on bloodstream and urinary tract infections. K. pneumoniae and E. coli are originally present in the intestinal tract. This intestinal colonization causes both lower respiratory tract infection due to gastroesophageal reflex and urinary tract infection due to bacterial migration from the anus to meatus urinarius (45). Given that the pathogen is derived from the same source, the similar results obtained in the current study appear reasonable.
However, this study also has several potential limitations. First, this study revealed that the use of antibiotics in the past year was associated with ESBL-producing bacteria isolation. However, the methods of using these antibiotics may vary. Further analyses focusing on drug dosage and the duration or frequency of antibiotics may help obtain true risk factors. Second, we did not evaluate the sputum quality, so whether the isolated bacteria denote infection or colonization remains unclear. Nevertheless, colonized pathogens can induce respiratory infectious diseases through the aspiration of oral secretion (46). Indeed, to date, no gold standard for determining whether isolated bacteria denote infection or colonization is available. Finally, since the present study was conducted at a single hospital, the sample size was small, despite collecting cases over the past decade. The prevalence of antibiotic pathogens may be affected by local antibiograms. Thus, a large-scale multicenter study is needed to address this problem.
In conclusion, a history of cephem and macrolide usage can be considered a risk factor for ESBL-producing bacteria isolation from respiratory samples. Physicians need to consider these risk factors when determining antibiotics for treatment of elderly patients with respiratory infections and simultaneously address appropriate antibiotic usage for patients with no risk of exposure to ESBL-producing bacteria.
The study protocol was approved by the Institutional Ethics Committee of Oita University Hospital (approval number: 2304; approval date: May 23, 2022). The requirement for informed consent was waived by the ethics committee because of the retrospective nature of the study.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
The authors thank Dr. Atsushi Yokoyama for the advice and support.
References
- 1.Larramendy S, Deglaire V, Dusollier P, et al. Risk factors of extended-spectrum beta-lactamases-producing Escherichia coli community acquired urinary tract infections: a systematic review. Infect Drug Resist 13: 3945-3955, 2020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Kawamura I, Ohmagari N, Tsukahara M, Kudo T, Kurai H. Surveillance of extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae at a comprehensive cancer center in Japan, 2009-2013. Am J Infect Control 43: 185-187, 2015. [DOI] [PubMed] [Google Scholar]
- 3.Chen Q, Ma G, Cao H, Yang X, Jiang Y. Risk factors and diagnostic markers for Escherichia coli bloodstream infection in older patients. Arch Gerontol Geriatr 93: 104315, 2021. [DOI] [PubMed] [Google Scholar]
- 4.Bader MS, Loeb M, Brooks AA. An update on the management of urinary tract infections in the era of antimicrobial resistance. Postgrad Med 129: 242-258, 2017. [DOI] [PubMed] [Google Scholar]
- 5.Mita Y, Shigemura K, Osawa K, et al. Clinical risk factors for death caused by extended-spectrum beta-lactamase: producing bacteria. Urol Int 102: 205-211, 2019. [DOI] [PubMed] [Google Scholar]
- 6.Belibasakis GN. Microbiological changes of the ageing oral cavity. Arch Oral Biol 96: 230-232, 2018. [DOI] [PubMed] [Google Scholar]
- 7.Richelsen R, Smit J, Laxsen Anru P, Schønheyder HC, Nielsen H. Risk factors of community-onset extended-spectrum β-lactamase Escherichia coli and Klebsiella pneumoniae bacteraemia: an 11-year population-based case - control - control study in Denmark. Clin Microbiol Infect 27: 871-877, 2021. [DOI] [PubMed] [Google Scholar]
- 8.Baek YJ, Kim YA, Kim D, et al. Risk factors for extended-spectrum-β-lactamase-producing Escherichia coli in community-onset bloodstream infection: impact on long-term care hospitals in Korea. Ann Lab Med 41: 455-462, 2021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Xiao Y, Hang Y, Chen Y, et al. A retrospective analysis of risk factors and patient outcomes of bloodstream infection with extended-spectrum β-lactamase-producing Escherichia coli in a Chinese tertiary hospital. Infect Drug Resist 13: 4289-4296, 2020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Rodríguez-Baño J, Picón E, Gijón P, et al. Risk factors and prognosis of nosocomial bloodstream infections caused by extended-spectrum-β-lactamase-producing Escherichia coli. J Clin Microbiol 48: 1726-1731, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Tumbarello M, Spanu T, Sanguinetti M, et al. Bloodstream infections caused by extended-spectrum-β-lactamase-producing Klebsiella pneumoniae: risk factors, molecular epidemiology, and clinical outcome. Antimicrob Agents Chemother 50: 498-504, 2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Chopra T, Marchaim D, Johnson PC, et al. Risk factors for bloodstream infection caused by extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae: a focus on antimicrobials including cefepime. Am J Infect Control 43: 719-723, 2015. [DOI] [PubMed] [Google Scholar]
