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Nosocomial Gram-negative bacteremia in intensive care: epidemiology, antimicrobial susceptibilities, and outcomes
Accepted Manuscript Title: Nosocomial gram-negative bacteremia in intensive care: epidemiology, antimicrobial susceptibilities and outcomes Author: Wendy Irene Sligl Tatiana Dragan Stephanie Wrenn Smith PII: DOI: Reference:
S1201-9712(15)00162-9 http://dx.doi.org/doi:10.1016/j.ijid.2015.06.024 IJID 2376
To appear in:
International Journal of Infectious Diseases
Received date: Revised date: Accepted date:
20-4-2015 3-6-2015 28-6-2015
Please cite this article as: Sligl WI, Dragan T, Smith SW, Nosocomial gram-negative bacteremia in intensive care: epidemiology, antimicrobial susceptibilities and outcomes, International Journal of Infectious Diseases (2015), http://dx.doi.org/10.1016/j.ijid.2015.06.024 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Nosocomial gram-negative bacteremia in intensive care: epidemiology, antimicrobial susceptibilities and outcomes Wendy Irene Sligla, Tatiana Draganb, Stephanie Wrenn Smithc a
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MD, MSc, FRCPC, Associate Clinical Professor, Divisions of Critical Care Medicine and Infectious Diseases, Faculty of Medicine and Dentistry, University of Alberta. Address: 2-124 Clinical Sciences Building, 8440 112 Street, Edmonton, AB, T6G 2B7, CANADA; [email protected] b MD, Department of Medical Microbiology & Immunology, Faculty of Medicine and Dentistry, University of Alberta. Address: 2B3 Walter Mackenzie Centre, 8440 112 Street, Edmonton, AB, T6G 2H7, CANADA; [email protected] c MD, MSc, FRCPC, Associate Professor, Division of Infectious Diseases, Faculty of Medicine and Dentistry, University of Alberta. Address: 1-124 Clinical Sciences Building, 8440 112 Street, Edmonton, AB, T6G 2B7, CANADA; [email protected]
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Address correspondence to: Wendy Sligl Divisions of Critical Care Medicine and Infectious Diseases University of Alberta 2-124 Clinical Sciences Building 8440-112 Street Edmonton, AB, Canada T6G 2B7 Phone 780-492-8311 Fax 780-492-1500 E-mail: [email protected]
Reprints not required Work performed at University of Alberta Category: Original Article Conflicts of Interest and Source of Funding: None declared for all authors.
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We describe the epidemiology and outcomes of ICU-acquired gramnegative bacteremia. Resistance to ciprofloxacin and piperacillin/tazobactam was common.
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Carbapenem resistance among pseudomonal isolates was surprisingly high. Most patients received adequate empiric antimicrobial therapy.
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Coronary disease, immunosuppression and antimicrobial therapy predicted mortality.
ABSTRACT
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Objectives: To describe the epidemiology, antimicrobial susceptibilities, treatment and outcomes of ICU-acquired gram-negative bacteremia.
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Methods: Patients with ICU-acquired gram-negative bacteremia from 2004-2012 were retrospectively reviewed. Independent predictors of mortality were examined using multivariable Cox regression.
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Results: Seventy-eight ICU-acquired gram-negative bacteremias occurred in 74 patients. Infection rate was 0.97/1000 patient days. Mean patient age was 55 years, 62% were male. Most common admission diagnoses were respiratory failure (34%) and sepsis/septic shock (45%). Mortality was 35% at 30-days.
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The most common source of bacteremia was pneumonia (33%). Of 83 gramnegative isolates, Escherichia coli (20%), and Pseudomonas aeruginosa (18%) were most common. For aerobic isolates, susceptibilities to ciprofloxacin (61%) and piperacillin/tazobactam (68%) were low. For pseudomonal isolates, susceptibilities to ciprofloxacin (53%), piperacillin/tazobactam (67%) and imipenem (53%) were equally disappointing. Adequate empiric antimicrobial therapy was prescribed in 85% bacteremias. On multivariable analysis, adequate empiric therapy (adjusted hazard ratio [aHR] 0.38, 95%CI 0.16-0.89), immune suppression (aHR 3.4; 95%CI 1.4-8.3) and coronary artery disease (aHR 4.5; 95%CI 1.7-11.9) were independently associated with 30-day mortality. Conclusions: ICU-acquired gram-negative bacteremia is associated with high mortality. Resistance to ciprofloxacin, piperacillin/tazobactam, and carbapenems was common. Coronary artery disease, immune suppression and inadequate empiric antimicrobial therapy were independently associated with increased mortality.
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Key words: bacteremia; gram negative; critical care; intensive care; nosocomial infection; antimicrobial resistance
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Word counts and numbers: Abstract – 201 Manuscript – 3016 References – 40 Tables – 4 Figures – 3
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INTRODUCTION Despite considerable preventative efforts, hospital-acquired infections
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continue to contribute to substantial morbidity and mortality 1 occurring in approximately 4% of hospitalized patients 2. An estimated 250,000 nosocomial
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bloodstream infections occur each year in the United States 3 with approximately 30% due to gram-negative bacilli. Mortality rates in gram-negative sepsis are
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high, and can be up to 50% depending on patient factors, as well as timing and
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appropriateness of empiric antimicrobial therapy 4-7.
