The role of extended-spectrum β-lactamase (ESBL)-producing or multidrug-resistant (MDR) organisms in patients with sepsis secondary to urinary traction infection (UTI) has not been investigated extensively in the intensive care unit (ICU) setting.
Patients with UTI sepsis admitted to the ICU were retrospectively enrolled in this study (January 2009–December 2012). We investigated the impact of ESBL-producing and ESBL-negative MDR organisms on hospital outcome.
In total, 94 patients were enrolled (median age, 73.0 years; female, 81.9%), and ESBL-producing and ESBL-negative MDR organisms accounted for 20.2% (n = 19) and 30.9% (n = 29), respectively. Both patients with ESBL-producing and ESBL-negative MDR organisms were more likely to experience a delay in adequate antibiotic therapy than those with non-ESBL/non-MDR organisms (p < 0.001 and p = 0.032, respectively). However, only patients with ESBL-producing organisms showed a higher mortality rate (ESBL vs. ESBL-negative MDR vs. non-ESBL/non-MDR, 31.6% vs. 10.3%.vs. 10.9%, respectively). In multivariate analyses, ESBL production was significantly associated with hospital mortality (odds ratio, 11.547; 95% confidence interval, 1.047–127.373), and prior admission was a significant predictor of ESBL production.
Although both ESBL-producing and ESBL-negative MDR organisms are associated with delayed administration of appropriate antibiotics, only ESBL production is a significant predictor of hospital mortality among patients with UTI sepsis in the ICU setting.
Urinary tract infection (UTI) is one of the most common infectious diseases in both community and hospital settings and may be responsible for 20–30% of all cases of sepsis.[
Multidrug resistance (MDR) is an increasing concern worldwide, and extended-spectrum β-lactamase (ESBL) is one of the most important plasmid-mediated β-lactamases produced by drug-resistant enterobacteria. Recently, the prevalence of ESBL producers in UTIs caused by
To date, many authors have investigated the prevalence of and risk factors for MDR or ESBL in patients with UTI.[
This was a retrospective cohort study conducted in a 16-bed medical ICU at Hallym University Sacred Heart Hospital (an 800-bed tertiary university hospital) between January 2009 and December 2012. Adult patients (≥ 18 years) diagnosed with UTI sepsis and admitted to the ICU were included in the study. The following were used as exclusion criteria: no organisms identified or polymicrobial infection, no outcome data due to transfer to another hospital, do-not-resuscitate status or treatment restrictions, cardiopulmonary resuscitation at an emergency department or ICU admission, or an immunocompromised status (e.g., inherited genetic diseases, acquired diseases [e.g., HIV, solid or hematologic cancer], and medications [e.g., steroid, chemotherapy, radiotherapy, other immunosuppressant agents]). However, patients were eligible when their cancers had been in complete remission for > 6 months or when they were being treated with a low-dose steroid (i.e., ≤ 10 mg/day prednisolone or equivalent).
We collected the following data: age, gender, prior history, comorbid illnesses, Charlson comorbidity index, and Simplified Acute Physiology Score (SAPS) II at ICU admission. Laboratory data, including routine chemistry and cardiac markers, were also collected. We evaluated the inappropriateness of empirical antibiotics and measured time intervals (i.e., hour) from ICU admission to the treatment with appropriate antibiotics for all patients that were enrolled. We investigated the ICU and hospital mortality rates, as well as the length of hospital stay (i.e., from ICU admission to hospital discharge). The Institutional Review Board at Hallym University Sacred Heart Hospital approved this study (IRB No. 2014-I134), and the requirement for informed consent was waived due to the retrospective nature of the study.
