JAC Advance Access published online on April 17, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn155
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Original research |
Effect of antimicrobial therapy on mortality in 377 episodes of Enterobacter spp. bacteraemia
1 Department of Infectious Diseases, Hospital Clinic of Barcelona, C/ Villarroel 170, Barcelona 08036, Spain 2 Department of Microbiology, Hospital Clinic of Barcelona, C/ Villarroel 170, Barcelona 08036, Spain
* Corresponding author. Tel: +34-932275707; Fax: +34-4514438; E-mail: migmarmar10{at}hotmail.com
Received 19 December 2007; returned 11 March 2008; revised 7 February 2008; accepted 13 March 2008
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Abstract |
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Objectives: The impact of appropriate antimicrobial therapy and antimicrobial resistance on the outcome of bacteraemia due to Enterobacter spp. remains unclear. The aim of our study was to evaluate the effect of antimicrobial therapy in 377 consecutive episodes of Enterobacter bacteraemia.
Patients and methods: This includes retrospective analysis of a prospectively collected cohort. Clinical variables recorded were age, underlying diseases, use of corticosteroids, prognosis of underlying disease according to the McCabe and Jackson criteria, source of bacteraemia, need for mechanical ventilation, empirical antibiotic treatment, definitive treatment, antimicrobial susceptibility, presentation with septic shock and 30 day mortality rate. Univariate and multivariable analyses were performed to analyse the influence of antibiotic treatment and cephalosporin resistance on mortality.
Results: Between 1991 and 2006, 377 episodes of bacteraemia due to Enterobacter spp. (2.2%) were recorded. The frequency of Enterobacter bacteraemia significantly increased over these years. The overall mortality rate was 12.5% (47 of 377). Independent factors associated with 30 day mortality in patients with monomicrobial bacteraemia were rapidly fatal prognosis when compared with non-fatal prognosis, presentation with septic shock, patient under mechanical ventilation and unknown source of infection. The only factor independently associated with lower 30 day mortality was the empirical use of piperacillin/tazobactam.
Conclusions: Enterobacter spp. are an increasing cause of bacteraemia. The empirical use of piperacillin/tazobactam was independently associated with a lower 30 day mortality rate.
Key Words: cephalosporin resistance , Enterobacteriaceae infections , drug therapy , mortality , piperacillin , pharmacology
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Introduction |
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Enterobacter species are associated with wound, intra-abdominal, respiratory, urinary and bloodstream infections, representing an increasingly important nosocomial pathogen.1,2 Although a growing number of resistant Enterobacter strains, particularly to broad-spectrum cephalosporins (BSC), have been observed3,4 and Enterobacter spp. are also capable of developing resistance during β-lactam therapy,2,5 the impact of antibiotic resistance on mortality is still under debate.6–10 In addition, the role of appropriate antimicrobial therapy and the effect of specific antimicrobials in this setting have not yet been clarified.5,8,9 Our study was performed to characterize the clinical features of Enterobacter bacteraemia and to analyse the impact of antimicrobial resistance and the effect of empirical and definitive therapy in the mortality of patients with bloodstream infections due to Enterobacter spp.
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Patients and methods |
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Patients and setting
The present study focuses on episodes of significant bacteraemia due to Enterobacter spp. diagnosed from January 1991 to December 2006 at a single centre, the Hospital Clinic in Barcelona, Spain (a 700 bed university centre equipped with an intensive care unit and a post-surgical unit that serves an urban population of about 500 000 people). All patients with Enterobacter species isolated from blood during this period were included.
Between 1991 and 1997, blood samples were processed by the Bactec NR-730 system (Becton–Dickinson Microbiology System) and maintained routinely for 7 days. Since 1998, we have used the Bactec system (Becton–Dickinson Microbiology System), with an incubation period of 5 days. Isolates were identified according to standard techniques. Antibiotic susceptibility was determined by the disc diffusion method, according to the recommendations of the CLSI (formerly NCCLS) guidelines.11 Intermediate susceptibility to each antibiotic was considered as resistance. BSC resistance was defined as in vitro resistance to cefotaxime or ceftazidime. A multiresistant Enterobacter spp. was defined as a strain with in vitro resistance to BSC, ciprofloxacin and gentamicin.9
A retrospective observational cohort study was conducted by reviewing the data previously collected from patients with Enterobacter bacteraemia. The following data were collected from all patients at the time of bacteraemia diagnosis: age, sex, pre-existing co-morbidities, prognosis of the underlying disease, administration of immunosuppressive therapy, origin of infection, source of bacteraemia, post-operative status, empirical antimicrobial regimen and definitive antimicrobial regimen. The presence of the following factors when the blood cultures were taken was also documented: need for mechanical ventilation, presentation with septic shock (early shock), a central venous catheter or an indwelling urinary catheter. Patients were followed-up from the time of bacteraemia diagnosis to assess the 30 day overall mortality (main outcome measure) and infection mortality rate.
