JAC Advance Access published online on July 20, 2007
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkm279
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Impact of antibiotic resistance and of adequate empirical antibiotic treatment in the prognosis of patients with Escherichia coli bacteraemia
1 Internal Medicine Service, Sierrallana Hospital, Barrio de Ganzo s/n, Torrelavega, Cantabria, Spain 2 Clinical Pharmacology Service, University Hospital ‘Marqués de Valdecilla’, Avda de Valdecilla s/n, 39008 Santander, Spain 3 Biochemistry Service, Sierrallana Hospital, Barrio de Ganzo s/n, 39300 Torrelavega, Cantabria, Spain 4 Microbiology Service, Sierrallana Hospital, Barrio de Ganzo s/n, 39300 Torrelavega, Cantabria, Spain 5 Microbiology Service, University Hospital ‘Marqués de Valdecilla’, Avda de Valdecilla s/n, 39008 Santander, Spain 6 Department of Molecular Biology, School of Medicine, University of Cantabria, Avda Cardenal Herrera Oria s/n, 39008 Santander, Spain
* Corresponding author. Tel: +34-942-847400; Fax: +34-942-847501; E-mail: gpf{at}mundivia.es
Received 3 March 2007; returned 21 April 2007; revised 25 June 2007; accepted 2 July 2007
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Abstract |
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Background: Escherichia coli is the most frequent Gram-negative organism causing bacteraemia. There are few data about prognostic factors of bloodstream infections due to E. coli. In particular, the consequences of antibiotic resistance and of adequate empirical antibiotic treatment on outcome remain broadly unknown.
Methods: We conducted a retrospective cohort study of patients with E. coli bacteraemia between January 1997 and June 2005 to identify any association between antibiotic resistance, adequacy of empirical antibiotic therapy and mortality.
Results: Of 663 patients with E. coli bacteraemia, 36 (5.4%) died. Patients with multidrug-resistant (MDR) E. coli bacteraemia had a significantly lower frequency of correct empirical antibiotic treatment than patients with non-MDR E. coli bacteraemia [relative risk (RR) 0.53; 95% confidence interval (CI) 0.48–0.67], and also had a significantly higher mortality (RR 3.31; 95% CI 1.72–6.36). An association between the number of antibiotics to which E. coli was resistant with adequacy of empirical antibiotic (P < 0.001) and with mortality (P < 0.001) was detected. After adjustment for other significant risk factors and confounders, the inadequacy of empirical antibiotic treatment was associated with an increased mortality (adjusted OR 2.98; 95% CI 1.25–7.11). When the adequacy of empirical treatment was excluded from the model, the presence of MDR E. coli in blood cultures was also associated with the prognosis (adjusted OR 3.11; 95% CI 1.3–7.44). In multivariate analysis, other variables associated with the outcome were age, the presence of severe sepsis or shock, Charlson index score and a non-urinary origin of the bacteraemia.
Conclusions: Adequacy of empirical antibiotic treatment is an independent risk factor for mortality in patients with E. coli bacteraemia. MDR E. coli bacteraemia had a worse prognosis due, at least in part, to a lower frequency of correct empirical treatment.
Key Words: bloodstream infections , antimicrobial susceptibility , mortality , inadequate therapy , antimicrobial treatments , Gram-negative bacteria
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Introduction |
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Escherichia coli is the most frequent Gram-negative organism causing bacteraemia.1,2 Despite this fact, few data exist regarding prognostic factors of bloodstream infections due to E. coli.3–8 Over the last two decades, there has been a marked increase in infections caused by antibiotic-resistant E. coli that could have changed the outcome in patients with bacteraemia. Multidrug-resistant (MDR) E. coli and particularly extended-spectrum ß-lactamase (ESBL)-producing E. coli are of great concern due to their increased incidence and their resistance to a broad range of ß-lactams and to other groups of antimicrobial agents.9–12 This increasing resistance contributes to limit treatment options and may affect the prognosis of the E. coli infections.13–17 Promptness of adequate antibiotic therapy can influence the outcome of E. coli bloodstream infections. Growing resistance to antibiotics may lead to an increase in inappropriate empirical antimicrobial treatment of infections with a delay in the correct therapy.18,19 Knowledge of the relationships between MDR E. coli bacteraemia, adequacy of empirical therapy and outcome are key in order to establish strategies that may improve the prognosis of patients with bloodstream infections caused by this microorganism.
In this study, we evaluated cases of bloodstream infection due to E. coli that occurred in a single hospital from January 1997 to June 2005. The primary objective of this study was to specifically evaluate the association between inadequate empirical treatment and mortality due to E. coli bacteraemia with special emphasis on the study of MDR E. coli.