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Although intensive care units (ICUs) account for less than 10% of the total number of beds in most hospitals, more than 20-30% of all nosocomial infections
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are acquired in the ICU 2 8, with high rates of antimicrobial resistance 9 10 and
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mortality 7 11 when compared with the general hospital population. Understanding
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the local epidemiology and antimicrobial susceptibility patterns in ICU-acquired gram-negative bacteremia may facilitate development of empiric therapy guidelines, formulary restrictions and/or antimicrobial stewardship programs, resulting in improved patient outcomes.
The aim of our study is to provide up-to-date data on the epidemiology
(including incidence, source, microbial etiology, antimicrobial susceptibilities, and outcomes) of nosocomial gram-negative bacteremia in a population of critically ill patients. We also compare rates, microbiology, antimicrobial susceptibilities and
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appropriateness of empiric therapy over time, in particular compared to data previously published in the same patient population 12.
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MATERIALS AND METHODS
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We conducted a retrospective observational cohort study at the University
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of Alberta Hospital, a 650-bed academic quaternary care referral hospital in Edmonton, Canada and the principal teaching hospital of the University of
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Alberta, Faculty of Medicine and Dentistry. It is a level-one trauma center, the largest solid organ transplantation center in Western Canada, and has a referral
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area of over two million.
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The University of Alberta Hospital contains a 32-bed adult general systems intensive care unit (ICU) that admits general medical, surgical, trauma,
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and solid organ transplant patients. The ICU provides general invasive hemodynamic monitoring and support, mechanical ventilation, renal replacement therapy, as well as extracorporeal liver support. Other specialized support therapies such as extracorporeal membrane oxygenation (ECMO) are provided in the cardiovascular ICU.
This study was conducted as part of a quality improvement study through Infection Prevention and Control and was therefore exempt from ethics submission as per the Research Ethics Board at the University of Alberta.
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Infection Prevention and Control (IPC) prospectively monitors all inpatient populations, including ICU patients, for the development of nosocomial infection(s). Positive blood cultures are identified by the clinical microbiology
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laboratory (BACTEC 9240 Blood Culture System; Becton Dickinson Biosciences) and reviewed by IPC daily. Charts are subsequently reviewed and blood culture
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isolates categorized as contaminants, community-acquired, or nosocomial using
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source is then identified and subcategorized.
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standardized CDC/NHSN criteria 13. For nosocomial bacteremia, the originating
All cases of ICU-acquired gram-negative bacteremia from January 1, 2004
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to December 31, 2012 were reviewed. Demographic data, source of bacteremia,
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causative micro-organisms, antimicrobial susceptibilities, choice of empiric
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antibiotic therapy, ICU and hospital lengths of stay and 30-day mortality rates were collected. Data were subsequently compared to previously published data
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from 1999-2003 in the same patient population 12.
Immune compromise was defined as chronic steroid use (daily equivalent
of 20mg prednisone for ≥1 month per year), solid organ or hematopoietic stem cell transplantation, receipt of chemotherapy within the previous month, neutropenia (absolute neutrophil count <1.0 cells/L) at the time of admission, or HIV/AIDS (CD4 count <200 cells/µL). End-stage renal disease (ESRD) was defined as kidney failure necessitating either peritoneal or intermittent hemodialysis prior to admission. Empiric therapy was deemed effective if
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treatment was with an agent to which the microorganism was ultimately susceptible. Multi-drug resistance in Pseudomonas species was defined as resistance to three or more first line antimicrobials in the following classes: β-
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lactams, carbapenems, aminoglycosides (AGs), and fluoroquinolones.
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Statistical analysis
Epidemiologic data was reported including descriptive statistics such as
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proportions, percentages, means or medians. Characteristics for subjects dead or alive were compared using t-tests or Mann-Whitney U tests (as appropriate
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based on their distribution) for continuous variables. Chi-square or Fisher’s exact
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tests were used for categorical variables.
We then constructed Kaplan-Meier survival curves and performed log-rank
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tests for variables associated with mortality on univariate analysis.
Multivariable Cox regression modeling was subsequently performed to
identify variables independently associated with 30-day mortality. APACHE II was included for clinical significance. Otherwise variables identified to be significantly associated with increased mortality (p<0.1) on univariate analyses were entered into the model. There were no proportional hazards violations, which we tested using time covariate interaction terms. Results are presented as adjusted hazard
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ratios (aHR) and 95% confidence intervals (CI). All statistical tests were twosided and p-values <0.05 were considered statistically significant.
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Statistical analyses were performed using SPSS statistical software
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version 22.0 (IBM Corp. Released 2013. IBM SPSS Statistics. Armonk, NY).
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RESULTS
There were 11,602 admissions to the general systems ICU from January
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1, 2004 to December 31, 2012. A total of 78 episodes of ICU-acquired gram-
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negative bacteremia occurred in 74 patients, resulting in overall infection rates of
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6.7 per 1000 ICU admissions or 9.7 per 10,000 patient days. These rates were similar to those observed in our previous study (6.9 per 1000 ICU admissions
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and 11.3 per 10,000 patient days). Annual infection rates fluctuated by year from 1.6-9.6 per 1000 admissions and 2.3-15.0 per 10,000 patient days consistent with expected year-to-year variation.