Enterobacter bacteraemia was defined as at least one blood culture positive for Enterobacter spp. and clinically apparent signs or symptoms of sepsis. Co-morbidity was defined as a disease or therapy that could predispose patients to infection, alter defence mechanisms or cause functional impairment, such as diabetes; liver cirrhosis; renal failure; active neoplastic disease; solid organ or bone marrow transplantation; neutropenia; severe chronic obstructive pulmonary disease; severe cardiac disease with symptomatic heart failure; HIV infection and administration of immunosuppressive drugs (>20 mg of corticosteroids/day on a regular basis or antineoplastic chemotherapy). Prognosis of the underlying disease was classified, according to the McCabe and Jackson modified criteria,12 as rapidly fatal (when death was expected within 3 months), ultimately fatal (when death was expected within a period of >3 months but <5 years) and non-fatal (when life expectancy was >5 years). The following potential sources of bacteraemia were recorded: iv catheter, urinary tract, upper respiratory tract, gynaecological, osteoarticular, soft-tissue, endovascular, lower respiratory tract, abdominal, central nervous system and unknown focus. Bacteraemia was classified as polymicrobial if two or more microorganisms were obtained from blood cultures. Shock was defined as sepsis associated with evidence of organ hypoperfusion and a systolic blood pressure <90 or >30 mmHg less than the baseline that did not respond to fluid treatment and required vasoactive drug therapy.13
The origin of bloodstream infections was considered as: (i) nosocomial when cultures of blood specimens obtained >48 h after admission were positive; (ii) community-acquired when cultures were obtained prior to admission or during the first 48 h without hospitalization or healthcare contact during the month before bacteraemia; and (iii) healthcare-related when there was hospitalization or healthcare contact during the month before bacteraemia (i.e. dialysis patients).14 Empirical antimicrobial therapy was defined as the initial therapy before the results of blood culture were available. This therapy was deemed as appropriate if the isolate was susceptible to any of the administered antibiotics and if the dose and route of administration were in accordance to the current medical standards. Inappropriate empirical therapy was defined as the use of antibiotics without in vitro activity against isolated Enterobacter strains or no antibiotic use. Definitive antimicrobial therapy was defined as therapy after the result of antibiotic susceptibility tests had been received. Mortality was defined as death occurred within 30 days of bacteraemia and infection-related mortality when death occurred before the resolution of symptoms or signs or within 7 days from the onset of Enterobacter bacteraemia and there was no other explanation. Catheter-related sepsis is considered definite when there is at least one positive peripheral blood culture and one of the following findings: (i) a positive semi-quantitative or quantitative catheter-tip culture that grows the microorganism found in the peripheral blood; and (ii) positive paired central and peripheral blood cultures that grow the same microorganism; the former blood culture is positive at least 2 h earlier or shows five times the growth.15
Categorical variables were compared by 
2 test or Fisher's exact test (if expected cell counts were less than 5), and continuous variables were compared by Student's t-test. A 2 trend test was used to evaluate the differences observed during the study period. A multivariable regression model was used to identify independent risk factors of mortality. Variables with a P value less than 0.20 in the univariate analysis were subjected to further selection by using a backwards non-conditional logistic procedure. Potential confounding factors were also included and interactions were tested. Patients with polymicrobial bacteraemia were excluded from the mortality analysis to adjust for confounding. A two-tailed P value less than 0.05 was regarded as significant. Statistical analyses were performed using Statistical Package for the Social Sciences (SPSS) version 12.0 (Chicago, IL, USA).
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Results |
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During the 16 year study period, 16 959 positive blood cultures were obtained and 377 episodes (2.2%) of Enterobacter bacteraemia were found in 370 patients. Enterobacter spp. isolated were as follows: Enterobacter cloacae, 271 (71.9%); Enterobacter aerogenes, 87 (23.1%); Enterobacter amnigenus, 6; Enterobacter sakazakii, 5; Enterobacter gergoviae, 2; Enterobacter asburiae, 1; Enterobacter taylorae, 1; Enterobacter intermedium, 1 and 3 Enterobacter spp. Antibiotic resistance was found as follows: 78 (20.7%) strains were resistant to BSC, 77 (20.4%) to piperacillin/tazobactam, 13 (3.5%) to ciprofloxacin, 4 (1.1%) to gentamicin and 3 (0.8%) to carbapenems. Only one strain was found to be multiresistant. There was no evidence of a clustering of cases to suggest an outbreak. As shown in Table 1, the incidence of Enterobacter bacteraemia has risen over the last years (P < 0.001), but the presence of BSC-resistant strains has not increased (P = 0.426).