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Population studied
The Sierrallana Hospital is an adult acute-care centre in Torrelavega, a city in the province of Cantabria, Spain, that forms part of a health district of 160 000 inhabitants. It is a community teaching hospital with 250 beds that has 
8000 admissions and 65 000 assistances at the emergency service annually. It includes most major departments and specialties, except transplantation, thoracic, cardiovascular surgery and neurosurgery units.
Blood cultures are performed in around 1800 patients per year in the hospital. A retrospective cohort study design was employed, with the main outcome measure being hospital mortality. The microbiology laboratory database was used to identify patients with E. coli bacteraemia. To study prognostic factors, a comparison of surviving and non-surviving patients during hospital stay was carried out. For these purposes, we retrospectively examined all episodes of documented E. coli bacteraemia from January 1997 to June 2005. Only the first episode of bacteraemia on each admission was included. All charts except two were available for reviewing. A standardized data collection form was used to review the hospital records. The following data were collected: age; sex; underlying diseases; dates of hospital admission and discharge; temperature, systolic and diastolic blood pressures and level of consciousness, when blood cultures were performed; presence of sepsis, severe sepsis or shock at the moment of blood culture extraction; specific antimicrobials administered during hospitalization; dates of beginning and finishing of antimicrobial administration; surgical procedures; and hospitalization in an intensive care unit. The study was approved by the Institutional Review Board of the hospital.
Clinically significant bacteraemia was defined as at least one positive blood culture together with clinical features compatible with systemic inflammatory response syndrome. Bacteraemia was considered to have been nosocomially acquired if appearing 48 h after admission and no evidence of infection was present on admission. The bacteraemia was categorized as polymicrobial if additional microorganisms were recovered from the blood cultures. The source of the bacteraemia was determined on the basis of the isolation of E. coli from the presumed portal of entry and clinical evaluation. Renal insufficiency was indicated by a creatinine value >2.0 mg/dL. Neutropenia was defined as an absolute neutrophil count of 
500 cells/mm3 at the onset of the bacteraemia. Immunosuppression was defined as the presence of neutropenia or HIV infection (with CD4 count 350 cells/mm3), or receipt of immunosuppressive agents. Co-morbidities were assessed by using the Charlson co-morbidity score.20 Sepsis, severe sepsis and septic shock were defined according to the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference.21 Empirical antimicrobial therapy was judged to be either adequate or inadequate on the basis of the in vitro susceptibility of an isolated organism, and/or the initiation of antibiotic treatment within 24 h of blood culture extraction. Oxyimino-ß-lactams (cefuroxime, cefotaxime, ceftriaxone, ceftazidime and aztreonam) were considered to be inappropriate regardless of the MIC for the treatment of infections caused by ESBL-producing E. coli. Therapy with urinary antiseptics such as norfloxacin, fosfomycin, pipemidic acid or nalidixic acid was considered inadequate.
The common practice for blood cultures at our hospital is to obtain 20 mL of venous blood and to inoculate it in equal parts into one aerobic (BacT/ALERT FA aerobic, bioMérieux Corporation, Durham, NC, USA) and one anaerobic blood culture bottle (BacT/ALERT FN, bioMérieux). Blood extraction is performed by nurses, from a peripheral vein three times at intervals of 30 min, sent to the microbiology laboratory and loaded into the blood culture instrument (BacT/ALERT microbial detection system, bioMérieux). E. coli strains recovered from blood were identified and tested for antimicrobial susceptibility by MicroScan (Dade Behring, Sacramento, CA, USA) or BD Phoenix (Becton–Dickinson Biosciences, Sparks, MD, USA) automated systems. ESBL production was screened at the same time by the double disc synergy method as a complementary test for automated systems.22,23 In addition, ESBL was confirmed as indicated by the CLSI (formerly the NCCLS), using discs of cefotaxime and ceftazidime with or without clavulanic acid. After February 2004 when an ESBL confirmation test was observed, the presence of ESBL-encoding genes in the corresponding microorganisms was detected by PCR and sequencing using specific primers for TEM, SHV, CTX-M1 and CTX-M9 groups as previously described.23,24 The DNA sequences were aligned with the GenBank/EMBL sequences using BLAST software (available at http://www.ncbi.nlm.nih.gov/BLAST/). MICs were interpreted according to CLSI guidelines.25 Organisms reported as intermediate in susceptibility to a particular antibiotic were classified as non-susceptible for this report, unless otherwise indicated. MDR E. coli was defined as an isolate producing ESBL, presenting hyperproducing AmpC or hyperproducing SHV-1 phenotypes and/or showing resistance to three or more of the following antibiotics: amoxicillin/clavulanate, cefotaxime or ceftazidime, ciprofloxacin, gentamicin, piperacillin/tazobactam and trimethoprim/sulfamethoxazole.