The mean patient age was 55 years (range 18-85 years; SD 15.8) and
46/74 (62.2%) were male. A large number of patients [26/74 (35%)] were immune compromised. Additional specific patient demographics can be found in Table 1.
The majority of patients were admitted with medical diagnoses [51/72 (69%)].
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Admitting diagnoses included: respiratory failure 25/74 (34%), sepsis or septic shock 33/74 (45%), liver transplantation 7/74 (10%), and trauma/major
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burns 5/75 (7%). Mean APACHE II score was 25 (SD 8.3) at the time of
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admission and 73/78 (94%) patients required invasive mechanical ventilation.
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The most common source of bacteremia was pneumonia in 26/78 (33%) patients, as was observed in our previous study. Other common sources included
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gastrointestinal tract (not endoscopy related) [17/78 (22%)] and catheter-related bloodstream infections [10/78 (13%)]; see Figure 1. A decrease in catheter-
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related bloodstream infections was observed from 1999-2003 to 2004-2012 (22%
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vs. 13%, respectively).
Bacterial species identified can be found in Figure 2. In summary, the
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most common bacterial pathogen was Escherichia coli 17/83 (21%), followed by Pseudomonas aeruginosa 15/83 (18%) and Klebsiella species (13/83; 16%). The majority of isolates were aerobic gram-negative bacilli (71/83 [86%]) of which 49/83 (59%) were Enterobacteriaceae. Glucose non-fermenting organisms (Pseudomonas and Stenotrophomonas) accounted for 21/83 (25%) of bacteremias.
Multi-drug resistant (MDR) pathogens were isolated in 14/83 (17%) of cases including extended spectrum beta-lactamase producers (ESBLs; 5/83
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[5%]), carbapenem-resistant Enterobacteriaceae (CRE; 2/83 (2%) and MDRPseudomonas (7/83 [8%]).
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The majority [63/78 (81%)] of infections were monomicrobial. In fifteen polymicrobial infections, three were with another gram-negative organism, 10
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with gram-positive organisms, and two events in which additional gram-negative
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and gram-positive organisms were identified.
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Overall aerobic gram-negative and pseudomonal susceptibilities are shown in Table 2. Of all aerobic isolates tested, susceptibilities to ciprofloxacin
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[40/66 (61%)] and piperacillin/tazobactam [44/65 (68%)] were low. Similar
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numbers were observed for Enterobacteriaceae alone. For pseudomonal
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isolates, susceptibility to ciprofloxacin (8/15 [53%]), piperacillin/tazobactam [10/15 (67%)], and imipenem [8/15 (53%)] were equally disappointing. Changes
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in antimicrobial susceptibilities over time are demonstrated in Figure 3. Comparison of the two study periods demonstrates 1) sustained resistance to ciprofloxacin (in both aerobic isolates as well as Pseudomonas alone) in 30-50% of isolates, 2) increased resistance to piperacillin/tazobactam in aerobic isolates (from 11% to 32%) and in Pseudomonal isolates alone (0% to 33%), and 3) substantially increased carbapenem resistance in Pseudomonas (9% to 47% for imipenem). Surprisingly, only 2/6 (33%) strains of Stenotrophomonas maltophilia were susceptible to trimethoprim/sulfamethoxazole (TMP/SMX).
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Empiric therapy was appropriate in 66/78 (85%) of aerobic gram-negative bacteremias and 11/15 (73%) of pseudomonal bacteremias. Most commonly prescribed empiric antibiotics were piperacillin/tazobactam [31/78 (40%)] and
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anti-pseudomonal carbapenems [29/78 (37%)]. After excluding cases of
Stenotrophomonas maltophilia, for which empiric therapy is not common or
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standard of care, effective empiric coverage increased to 63/72 (88%). In the six
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cases of Stenotrophomonas maltophilia bacteremia, three (50%) patients
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received adequate empiric therapy.
Crude 30-day mortality was 26/74 (35%) and hospital mortality was 36/74
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(49%). Our previous data demonstrated higher mortality rates (53% and 60%,
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respectively). Comparing rates over time, there was a trend to decreased 30-day
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mortality (p=0.07) only (p=0.3 for in-hospital mortality). Median ICU length of stay (LOS) was 20.5 days (IQR 7-33) while hospital LOS was substantially longer
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[49.5 days (IQR 25.3-109)]. Median ICU LOS following the first date of bacteremia was 6.5 days (IQR 2-20).
On univariate analysis (see Table 3), immune suppression, steroid use,
and adequate empiric antimicrobial therapy were associated with mortality. We observed a trend to increased mortality with pseudomonal bacteremia and coronary artery disease.
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On multivariable analysis (see Table 4) adequate empiric antimicrobial therapy [aHR 0.38 (95%CI 0.16-0.89; p=0.03)], immune suppression [aHR 3.44
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1.70-11.85; p=0.003)] were associated with 30-day mortality.