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Clinical characteristics of bacteraemia and underlying conditions of patients
The mean age ± SD of the patients was 61.69 ± 17.75 years. The rest of the characteristics of the patients are shown in Table 2. Forty-eight patients died from all causes at the end of follow-up (12.7%) and 35 (9.3%) due to infection.
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Antibiotic therapy and predictors of 30 day mortality in patients with monomicrobial bacteraemia by Enterobacter spp
Of 314 patients with monomicrobial Enterobacter bacteraemia, the overall 30 day mortality rate was 11.8% (37 of 314), and the infection-related mortality rate was 7.3% (23 of 314). No trend in mortality was observed over time. Two hundred and thirty-two patients (73.9%) received an appropriate empirical antibiotic, whereas 82 (26.1%) did not, with no significant differences in overall mortality between both groups (patients receiving appropriate therapy and those who did not) (Table 3). There were also no differences in infection-related mortality rates (19/232 versus 7/82, P = 0.922). Empirical antibiotics used were as follows: 124 (39.5%) patients received BSCs as empirical antimicrobial therapy, 38 patients (12.1%) piperacillin/tazobactam, 41 (13.1%) carbapenems, 5 (1.6%) aztreonam, 67 (21.3%) aminoglycosides and 48 (15.3%) quinolones. Other antibiotics administered were: first- or second-generation cephalosporins (23), glycopeptides (51), metronidazole (19), clindamycin (6) and macrolides (8). Thirteen (4.1%) patients did not receive any empirical antimicrobial therapy. Patients receiving carbapenems were more likely to die, and a statistical tendency was observed towards lower mortality in the group receiving piperacillin/tazobactam (Table 3). Regarding definitive antimicrobial therapy, 71 patients (22.6%) received BSCs, 19 (6.1%) piperacillin/tazobactam, 111 (35.4%) quinolones, 57 (18.2%) carbapenems and 43 (13.7%) aminoglycosides. Other antibiotics used were aztreonam (2), glycopeptides (20), clindamycin (2), metronidazole (11) and macrolides (2). Resistance to specific antimicrobials was not statistically associated with mortality (Table 4).
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Variables associated with the 30 day mortality rate in the univariate analysis were origin of bacteraemia, vascular catheter as source of infection, unknown source of infection, presentation with septic shock, McCabe prognosis, mechanical ventilation and presence of indwelling catheter (Table 5). Patients who finally died had a similar mean age (61.21 ± 21.5) to those who survived (61.24 ± 18.5, P = 0.992).
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The multivariable logistic regression model was performed including variables associated with mortality with a P value in the univariate analysis less than 0.20. Appropriateness of empirical antibiotic therapy and piperacillin/tazobactam resistance were also included in the model as potential confounding factors and interactions were tested. The final model showed the following independent risk factors associated with higher mortality: rapidly fatal prognosis compared with non-fatal prognosis of underlying disease (OR: 21.47; 95% CI: 5.42–84.95; P < 0.001), presentation with septic shock (OR: 12.67; 95% CI: 4.57–35.11; P < 0.001), unknown source of infection (OR: 3.44; 95% CI: 1.35–8.79; P = 0.010) and patient under mechanical ventilation (OR: 5.18; 95% CI: 1.59–16.85; P = 0.006) (Table 6). The empirical use of piperacillin/tazobactam was associated with a greater chance of survival (OR: 0.11; 95% CI: 0.01–0.99; P = 0.049). Thirteen of the 38 patients receiving empirical piperacillin/tazobactam had Enterobacter strains resistant to piperacillin/tazobactam and 25 did not (one of the latter patients was the only one who died after receiving this antibiotic).