UTI sepsis was defined by the International Sepsis Forum Consensus Conference Definitions of Infection in the ICU.[
Sepsis was defined as the probable or documented presence of infection in addition to systemic manifestations of infection. Severe sepsis was defined as sepsis plus sepsis-induced organ dysfunction or tissue hypoperfusion. Septic shock was defined as severe sepsis with hypotension despite adequate fluid resuscitation.[
Species identification and antimicrobial susceptibility tests were performed using the MicroScan Neg Breakpoint Combo Panel Type 42 (Siemens Healthcare Diagnostics, Inc., West Sacramento, CA, USA) in accordance with the manufacturer’s instructions. The production of ESBL was determined by a double-disk synergy test as described by the Clinical and Laboratory Standards Institute.[
In terms of antibiotic treatments, patients were treated empirically according to the treatment guidelines at ICU admission.[
The primary outcome was the relationship between ESBL-producing or ESBL-negative MDR organisms and hospital mortality in patients with UTI sepsis in the ICU setting. The secondary outcomes were the initial rates of inappropriate antibiotic administration for ESBL-producing or ESBL-negative MDR organisms and several risk factors for ESBL production in patients with UTI sepsis.
Data are presented as median (interquartile range, IQRs) for continuous data and percentage for categorical data. For comparisons between two groups, the Mann-Whitney
In total, 125 patients with UTI sepsis, severe sepsis, or septic shock were initially screened. Of these, 94 were enrolled in the present study (
Among the causal organisms,
In this study, β-lactams (n = 27) and quinolones (n = 28) were the most commonly used agents for empirical treatments (carbapenems, n = 22; β-lactam/β-lactamase inhibitors, n = 10; β-lactam/β-lactamase inhibitor and quinolone combinations, n = 6; other combinations, n = 1), and 16.0% (15/94) of all enrolled patients initially received inappropriate antibiotics. However, the rates of initial inappropriate antibiotic administration were higher in both patients with ESBL-producing and ESBL-negative MDR organisms compared with cases with non-ESBL/non-MDR organisms (42.1 % vs. 20.7% vs. 2.2%, respectively;
ICU and hospital mortality rates were 12.8% (12/94) and 14.9% (14/94), respectively. Patients with ESBL producers showed a higher mortality rate than the other two groups (31.6% vs. 10.3% [ESBL-negative MDR organisms] vs. 10.9% [non-ESBL/non-MDR organisms];
In univariate analyses, Charlson comorbidity index and comorbid illnesses were not associated with hospital mortality. However, hematocrit, brain natriuretic peptide (BNP), SAPS II, ESBL production, and inappropriate antibiotics were significant factors (
Among the clinical and laboratory variables, prior admission within one year (p = 0.005), hospital-acquired infection (p = 0.007), and a bed-ridden state (p = 0.009) were more frequently identified in ESBL-positive patients than in ESBL-negative patients. In the multivariate model (Hosmer-Lemeshow goodness-of-fit test, chi-square = 3.119, and p = 0.682), prior admission within one year (p = 0.032) and hospital-acquired infection (p = 0.047) were significantly associated with ESBL production; however, when the age variable was added to the model, only prior admission within one year (p = 0.032) was a significant risk factor.
This study had several findings; first, ESBL-producing and ESBL-negative MDR organisms accounted for 20.2% and 33.9%, respectively, of infections in patients admitted to the ICU for UTI sepsis. Second, both ESBL production and ESBL-negative MDR were associated with a delay in the administration of appropriate antibiotic treatment; however, only ESBL production, not ESBL-negative MDR, was an independent risk factor for hospital mortality in patients with UTI sepsis. Third, a history of hospital admission was a significant risk factor for ESBL production.