As a routine practice in our hospital, a positive finding of microbial growth in the blood culture is reported to the attending physicians before the results of antimicrobial susceptibility testing are known and the organism identification is established.
Categorical data were compared by the 
2 or Fisher's exact tests. Quantitative data were compared by Student's t-test or the Mann–Whitney U-test, as appropriate. The 2 test for linear trend was used to assess trends over time. Variables with a P value of 0.05 in the univariate analysis were candidates for multivariate analysis. In stepwise logistic regression analysis, factors were added to a base model by forward selection, followed by a comparison of goodness of fit (Hosmer–Lemeshow method). The level of significance was set at P < 0.05. The SPSS (version 12) software package was used for all analyses.
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Results |
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Patient population
During the study period, blood cultures were performed in 15 045 patients and were positive in 2241 patients (14.9%). In 663 patients (4.4%), E. coli was isolated from blood cultures. Of the patients with E. coli bacteraemia, 525 (79.2%) were hospitalized, so the calculated average incidence of E. coli bacteraemia was 9.8/1000 admissions/year. The other 138 patients were diagnosed with E. coli bacteraemia after the patients had been discharged from the emergency department, and re-evaluated in an outpatient clinic. The mean ± standard deviation patient age was 70.7 ± 16.2 years (range 14–98), and 339 (51.1%) patients were male. In 62 (9.4%) cases, the bacteraemia was nosocomial and in six cases (0.9%), it was acquired in the intensive care unit. In 43 (6.5%) patients the bacteraemia was polymicrobial. The most frequent bacteria isolated in combination with E. coli were Bacteroides spp. in eight patients, viridans group streptococci in seven cases, Proteus spp. in four cases and Enterococcus faecalis in four cases. Among 25 patients with immunosuppression (3.8%), nine were treated with steroids, four had HIV infection and three had neutropenia. Sixty-five patients (9.8%) had severe sepsis and four (0.6%) had septic shock as a manifestation of the E. coli bacteraemia. Thirty-six (5.4%) patients died during hospital stay, after a mean of 10.8 days (range 0–37 days) of the bacteraemia. Demographics and clinical characteristics of these patients are listed in Table 1.
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Antibiotic resistance
The antibiotic susceptibility pattern of E. coli isolated from blood cultures is reflected in Table 2. Only 246 of the cases of E. coli bacteraemia (37.1%) were caused by E. coli susceptible to all of the tested antibiotics, 87 (13.1%) by MDR E. coli, 22 (3.3%) by ESBL-producing E. coli, 3 by AmpC-hyperproducing E. coli and 1 by an SHV-1-hyperproducing E. coli. With respect to the type of ESBL, of the nine isolates analysed, two produced an SHV-2 and seven produced a CTX-M-type enzyme (CTX-M-14 in six cases and CTX-M-9 in one case). Statistically significant increases in the proportions of ampicillin-, trimethoprim/sulfamethoxazole-, ciprofloxacin- and cefotaxime-resistant E. coli, MDR E. coli and ESBL-producing E. coli were detected from 1997 to 2005 (Table 2).
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The mean duration of hospital stay after the bacteraemic episode was significantly longer in patients with MDR E. coli than in those with non-MDR E. coli bloodstream infections (17.01 ± 19.25 days versus 12.15 ± 10.43 days, P = 0.03). Mortality in patients with bacteraemia due to E. coli resistant to any of the following antibiotics: ampicillin, amoxicillin/clavulanate, piperacillin/tazobactam, cefotaxime and trimethoprim/sulfamethoxazole was higher than in patients with bacteraemia caused by E. coli susceptible to them (Table 3). Mortality in patients with MDR E. coli bloodstream infection was significantly higher than in patients with non-MDR E. coli bloodstream infection: 13.8% (12/87) versus 5% (24/576) [relative risk (RR) 3.31; 95% confidence interval (CI) 1.72–6.36; P = 0.001] and also higher in patients with bacteraemia due to ESBL-producing E. coli: 18.2% (2/22) versus 5% (32/641), (RR 3.64; 95% CI 1.41–9.4; P = 0.03). An association between the number of antibiotics to which E. coli was resistant and mortality was detected (Figure 1a).