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Discussion |
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During the last 16 years, we have observed a significant increase in the incidence of Enterobacter species as a cause of bacteraemia, as other authors have stated.2,9 We have found, however, a relatively low rate of resistance to BSC (20.7%) when compared with the recent published rates (30.5% to 93.1%),6,8,9,16 as well as lower resistance rates to ciprofloxacin or aminoglycosides.3,8,9,17 Our 30 day mortality rate (12.7%) was also lower than the previously published results (20.6% to 42.6%).5,6,8,9 This difference may be explained by the fact that intravascular catheter-related infection (a low-mortality focus) was the most common portal of entry in our report; in contrast, other articles have shown a low frequency of this portal of entry.2,6,8,9,17
Thirty days post-bacteraemia, mortality due to monomicrobial bacteraemia was 11.8%. In regard to the variables associated with mortality in our study, the presence of septic shock has been previously related to a higher mortality among patients with Enterobacter bacteraemia.6,8 Mechanical ventilation and McCabe prognosis have not been analysed before in this bloodstream infection, but they have been widely described as prognostic factors in other infections.18–21 These three variables underscore the importance of infection severity and the prognosis of underlying diseases in mortality associated with Enterobacter bacteraemia. Although the presence of bacteraemia of unknown origin has previously been associated with good prognosis,6 it has also been shown to confer bad prognosis.22
Appropriateness of empirical therapy did not affect clinical outcomes despite unanticipated resistance, even after adjustment for possible confounding factors. This result is not surprising as most studies conducted in a multivariable manner have shown the same finding,6,8,9 with the exception of Chow et al.5 The findings of smaller studies using univariate methods are also conflicting.23–27 Bacteraemia-associated mortality depends not only on antimicrobial therapy but also on other aspects of treatment (such as the removal of infection foci), patient factors (e.g. underlying diseases) and microorganism variables (virulence or resistance).6,28 Therefore, differences in clinical and sociodemographic characteristics of patients and different resistance patterns among studies may explain, at least partly, the conflicting results about the influence of appropriateness of therapy on outcomes.28 Multivariable methods should take into account all these potential confounding variables, consequently requiring a large number of events in order to obtain unbiased estimates.28,29 To the best of our knowledge, this is the largest study assessing the impact of BSC resistance and appropriateness of therapy on monomicrobial Enterobacter bacteraemia outcome, but the number of deaths that occurred was small. This low number of events may favour overfitting and thus unreliable multivariable models,30 the same statistical restriction of previous studies.5,6,8,9 In addition to these methodological issues that may mask the true effect of antimicrobial empirical therapy, from a rational basis nobody can scientifically discard that correct antibiotic selection should be a compulsory objective for all clinicians.6,28
Regardless of the lack of significance for appropriateness of empirical therapy as a whole, we have found an interesting relationship between empirical treatment with piperacillin/tazobactam and lower mortality. The interest of this finding lies in the usual recommendation of not treating Enterobacter infections with β-lactam antibiotics different from carbapenems due to the capacity of these species for developing resistance to these antibiotics during therapy.2,5 Despite the possible biases of the multivariable analysis and the small number of patients receiving this antibiotic, this result seems plausible considering previous research. In a murine model of mixed-infection abscess, treatment with piperacillin/tazobactam suppressed the selection of resistant mutants of E. cloacae during early abscess development.31 Tazobactam has also shown some ability to potentiate the activity of piperacillin against derepressed mutants of E. cloacae,32 and the combination of piperacillin with tazobactam suppressed the emergence of resistant mutants of E. cloacae in comparison with piperacillin alone.33 The suppressive effect of tazobactam on the appearance of resistance could be mediated by the AmpC β-lactamase inhibitory activity in moderately resistant strains of E. cloacae.34 In addition to these microbiological issues, possibly better pharmacokinetic–pharmacodynamic parameters (T > MIC) obtained with the standard dosage of piperacillin/tazobactam (4/0.5 g every 6 h) than with the standard dosage of other β-lactams, i.e. cefepime (1 g every 12 h) or ceftriaxone (1 g every 24 h), may explain the higher efficacy of piperacillin/tazobactam.35
These data warrant further clinical and microbiological investigation to clarify the recommendation of not using piperacillin/tazobactam when Enterobacter is the possible cause of infection. Regrettably, questions regarding empirical therapy of bloodstream infections can only be assessed by means of potentially biased observational analyses, and therefore the methodological challenges stated above remain for future investigation.28,36,37
In our study, resistance to BSC was not associated with mortality as it was also previously stated,8–10 although other researchers have found an association with poorer outcome.6,7 Every methodological argument explained earlier can also explain the controversy regarding the impact of antimicrobial resistance on treatment outcome, and this issue remains also unclear for other pathogens.10,38
In summary, severity of presentation and prognosis of underlying diseases were the main predictor factors of mortality in Enterobacter bacteraemia, whereas BSC resistance or appropriateness of empirical therapy were not associated with mortality in our series. The empirical use of piperacillin/tazobactam was associated with a lower mortality, and this antibiotic should not be discarded for treating Enterobacter infections.
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None to declare.
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Acknowledgements |
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This study was presented in part at the Forty-seventh Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2007 (M. Marcos, A. Iñurrieta, A. Soriano et al., Abstract K-440).
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References |
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