There has been an increase in the emergence of drug-resistant organisms in the past two decades, and many authors have studied the incidence and risk factors of ESBL production in patients with UTI.[
Worldwide, 17.9% of
Many risk factors associated with ESBL production have been identified in previous studies,[
Infections caused by ESBL or MDR organisms are known to be associated with increased morbidity and mortality,[
With regard to patient outcome, we reported a hospital mortality of 14.9% in the present study. Although this result is higher than those of other studies,[
Many authors have discussed ESBL production rather than MDR when studying patients with UTI. Although all ESBL producers were MDR organisms in our study, we found that only ESBL production, not ESBL-negative MDR, was significantly associated with increased mortality in the multivariate analysis. This suggests that the important prognostic factor among patients with UTI sepsis admitted to the ICU is not whether the causal organism is MDR, but rather, whether the organism is an ESBL producer. In previous studies, Menashe et al.[
There were several limitations to this study. First, the 95% CIs for ESBL producers in the multivariate analysis were wide because the sample size was small. Second, there is a possibility of unintended bias due to the retrospective nature of the study. Third, the ESBL-negative MDR organisms were heterogeneous and may have different antibiotic resistance mechanisms. Therefore, these limitations should be considered when the results are interpreted. However, despite these limitations, our study had several major strengths. First, we collected an extensive range of patient data, including the status of indwelling urinary catheters, structural lesions in the urinary tract, and prior history of UTI. In addition, we focused only on septic patients with a severe illness diagnosis who had been admitted to the ICU.
This study determined that, although both ESBL-producing and ESBL-negative MDR organisms are associated with a delay in appropriate empirical treatments, only ESBL production, not ESBL-negative MDR, is a significant predictor of hospital mortality. Therefore, it is necessary to evaluate the possibility of ESBL-producing organisms when deciding on empirical antibiotic treatment, and ESBL production should be considered when diagnosing patients with UTI sepsis in the ICU setting.
No potential conflict of interest relevant to this article was reported.
The authors thank resident physicians and registered nurses in the ICU for their dedication to this study.
Schematic overview of the study. CPR: cardiopulmonary resuscitation; DNR: do-not-resuscitate.
Rates of initial inappropriate antibiotic administration in patients with extended-spectrum β-lactamase, ESBL-negative multi-drug-resistant (ESBL-negative MDR), and non-ESBL/non-MDR organisms (42.1 % vs. 20.7% vs. 2.2%, respectively; ESBL vs. non-ESBL/non-MDR, p < 0.001; ESBL-negative MDR vs. non-ESBL/non-MDR, p = 0.012). ESBL: extended-spectrum β-lactamase; MDR: multidrug-resistant.
Kaplan-Meier curves to compare time intervals to appropriate antibiotic therapy among the three groups. Both patients with extended-spectrum β-lactamase (5.0 h [1.5–72.0 h]) and ESBL-negative multidrug-resistant (ESBL-negative MDR; 2.0 h [1.5–4.5 h]) organisms had a longer time to appropriate antibiotic treatment than those with non-ESBL/non-MDR organisms (2 h [1.5–3.0 h]; p < 0.001 and p = 0.032, respectively, by log-rank test). ESBL: extended-spectrum β-lactamase; MDR: multidrug-resistant.
Hospital mortality rates in patients with extended-spectrum β-lactamase, ESBL-negative multidrug-resistant (ESBL-negative MDR), and non-ESBL/non-MDR organisms (31.6% vs. 10.3% vs. 10.9%, respectively; ESBL organisms vs. others, p = 0.033). ESBL: extended-spectrum β-lactamase; MDR: multidrug-resistant.
Patient characteristics
Variables | N (%) |
---|---|
Age, yr | 73.0 (65.0–81.0) |
Gender, M/F | 17/77 |
Co-morbid illnesses | |
Charlson comorbidity index | 5.5 (4.0–7.0) |
Diabetes | 40 (42.6%) |
Hypertension | 53 (56.4%) |
COPD/BA | 3 (3.2%) |
CVA | 29 (30.9%) |
Heart disease | 14 (14.9%) |
Liver cirrhosis | 5 (5.3%) |
CKD | 16 (17.0%) |
Cancer | 9 (9.6%) |
SAPS II at admission | 47.0 (41.0–56.0) |
Prior admission within one year | 52 (55.3%) |
CA/HCA/HA | 55/25/14 |
Bacteremia | 65 (69.1%) |
Severe sepsis/Septic shock | 21 (22.3%)/57 (60.6%) |
Catheter-associated UTI |
20 (21.3%) |
Urinary catheter for two weeks or longer. COPD: chronic obstructive pulmonary disease; BA: bronchial asthma; CVA: cerebrovascular accident; CKD: chronic kidney disease; SAPS: simplified acute physiology score; CA: community-acquired; HCA: healthcare-associated; HA: hospital-acquired; UTI: urinary traction infection.