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(95%CI 1.43-8.27; p=0.006)], and coronary artery disease [aHR 4.48 (95%CI
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DISCUSSION
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The incidence of ICU-acquired gram-negative bacteremia in our general systems ICU has been stable over the past one and a half decades. Catheter-
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related bloodstream infections, however, have decreased over time likely due to
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major preventative efforts (zero tolerance) including a prevention bundle
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introduced in 2006, as well as increased education and awareness.
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Similar to our previous study, we identified a large cohort of immune
suppressed patients, which is not surprising for a quaternary care ICU with expertise in solid organ transplantation. In fact 13/74 (18%) of our patients were post-operative liver transplant recipients. In this subgroup, we demonstrated higher risk-adjusted mortality. Several studies have demonstrated similarly poor outcomes in immunocompromised critically ill patients who develop sepsis 1 14 including liver transplant patients with gram-negative sepsis 15 16.
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The most common source of ICU-acquired gram-negative bacteremia was pneumonia in both study periods, as has been observed in a number of other studies 12 17 18. We also observed consistently high rates of Pseudomonal
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infection (22% and 18% of all isolates for both study periods). Multi-drug resistant (MDR) organisms were common (17% of all isolates) and included extended
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spectrum beta-lactamase (ESBL) producers, carbapenem-resistant
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Enterobacteriaceae (CREs), and MDR-Pseudomonal infections.
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Perhaps of most interest, antimicrobial susceptibility patterns demonstrated persistent and increasing resistance over time. Ciprofloxacin
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resistance remained high among pseudomonal isolates making this drug an
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unattractive choice for empiric therapy. Ciprofloxacin resistance in Pseudomonas
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has been steadily increasing over the past decade due to high fluoroquinolone use in both community and hospital settings 19 20, and although recent studies
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suggest resistance may actually be decreasing due to decreased fluoroquinolone use 21, we did not observe this in our data. Ciprofloxacin resistance among all aerobic isolates (including the Enterobacteriaceae) was high, essentially ruling out ciprofloxacin as an option for empiric therapy in ICU-acquired gram-negative bacteremia.
More concerning was the substantial increase in both piperacillin/tazobactam and carbapenem resistance over time. This resistance was demonstrated in all aerobic isolates as well as Pseudomonal isolates alone.
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Other studies have also demonstrated high rates of carbapenem resistance 14 22 23
in Enterobacteriaceae (predominantly Klebsiella pneumoniae) as well as
Pseudomonas aeruginosa, which relates mainly to prior patient antimicrobial
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exposure as well as unit antimicrobial pressure. Although AGs demonstrated the highest activity overall, substantial resistance to these agents was also observed,
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with approximately 17% resistance among aerobic isolates and up to one quarter
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resistance among Pseudomonal isolates.
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We postulate the increasing resistance observed may be due to widespread use as well as longer than necessary, or even unnecessary, courses
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of antimicrobial therapy in critically ill patients in general. The use of
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piperacillin/tazobactam or anti-pseudomonal carbapenems as empiric therapy in
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77% of our cases demonstrates these are preferred agents in our institution. In addition, the increasing incidence of MDR-pathogens such as ESBLs and CREs
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likely contributes to the observed increase in antimicrobial resistance, as these organisms may be inherently resistant to specific antimicrobials (e.g. ESBLs to piperacillin/tazobactam). The incidence of drug-resistant gram negatives has become a global problem for a number of reasons 24-26, particularly in ICUs, and will pose more and more of a challenge in the future given the lack of investment in antimicrobial research and development.
Despite increasing antimicrobial resistance however, most patients (85%) received appropriate empiric therapy. After excluding cases of
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Stenotrophomonas, for which empiric therapy would not be considered standard of care, even higher effective therapy rates (88%) were observed. To compare, a recent study by Shorr et al. observed lower (66%) rates of appropriate therapy in
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patients with gram-negative bacteremia and severe sepsis or septic shock 27.
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Nonetheless, 85% is still suboptimal, as 15% of patients received
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ineffective empiric therapy for a serious, life-threatening infection. The results of this study, however, serve to provide us with the knowledge required to improve
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care. Effectiveness of empiric therapy is indeed an important quality indicator as recent studies have shown that both inadequate empiric therapies, as well as
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delays in therapy, are associated with increased mortality 4 27-32.
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Based on our data, we would recommend empiric therapy with an AG in addition to a carbapenem or ureidopenicillin for ICU-acquired gram-negative
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bacteremia in our centre. However, local epidemiology must be considered in each unit and empiric therapy prescribed based on local susceptibility patterns and patient risk factors. Regarding the short-term safety profile of AGs, the risk of nephro- and oto-toxicity is minimal if administered for 24-48 hours as a bridge to definitive therapy until susceptibility results are available. Despite the low risk of toxicity with one to two doses, many intensivists are still very reluctant to prescribe AGs even short-term, particularly in patients presenting with acute kidney injury. We would strongly argue that the risks of ineffective empiric therapy in patients with ICU-acquired gram-negative bacteremia far exceed the
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risks of short-course AG therapy, and we would urge intensivists to reconsider their prescribing practices. However, when prescribing longer courses of AGs, which can result in toxicity due to cumulative doses, a more careful evaluation of
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risks versus benefits is necessary.