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Empirical antibiotic treatment
In six cases, the empirical antibiotic treatment of the E. coli bacteraemia was unknown. The most frequent empirical antibiotic treatments in the other 657 were amoxicillin/clavulanate (43.3%), piperacillin/tazobactam (15.1%), ceftriaxone or cefotaxime (14.2%), ciprofloxacin (8.7%), cefuroxime (4.7%), imipenem or meropenem (2%), levofloxacin (1.2%), gentamicin (0.8%) and cefepime (0.6%). Empirical antibiotic combinations were used in 5% of the bacteraemias. In 551 (83.9%) episodes of bacteraemia, the empirical antibiotic treatment was adequate according to the microbiological results. Among the 106 patients treated with inadequate empirical therapy, 92 patients were treated with antibiotics without activity against the isolated E. coli, 6 with urinary antiseptics administered orally (3 with norfloxacin, 2 with fosfomycin and 1 with pipemidic acid) and 8 did not receive initial antimicrobial treatment.
There were no statistically significant differences in the characteristics of patients treated adequately or inadequately with empirical antibiotic therapy except for the proportion of patients with post-surgical bacteraemia and bacteraemia of biliary origin (Table 4). Patients with MDR E. coli bacteraemia had a significantly lower frequency of correct empirical antibiotic treatment than patients with non-MDR E. coli bacteraemia: 47.7% (41/86) versus 89.3% (510/572) (RR 0.53; 95% CI 0.42–0.67; P < 0.0001). Also, cases of ESBL-producing E. coli bacteraemia had a significantly lower frequency of correct empirical treatment than non-ESBL: 31.8% (7/22) versus 85.7% (544/635) (RR 0.37; 95% CI 0.2–0.69; P < 0.0001). A relationship between the number of antibiotics to which E. coli was resistant and the probability of adequacy of empirical antibiotic treatment was found (Figure 1b).
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After excluding one patient who died on the same day of the bacteraemia, the proportion of patients who died among those who received inadequate empirical antibiotic treatment according to the microbiological results was 11.3% (12/106) versus 4.2% (23/550) among those treated with an adequate antibiotic (RR 2.26; 95% CI 1.38–3.71; P = 0.005). In patients with urinary tract infections, there was no significant association between adequacy of empirical antibiotic and mortality (RR 0.39; 95% CI 0.12–1.26). In contrast, for patients with non-urinary infections, a significant association existed (RR 0.38; 95% CI 0.17–0.83). In patients with severe sepsis or shock, mortality among those who received inadequate empirical treatment was 58.3% (7/12) and 19.6% (11/56) in patients who received adequate empirical treatment (P = 0.01).
Most frequent definitive antibiotic treatment in the 22 cases of ESBL E. coli bacteraemia included a carbapenem in 14 patients (63.6%), followed by amoxicillin/clavulanate in 2 patients and quinolones in 2 patients. In 19 of 20 patients with an ESBL-producing E. coli bacteraemia who survived more than 3 days after the day of the bacteraemia, definitive antibiotic treatment was adequate.
Table 5 shows the results of the univariate analysis to identify predictors of mortality in the study cohort. The following significant univariate predictors of mortality were included in a logistic regression model to define independent predictors: age, presence of severe sepsis or shock, presence of altered mental status, a non-urinary origin of the bacteraemia, lung origin of the bacteraemia, MDR E. coli as causal agent of the bacteraemia, Charlson index score, systolic blood pressure, diastolic blood pressure and the adequacy of empirical antibiotic treatment. In multivariate analysis (Table 6), age, the presence of severe sepsis or shock, Charlson index score, a non-urinary origin of the bacteraemia and the adequacy of empirical antibiotic treatment were associated with prognosis. When the adequacy of empirical treatment was excluded from the model, the presence of MDR E. coli in the blood cultures was also associated with the prognosis [adjusted OR (95% CI) 3.11 (1.3–7.44); P = 0.01]. Considering E. coli reported as intermediate in sensitivity to a particular antibiotic as susceptible, did not alter the predictors of mortality in the model.
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Discussion |
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E. coli is one of the main causal agents of both community- and hospital-acquired bloodstream infections.1,2 Despite this fact only a few studies, most of which are not recent ones, describe the characteristics of patients with E. coli bacteraemia and their prognostic factors.3–8 Because most of this information pre-dates the dissemination of E. coli resistant to several antibiotics such as quinolones,26–39 and the increase in MDR E. coli infections,29 including infections due to ESBL-producing E. coli,9–17 updated information is essential. This study was undertaken to evaluate clinical characteristics and prognostic factors in patients with E. coli bacteraemia. We found that several clinical characteristics are associated with mortality in these patients. In this study, age, the presence of severe sepsis or shock, Charlson index score, a non-urinary origin of the bacteraemia and a delay in starting effective antimicrobial therapy were associated with a worse prognosis.