Causal organisms of UTI sepsis
Organisms | N (%) | Bacteremia | ESBL | MDR |
---|---|---|---|---|
66 (70.2%) | 46 (69.7%) | 14 (21.2%) | 21 (31.8%) | |
7 (7.4%) | 7 (100.0%) | 3 (42.9%) | 1 (14.3%) | |
6 (6.4%) | 4 (66.7%) | 2 (33.3%) | 1 (16.7%) | |
4 (4.3%) | 1 (25.0%) | 0 (0.0%) | 1 (25.0%) | |
1 (1.1%) | 1 (100.0%) | 0 (0.0%) | 1 (100.0%) | |
3 (3.2%) | 1 (33.3%) | 0 (0.0%) | 2 (66.7%) | |
1 (1.1%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | |
1 (1.1%) | 1 (100.0%) | 0 (0.0%) | 0 (0.0%) | |
1 (1.1%) | 1 (100.0%) | 0 (0.0%) | 0 (0.0%) | |
1 (1.1%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | |
1 (1.1%) | 1 (100.0%) | 0 (0.0%) | 1 (100.0%) | |
1 (1.1%) | 1 (100.0%) | 0 (0.0%) | 1 (100.0%) | |
1 (1.1%) | 1 (100.0%) | - | - |
ESBL-negative MDR. UTI: urinary traction infection; ESBL: extended-spectrum β-lactamase; MDR: multidrug-resistance.
Clinical and laboratory variables of survivors and non-survivors
Variables | Survivors (n = 80) | Non-survivors (n = 14) | p value | p value |
---|---|---|---|---|
Age, yr | 73.0 (65.3–80.8) | 73.5 (66.8–82.3) | 0.614 | - |
Gender, M/F | 16/64 | 1/13 | 0.435 | - |
Charlson comorbidity index | 5.0 (4.0–7.0) | 6.0 (4.8–8.0) | 0.241 | - |
Laboratory findings |
||||
Hematocrit, % | 34.1 (29.1–37.9) | 28.1 (26.1–33.2) | 0.046 | 0.113 |
Lactate, mmol/L | 3.8 (2.3–5.4) | 4.5 (3.3–10.5) | 0.079 | - |
BNP, pg/ml | 236.2 (119.9–490.5) | 1102.6 (389.0–2234.4) | 0.001 | 0.024 |
Troponin I, ng/ml | 0.03 (0.02–0.11) | 0.13 (0.04–0.22) | 0.074 | - |
SAPS II at admission | 45.0 (40.0–51.8) | 60.5 (56.3–74.8) | < 0.001 | < 0.001 |
Prior admission within one year | 41 (51.3%) | 11 (78.6%) | 0.058 | - |
Catheter-associated UTI |
17 (21.3%) | 3 (21.4%) | 0.988 | - |
Hospital-acquired infection | 11 (18.3%) | 3 (21.4%) | 0.433 | - |
Prior history of UTI within one year | 14 (17.5%) | 5 (35.7%) | 0.117 | - |
Structural abnormalities or lesions | 25 (31.3%) | 5 (35.7%) | 0.762 | - |
ESBL production | 13 (16.3%) | 6 (42.9%) | 0.033 | 0.046 |
ESBL-negative MDR | 26 (32.5%) | 3 (21.4%) | 0.376 | - |
Bacteremia | 55 (68.8%) | 10 (71.4%) | 1.000 | - |
Inappropriate antibiotics | 10 (12.5%) | 5 (35.7%) | 0.044 | 0.210 |
Multivariate logistic regression analysis.
Other laboratory data (white blood cell count, platelet, blood urea nitrogen, bilirubin, and albumin) were not significantly associated with hospital mortality.
Urinary catheter for two weeks or longer. BNP: brain natriuretic peptide; SAPS: simplified acute physiology score; UTI: urinary tract infection; ESBL; extended-spectrum β-lactamase; MDR: multi-drug resistance.