Once susceptibilities are confirmed, it is also imperative to narrow and
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discontinue antimicrobial therapy at the earliest time possible to decrease
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adverse impacts on both the individual patient (alterations in microbiome) and the unit microbial ecology. Data from several studies 33-35 suggests that restricting
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antimicrobial use, with respect to duration and breadth, can decrease resistance rates. Clearly, with increasing resistance this needs to be a priority. The
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institution of antimicrobial stewardship programs can be an effective way to
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instituted in all ICUs.
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decrease unnecessary and inappropriate antibiotic use 36 37 and should be
Our observed mortality rates remained high in this patient population, with
35% 30-day mortality. However, when compared to our previous data from 19992003 (30-day mortality 53%), a substantial 18% reduction was observed with a trend to statistical significance. This hopefully reflects improvements in care, but we recognize may also be due to any number of confounders.
Independent predictors of mortality, identified on multivariable analysis, included coronary artery disease, immune suppression and effective empiric
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antimicrobial therapy. Other studies have demonstrated similar results 1 4 14 27-31 38
, including a study that demonstrated an association between reduced coronary
flow reserve and mortality in sepsis 38. Despite an association on univariate
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analysis, Pseudomonal infection was not predictive of mortality on multivariable
analysis. This may be due to lack of power given the relatively small sample size
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of our study, as pseudomonal infection has been clearly associated with inferior
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outcomes in a number of studies 28 31.
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Lastly, it may seem surprising that APACHEII scores did not correlate with mortality in this study, however it is important to recognize that APACHE II scores
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were collected within the first 24 hours of ICU admission, which was temporally
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distinct from the time of ICU-acquired bacteremia (which by definition occurred
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>48 hours after ICU admission). So although we included the APACHE II score in our model for exploratory purposes (as it captures chronic as well as acute
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disease) we were not surprised by the lack of association.
Despite some strengths of our study, we also recognize several
limitations. First, all observational data is inherently at risk of confounding even with rigorous risk-adjustment. In our study, the number of bacteremic events was small (78 total events) with only 26 deaths at 30-days thus we were limited in our ability to risk-adjust and may have been underpowered to detect predictors of mortality. The small size of the study also limited our ability to perform sensitivity analyses. For example, analyses in specific subgroups such as those with
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immune suppression, septic shock, or specific microbial etiologies were not feasible. Although this is a weakness of our study, we are proud to report so few nosocomial bloodstream infections over the past decade as this reflects high
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quality care provided in our institution.
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Second, empiric therapy was deemed to be adequate if treatment was
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prescribed with an effective agent once positive blood culture results were reported (all results are called directly to the bedside nurse at our institution)
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however actual antimicrobial administration times may have varied. Delays in effective antimicrobial administration have been associated with poor outcomes
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in a number of studies 27 30-32 39 40 and clearly could have confounded our results.
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In addition, specific doses of empiric antimicrobial therapies were not collected.
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Antimicrobial under-dosing (due to obesity or inaccurate estimation of creatinine clearance), for example, may have occurred and altered patient outcomes.
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Lastly, the single center design also limits generalizability of our results, particularly given the high proportion of immune suppressed (predominantly solid organ transplant) patients in our population.
CONCLUSIONS
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In conclusion, ICU-acquired gram-negative bacteremia is associated with high mortality. The most common source of ICU-acquired gram-negative bacteremia continues to be pneumonia. Resistance to ciprofloxacin remains high,
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while resistance to piperacillin/tazobactam increased substantially over the past decade. A substantial increase in carbapenem resistance in Pseudomonas
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aeruginosa was also observed. Despite increasing antimicrobial resistance most
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patients received adequate empiric antimicrobial therapy. We would suggest empiric treatment regimens be based on unit-specific data. Coronary artery
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disease, immune suppression and inadequate empiric antimicrobial therapy were
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independently associated with increased 30-day mortality.
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ACKNOWLEDGEMENTS
We thank the Infection Control Practitioners at the University of Alberta for
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their collection of data.
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Figure 1 – Sources of bacteremia
Figure 2 – Microbial isolates
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Figure 3 – Comparison of antimicrobial susceptibilities over time
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a. Aerobic isolates
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b. Pseudomonal isolates
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Table 1 – Baseline characteristics
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12 (16) 7 (10) 2 (3) 2 (3) 2 (3) 1 (1) 18 (24) 19 (26) 8 (11) 4 (5) 11 (15) 2 (3) 9 (12) 15 (20) 5 (7) 7 (10) 12 (16) 26 (35) 4 (5) 5 (7) 3 (4) 3 (4) 19 (26) 13 (18) 1 (1) 2 (3) 3 (4) 5 (7) 8 (11)
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51 (69) 23 (31)
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Age, in years (mean, SD) Male sex Admission class Medical Surgical Comorbidities Chronic lung disease COPD Pulmonary fibrosis Asthma Bronchiectasis Neuromuscular disease Diabetes mellitus ESLD HCV infection Autoimmune hepatitis Alcoholic liver disease Primary sclerosing cholangitis Coronary artery disease Hypertension Congestive heart failure Atrial fibrillation Malignancy Immune suppression Steroids Chemotherapy Neutropenia HIV/AIDS Solid organ transplant Liver transplant Lung transplant Heart transplant Renal transplant ESRD Psychiatric disease Admission diagnosis Respiratory failure Sepsis or septic shock Liver transplantation Trauma or major burn APACHE II score (mean, SD) ICU LOS Hospital LOS
N=74 No. (%) 55 (16) 46 (62)
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Variables
25 (34) 33 (45) 7 (10) 5 (7) 25 (8) 20.5 (7-33) 50 (25-109)
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30-day mortality Hospital mortality
26 (35) 36 (49)
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Legend: SD, standard deviation; COPD, chronic obstructive pulmonary disorder; ESLD, end stage liver disease; HCV, hepatitis C virus; HIV, human immunodeficiency virus; AIDS, acquired immunodeficiency syndrome; ESRD, end stage renal disease; APACHE, Acute Physiology and Chronic Health Evaluation; LOS, length of stay.