Increased mortality associated with bacteraemia caused by multiresistant microorganisms could be due to the presence of more severe infections or to the associated co-morbidity. There is growing evidence about a direct relationship of the outcome with the adequacy of initial empirical therapy in patients with severe bloodstream infections18,19,30 and specifically in those caused by methicillin-resistant Staphylococcus aureus,31 Streptococcus pneumoniae,32 vancomycin-resistant enterococci,33 Pseudomonas aeruginosa,34 Acinetobacter baumannii,35 antibiotic-resistant Gram-negative bacilli16 and Candida spp.36
If empirical therapy influences the prognosis of these patients, a lower frequency of correct empirical therapy could imply impaired outcome. In our study, we demonstrate that an increase in the number of resistances is associated with a lower incidence of correct empirical therapy in patients with E. coli bacteraemia. This could explain the other relationship that we found: the number of resistances and mortality. In fact, a correct empirical therapy is associated with the prognosis; but if this is excluded from the final analysis, we observe that the presence of MDR E. coli is an independent prognostic factor supporting the relationship between antibiotic resistance and outcome mediated by the adequacy of the empirical therapy.
A good example of the complexity of the interactions between antibiotic resistance, adequacy of empirical treatment and outcome are bloodstream infections caused by ESBL-producing Enterobacteriaceae. Some recent investigations have failed to demonstrate an association between poor clinical response and bloodstream infections arising from ESBL-producing bacteria,13–15,37–40 whereas other studies have reported such a relationship.15,18,41 In a similar way, the results of the studies that analyse the association of ESBL-producing Gram-negative infections with adequacy of empirical treatment are conflicting and several investigators have detected a negative effect of the presence of these MDR bacteria on the appropriateness of the initial antibiotic therapy,14,17,41 whereas others have not.38
Lautenbach et al.42 have demonstrated the association of fluoroquinolone resistance and mortality among patients with E. coli and Klebsiella pneumoniae infections, in a setting with a rate of empirical antibiotic therapy with quinolones higher than 50%. Although we have not found any relationship between fluoroquinolone resistance and outcome, the frequency of empirical use of this antibiotic class in our centre has been lower. Moreover, we detected a notable excess of mortality among patients with bacteraemia caused by amoxicillin/clavulanate-resistant E. coli, which is the most common empirical treatment in our series making this linking a plausible association. Taken together these data suggest that the effect of the use of specific empirical antibiotic therapies on outcome can differ between places depending on the local antibiotic resistances.
In our study, a 7.1% decrease in the overall crude mortality rate is associated with adequate early empirical antibiotic treatment. In patients with severe sepsis or shock, decreased mortality associated with an appropriate initial antibiotic reaches 38.7%. Several studies show a high disparity in the rate of adequacy of empirical therapy (35% to 86%) and mortality (17% to 56%) and indicate a decrease in the overall crude mortality rate associated with adequate early antibiotic treatment that ranges from 10% to 33%,13,14,16,30–36,41–43 higher than that in the present study. However, the relative decrease in mortality associated with adequate empirical treatment reaches 62%. Classically, bloodstream infections caused by E. coli have been associated with lower mortality than those caused by other microorganisms.1–8 The factors determining the lower mortality with E. coli are not well defined. Urinary origin of bloodstream infections (the first source of infection in E. coli bacteraemia)3–8 is associated with better prognosis.1,2 Other factors, such as a lower incidence of co-morbidity and a low proportion of patients with septic shock among our patients with E. coli bacteraemia may contribute to the low mortality.
Although this is a retrospective chart review study that may be limited by the availability and completeness of medical records, we found that all except two charts were available for review. Our study had several potential limitations. Due to its observational design, a definitive association between adequacy of antibiotic empirical therapy and prognosis cannot be deduced. Because our study was performed at a single site, the results may not be applicable to other settings, especially in centres with a high incidence of immunosuppressed patients. Another limitation is that we have not identified factors for MDR E. coli bacteraemia that can be helpful for optimizing empirical treatment.
In conclusion, receiving inappropriate empirical antimicrobial therapy is an independent risk factor for mortality in patients with E. coli bacteraemia and is related to the number of antibiotic resistances. This underscores the clinical importance of providing early appropriate treatment to patients with E. coli bacteraemia. These data indicate that continuing efforts should be aimed at earlier identification of patients with MDR E. coli bacteraemia in order to administer them adequate empirical antimicrobial treatment.
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None to declare.
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Acknowledgements |
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M. E. C. and L. M.-M. are supported by Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III-FEDER, Spanish Network for the Research in Infections Diseases (REIPI) RD 06/0008.
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References |
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