- 13.Tuon FF, Kruger M, Terreri M, Penteado-Filho SR, Gortz L. Klebsiella ESBL bacteremia-mortality and risk factors. Braz J Infect Dis 15: 594-598, 2011. [DOI] [PubMed] [Google Scholar]
- 14.Komatsu Y, Kasahara K, Inoue T, et al. Molecular epidemiology and clinical features of extended-spectrum beta-lactamase- or carbapenemase-producing Escherichia coli bacteremia in Japan. PLoS One 13: e0202276, 2018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Quirante OF, Cerrato SG, Pardos SL. Risk factors for bloodstream infections caused by extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae. Braz J Infect Dis 15: 370-376, 2011. [DOI] [PubMed] [Google Scholar]
- 16.Wu UI, Yang CS, Chen WC, Chen YC, Chang SC. Risk factors for bloodstream infections due to extended-spectrum β-lactamase-producing Escherichia coli. J Microbiol Immunol Infect 43: 310-316, 2010. [DOI] [PubMed] [Google Scholar]
- 17.Hsieh CJ, Shen YH, Hwang KP. Clinical implications, risk factors and mortality following community-onset bacteremia caused by extended-spectrum β-lactamase (ESBL) and non-ESBL producing Escherichia coli. J Microbiol Immunol Infect 43: 240-248, 2010. [DOI] [PubMed] [Google Scholar]
- 18.Kang CI, Kim SH, Kim DM, et al. Risk factors for and clinical outcomes of bloodstream infections caused by extended-spectrum beta-lactamase-producing Klebsiella pneumoniae. Infect Control Hosp Epidemiol 25: 860-867, 2004. [DOI] [PubMed] [Google Scholar]
- 19.Isendahl J, Giske CG, Tegmark Wisell K, Ternhag A, Nauclér P. Risk factors for community-onset bloodstream infection with extended-spectrum β-lactamase-producing Enterobacteriaceae: national population-based case-control study. Clin Microbiol Infect 25: 1408-1414, 2019. [DOI] [PubMed] [Google Scholar]
- 20.Kaya O, Akcam FZ, Gonen I, Unal O, Ceylan T. Risk factors for bacteremia due to extended-spectrum beta-lactamase-producing Escherichia coli in a Turkish hospital. J Infect Dev Ctries 7: 507-512, 2013. [DOI] [PubMed] [Google Scholar]
- 21.Xiao T, Wu Z, Shi Q, et al. A retrospective analysis of risk factors and outcomes in patients with extended-spectrum beta-lactamase-producing Escherichia coli bloodstream infections. J Glob Antimicrob Resist 17: 147-156, 2019. [DOI] [PubMed] [Google Scholar]
- 22.Quan J, Zhao D, Liu L, et al. High prevalence of ESBL-producing Escherichia coli and Klebsiella pneumoniae in community-onset bloodstream infections in China. J Antimicrob Chemother 72: 273-280, 2017. [DOI] [PubMed] [Google Scholar]
- 23.Mosqueda-Gómez JL, Montaño-Loza A, Rolón AL, et al. Molecular epidemiology and risk factors of bloodstream infections caused by extended-spectrum β-lactamase-producing Klebsiella pneumoniae: a case - control study. Int J Infect Dis 12: 653-659, 2008. [DOI] [PubMed] [Google Scholar]
- 24.Du B, Long Y, Liu H, et al. Extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae bloodstream infection: risk factors and clinical outcome. Intensive Care Med 28: 1718-1723, 2002. [DOI] [PubMed] [Google Scholar]
- 25.Koksal E, Tulek N, Sonmezer MC, et al. Investigation of risk factors for community-acquired urinary tract infections caused by extended-spectrum beta-lactamase Escherichia coli and Klebsiella species. Investig Clin Urol 60: 46-53, 2019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Lee H, Han SB, Kim JH, Kang S, Durey A. Risk factors of urinary tract infection caused by extended spectrum β-lactamase-producing Escherichia coli in emergency department. Am J Emerg Med 36: 1608-1612, 2018. [DOI] [PubMed] [Google Scholar]
- 27.Hertz FB, Schønning K, Rasmussen SC, et al. Epidemiological factors associated with ESBL- and non ESBL-producing E. coli causing urinary tract infection in general practice. Infect Dis (Lond) 48: 241-245, 2016. [DOI] [PubMed] [Google Scholar]
- 28.Søgaard M, Heide-Jørgensen U, Vandenbroucke JP, Schønheyder HC, Vandenbroucke-Grauls C. Risk factors for extended-spectrum β-lactamase-producing Escherichia coli urinary tract infection in the community in Denmark: a case - control study. Clin Microbiol Infect 23: 952-960, 2017. [DOI] [PubMed] [Google Scholar]