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Table 2 – Antimicrobial susceptibilities Intermediate 1 (2) 2 (3) 2 (3) 0 (0) 1 (1) 1 (2) 3 (5)
Pseudomonas aeruginosa (N=15) Ceftazidime (N=15) Cefepime (N=5) Ciprofloxacin (N=15) Gentamicin (N=15) Meropenem (N=12) Imipenem (N=15) Piperacillin/tazobactam (N=15) Tobramycin (N=15) Amikacin (N=15) Aztreonam (N=10) Colistin (N=4)
Susceptible 11 (73) 2 (40) 8 (53) 9 (60) 7 (58) 8 (53) 10 (67) 11 (73) 13 (87) 4 (40) 4 (100)
Intermediate 1 (7) 1 (20) 1 (7) 2 (13) 0 (0) 1 (7) 0 (0) 1 (7) 0 (0) 1 (10) 0 (0)
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Resistant 3 (20) 2 (40) 6 (40) 4 (27) 5 (42) 6 (40) 5 (33) 3 (20) 2 (13) 5 (50) 0 (0)
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Resistant 15 (28) 24 (36) 11 (17) 9 (16) 10 (17) 20 (31) 11 (18)
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Susceptible 37 (70) 40 (61) 53 (80) 46 (84) 47 (81) 44 (68) 49 (78)
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Aerobic isolates (N=71) Ceftriaxone (N=53) Ciprofloxacin (N=66) Gentamicin (N=66) Meropenem (N=55) Imipenem (N=58) Piperacillin/tazobactam (N=65) Tobramycin (N=63)
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Table 3 – Univariate analyses of 30-day mortality (78 bacteremic events) Variable
30-day mortality Deceased
p-value
N=51
N=27
(Chi-Square)
(65%)
(35%)
Age, in years (mean, SD)
54 (16)
56 (16)
Male sex
31 (61)
16 (60)
Admission class
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Alive
0.8 0.9
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0.7
34 (67)
19 (70)
Surgical
17 (33)
8 (30)
Comorbidities Chronic lung disease
7 (14)
COPD
5 (10)
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Medical
5 (18)
0.7
2 (7)
1.0
1 (2)
1 (4)
0.6
Asthma
1 (2)
1 (4)
1.0
Bronchiectasis
1 (2)
1 (4)
1.0
Neuromuscular disease
1 (2)
0 (0)
1.0
14 (28)
5 (19)
0.4
14 (28)
6 (22)
0.6
6 (12)
2 (7)
0.7
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Pulmonary fibrosis
Diabetes mellitus ESLD
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HCV infection Autoimmune hepatitis
3 (11)
0.3
5 (19)
0.5
Primary sclerosing cholangitis
2 (4)
0 (0)
0.5
Coronary artery disease
3 (6)
6 (22)
0.06
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2 (4)
6 (12)
Alcoholic liver disease
Hypertension
8 (16)
8 (30)
0.2
Congestive heart failure
2 (4)
3 (11)
0.3
Atrial fibrillation
4 (8)
3 (11)
0.7
7 (14)
5 (19)
0.7
Malignancy
Immune suppression
13 (26)
15 (56)
0.01
Steroids
1 (2)
4 (15)
0.046
Chemotherapy
2 (4)
3 (11)
0.3
Neutropenia
1 (2)
2 (7)
0.3
HIV/AIDS
2 (4)
1 (4)
1.0
Transplant
12 (24)
8 (30)
0.6
Liver transplant
11 (22)
3 (11)
0.4
Lung transplant
0 (0)
1 (4)
0.4
Heart transplant
1 (2)
1 (4)
1.0
Renal transplant
1 (2)
2 (7)
0.3
4 (8)
2 (7)
1.0
6 (12)
2 (7)
0.7
ESRD Psychiatric disease
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Admission diagnosis 16 (31)
10 (37)
0.6
Sepsis or septic shock
20 (39)
14 (52)
0.3
7 (14)
1 (4)
0.3
4 (8)
1 (4)
0.4
APACHE II score (mean, SD)
24 (8)
26 (9)
0.8
Pseudomonal bacteremia
7 (14)
8 (30)
Adequate empiric therapy
47 (92)
19 (70)
Liver transplantation Trauma or major burn
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Respiratory failure
0.09 0.01
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Legend: SD, standard deviation; COPD, chronic obstructive pulmonary disorder; ESLD, end stage liver disease; HCV, hepatitis C virus; HIV, human immunodeficiency virus; AIDS, acquired immunodeficiency syndrome; ESRD, end stage renal disease; APACHE, Acute Physiology and Chronic Health Evaluation; LOS, length of stay.
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Variable
30-day mortality aHR (95% CI) p-value 1.00 (0.96-1.05) 0.9 0.38 (0.16-0.89) 0.03 3.44 (1.43-8.27) 0.006 4.48 (1.70-11.85) 0.003 1.18 (0.48-2.90) 0.7
APACHE II score Adequate empiric therapy Immune suppression Coronary artery disease Pseudomonal bacteremia
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Table 4 – Multivariable regression analysis of 30-day mortality (78 bacteremic events)
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Legend: aHR, adjusted hazard ratio; APACHE, Acute Physiology and Chronic Health Evaluation
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REFERENCES
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1. Colpan A, Akinci E, Erbay A, et al. Evaluation of risk factors for mortality in intensive care units: a prospective study from a referral hospital in Turkey. American journal of infection control 2005;33(1):42-7. 2. Magill SS, Edwards JR, Bamberg W, et al. Multistate point-prevalence survey of health care-associated infections. The New England journal of medicine 2014;370(13):1198-208. 3. Pittet D, Li N, Woolson RF, et al. Microbiological factors influencing the outcome of nosocomial bloodstream infections: a 6-year validated, population-based model. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 1997;24(6):1068-78. 4. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Critical care medicine 2006;34(6):1589-96. 5. Kollef MH, Sherman G, Ward S, et al. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest 1999;115(2):462-74. 6. Alberti C, Brun-Buisson C, Burchardi H, et al. Epidemiology of sepsis and infection in ICU patients from an international multicentre cohort study. Intensive care medicine 2002;28(2):108-21. 7. Laupland KB, Kirkpatrick AW, Church DL, et al. Intensive-care-unit-acquired bloodstream infections in a regional critically ill population. The Journal of hospital infection 2004;58(2):137-45. 8. Fridkin SK, Welbel SF, Weinstein RA. Magnitude and prevention of nosocomial infections in the intensive care unit. Infectious disease clinics of North America 1997;11(2):479-96. 9. National Nosocomial Infections Surveillance (NNIS) system report, data summary from January 1992-April 2000, issued June 2000. American journal of infection control 2000;28(6):429-48. 10. Hidron AI, Edwards JR, Patel J, et al. NHSN annual update: antimicrobial-resistant pathogens associated with healthcare-associated infections: annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006-2007. Infection control and hospital epidemiology 2008;29(11):996-1011. 11. Karakoc C, Tekin R, Yesilbag Z, et al. Risk factors for mortality in patients with nosocomial Gram-negative rod bacteremia. European review for medical and pharmacological sciences 2013;17(7):951-7. 12. Sligl W, Taylor G, Brindley PG. Five years of nosocomial Gram-negative bacteremia in a general intensive care unit: epidemiology, antimicrobial susceptibility patterns, and outcomes. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 2006;10(4):320-5. 13. (CDC) CfDCaP. Bloodstream Infection Event (Central Line-Associated Bloodstream Infection and Non-central line-associated Bloodstream Infection). 2015.
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14. Boncagni F, Francolini R, Nataloni S, et al. Epidemiology and clinical outcome of Healthcare-Associated Infections: a 4-year experience of an Italian ICU. Minerva anestesiologica 2015. 15. Wan Q, Ye Q, Su T, et al. The epidemiology and distribution of pathogens and risk factors for mortality in liver transplant recipients with Gram negative bacteremia. Hepato-gastroenterology 2014;61(134):1730-3. 16. Shi SH, Kong HS, Xu J, et al. Multidrug resistant gram-negative bacilli as predominant bacteremic pathogens in liver transplant recipients. Transplant infectious disease : an official journal of the Transplantation Society 2009;11(5):405-12. 17. Meric M, Willke A, Caglayan C, et al. Intensive care unit-acquired infections: incidence, risk factors and associated mortality in a Turkish university hospital. Japanese journal of infectious diseases 2005;58(5):297-302. 18. Erbay H, Yalcin AN, Serin S, et al. Nosocomial infections in intensive care unit in a Turkish university hospital: a 2-year survey. Intensive care medicine 2003;29(9):1482-8. 19. Ray GT, Baxter R, DeLorenze GN. Hospital-level rates of fluoroquinolone use and the risk of hospital-acquired infection with ciprofloxacin-nonsusceptible Pseudomonas aeruginosa. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2005;41(4):441-9. 20. Zervos MJ, Hershberger E, Nicolau DP, et al. Relationship between fluoroquinolone use and changes in susceptibility to fluoroquinolones of selected pathogens in 10 United States teaching hospitals, 1991-2000. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2003;37(12):1643-8. 21. Pakyz AL, Lee JA, Ababneh MA, et al. Fluoroquinolone use and fluoroquinoloneresistant Pseudomonas aeruginosa is declining in US academic medical centre hospitals. The Journal of antimicrobial chemotherapy 2012;67(6):1562-4. 22. Porwal R, Gopalakrishnan R, Rajesh NJ, et al. Carbapenem resistant Gram-negative bacteremia in an Indian intensive care unit: A review of the clinical profile and treatment outcome of 50 patients. Indian journal of critical care medicine : peerreviewed, official publication of Indian Society of Critical Care Medicine 2014;18(11):750-3. 23. Routsi C, Pratikaki M, Platsouka E, et al. Risk factors for carbapenem-resistant Gram-negative bacteremia in intensive care unit patients. Intensive care medicine 2013;39(7):1253-61. 24. Voets GM, Platteel TN, Fluit AC, et al. Population distribution of Beta-lactamase conferring resistance to third-generation cephalosporins in human clinical Enterobacteriaceae in the Netherlands. PloS one 2012;7(12):e52102. 25. Seiffert SN, Hilty M, Perreten V, et al. Extended-spectrum cephalosporin-resistant Gram-negative organisms in livestock: an emerging problem for human health? Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 2013;16(1-2):22-45. 26. Curcio D. Multidrug-resistant Gram-negative bacterial infections: are you ready for the challenge? Current clinical pharmacology 2014;9(1):27-38.