- 29.Castillo-Tokumori F, Irey-Salgado C, Málaga G. Worrisome high frequency of extended-spectrum bet-lactamase-producing Escherichia coli in community-acquired urinary tract infections: a case - control study. Int J Infect Dis 55: 16-19, 2017. [DOI] [PubMed] [Google Scholar]
- 30.Bou Chebl R, Assaf M, Kattouf N, et al. The prevalence and predictors of extended spectrum B-lactamase urinary tract infections among emergency department patients: a retrospective chart review. Am J Emerg Med 49: 304-309, 2021. [DOI] [PubMed] [Google Scholar]
- 31.Tüzün T, Sayın Kutlu S, Kutlu M, Kaleli İ. Risk factors for community-onset urinary tract infections caused by extended-spectrum β-lactamase-producing Escherichia coli. Turk J Med Sci 49: 1206-1211, 2019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Kang CI, Wi YM, Lee MY, et al. Epidemiology and risk factors of community onset infections caused by extended-spectrum β-lactamase-producing Escherichia coli strains. J Clin Microbiol 50: 312-317, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Park SH, Choi SM, Lee DG, et al. Impact of extended-spectrum β-lactamase production on treatment outcomes of acute pyelonephritis caused by Escherichia coli in patients without health care-associated risk factors. Antimicrob Agents Chemother 59: 1962-1968, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Savatmorigkorngul S, Poowarattanawiwit P, Sawanyawisuth K, Sittichanbuncha Y. Factors associated with extended spectrum β-lactamase producing Escherichia coli in community-acquired urinary tract infection at hospital emergency department, Bangkok, Thailand. Southeast Asian J Trop Med Public Health 47: 227-233, 2016. [PubMed] [Google Scholar]
- 35.Søraas A, Sundsfjord A, Sandven I, Brunborg C, Jenum PA. Risk factors for community-acquired urinary tract infections caused by ESBL-producing Enterobacteriaceae - a case-control study in a low prevalence country. PLoS One 8: e69581, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Azap OK, Arslan H, Serefhanoğlu K, et al. Risk factors for extended-spectrum β-lactamase positivity in uropathogenic Escherichia coli isolated from community-acquired urinary tract infections. Clin Microbiol Infect 16: 147-151, 2010. [DOI] [PubMed] [Google Scholar]
- 37.Calbo E, Romaní V, Xercavins M, et al. Risk factors for community-onset urinary tract infections due to Escherichia coli harbouring extended-spectrum β-lactamases. J Antimicrob Chemother 57: 780-783, 2006. [DOI] [PubMed] [Google Scholar]
- 38.Almomani BA, Hayajneh WA, Ayoub AM, Ababneh MA, Al Momani MA. Clinical patterns, epidemiology and risk factors of community-acquired urinary tract infection caused by extended-spectrum beta-lactamase producers: a prospective hospital case-control study. Infection 46: 495-501, 2018. [DOI] [PubMed] [Google Scholar]
- 39.Blanco VM, Maya JJ, Correa A, et al. [Prevalence and risk factors for extended-spectrum β-lactamase-producing Escherichia coli causing community-onset urinary tract infections in Colombia]. Enferm Infecc Microbiol Clin 34: 559-565, 2016. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Deng J, Li YT, Shen X, et al. Risk factors and molecular epidemiology of extended-spectrum β-lactamase-producing Klebsiella pneumoniae in Xiamen, China. J Glob Antimicrob Resist 11: 23-27, 2017. [DOI] [PubMed] [Google Scholar]
- 41.Mazzei T, Dentico P. The pharmacokinetics of oral cephalosporins. Clin Microbiol Infect 6: 53-54, 2000. [DOI] [PubMed] [Google Scholar]
- 42.Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. Infectious Diseases Society of America guidance on the treatment of extended-spectrum β-lactamase producing Enterobacterales (ESBL-E), carbapenem-resistant enterobacterales (CRE), and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa). Clin Infect Dis 72: e169-e183, 2021. [DOI] [PubMed] [Google Scholar]
- 43.Kanoh S, Rubin BK. Mechanisms of action and clinical application of macrolides as immunomodulatory medications. Clin Microbiol Rev 23: 590-615, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Hayami H, Takahashi S, Ishikawa K, et al. Nationwide surveillance of bacterial pathogens from patients with acute uncomplicated cystitis conducted by the Japanese surveillance committee during 2009 and 2010: antimicrobial susceptibility of Escherichia coli and Staphylococcus saprophyticus. J Infect Chemother 19: 393-403, 2013. [DOI] [PubMed] [Google Scholar]
- 45.Houard M, Rouzé A, Ledoux G, et al. Relationship between digestive tract colonization and subsequent ventilator-associated pneumonia related to ESBL-producing Enterobacteriaceae. PLoS One 13: e0201688, 2018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Paju S, Scannapieco FA. Oral biofilms, periodontitis, and pulmonary infections. Oral Dis 13: 508-512, 2007. [DOI] [PMC free article] [PubMed] [Google Scholar]