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27. Shorr AF, Micek ST, Welch EC, et al. Inappropriate antibiotic therapy in Gramnegative sepsis increases hospital length of stay. Critical care medicine 2011;39(1):46-51. 28. Johnson MT, Reichley R, Hoppe-Bauer J, et al. Impact of previous antibiotic therapy on outcome of Gram-negative severe sepsis. Critical care medicine 2011;39(8):1859-65. 29. Zahar JR, Timsit JF, Garrouste-Orgeas M, et al. Outcomes in severe sepsis and patients with septic shock: pathogen species and infection sites are not associated with mortality. Critical care medicine 2011;39(8):1886-95. 30. Kang CI, Kim SH, Park WB, et al. Bloodstream infections caused by antibioticresistant gram-negative bacilli: risk factors for mortality and impact of inappropriate initial antimicrobial therapy on outcome. Antimicrobial agents and chemotherapy 2005;49(2):760-6. 31. Micek ST, Welch EC, Khan J, et al. Resistance to empiric antimicrobial treatment predicts outcome in severe sepsis associated with Gram-negative bacteremia. Journal of hospital medicine : an official publication of the Society of Hospital Medicine 2011;6(7):405-10. 32. Girometti N, Lewis RE, Giannella M, et al. Klebsiella pneumoniae bloodstream infection: epidemiology and impact of inappropriate empirical therapy. Medicine 2014;93(17):298-309. 33. Marra AR, de Almeida SM, Correa L, et al. The effect of limiting antimicrobial therapy duration on antimicrobial resistance in the critical care setting. American journal of infection control 2009;37(3):204-9. 34. Ntagiopoulos PG, Paramythiotou E, Antoniadou A, et al. Impact of an antibiotic restriction policy on the antibiotic resistance patterns of Gram-negative microorganisms in an Intensive Care Unit in Greece. International journal of antimicrobial agents 2007;30(4):360-5. 35. Furtado GH, Perdiz LB, Santana IL, et al. Impact of a hospital-wide antimicrobial formulary intervention on the incidence of multidrug-resistant gram-negative bacteria. American journal of infection control 2008;36(9):661-4. 36. Hurford A, Morris AM, Fisman DN, et al. Linking antimicrobial prescribing to antimicrobial resistance in the ICU: before and after an antimicrobial stewardship program. Epidemics 2012;4(4):203-10. 37. Katsios CM, Burry L, Nelson S, et al. An antimicrobial stewardship program improves antimicrobial treatment by culture site and the quality of antimicrobial prescribing in critically ill patients. Critical care 2012;16(6):R216. 38. Ikonomidis I, Makavos G, Nikitas N, et al. Coronary flow reserve is associated with tissue ischemia and is an additive predictor of intensive care unit mortality to traditional risk scores in septic shock. International journal of cardiology 2014;172(1):103-8. 39. Ferrer R, Martin-Loeches I, Phillips G, et al. Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance improvement program. Critical care medicine 2014;42(8):1749-55. 40. Kumar A. An alternate pathophysiologic paradigm of sepsis and septic shock: implications for optimizing antimicrobial therapy. Virulence 2014;5(1):80-97.
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S1201-9712(15)00162-9 http://dx.doi.org/doi:10.1016/j.ijid.2015.06.024 IJID 2376
To appear in:
International Journal of Infectious Diseases
Received date: Revised date: Accepted date:
20-4-2015 3-6-2015 28-6-2015
Please cite this article as: Sligl WI, Dragan T, Smith SW, Nosocomial gram-negative bacteremia in intensive care: epidemiology, antimicrobial susceptibilities and outcomes, International Journal of Infectious Diseases (2015), http://dx.doi.org/10.1016/j.ijid.2015.06.024 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Nosocomial gram-negative bacteremia in intensive care: epidemiology, antimicrobial susceptibilities and outcomes Wendy Irene Sligla, Tatiana Draganb, Stephanie Wrenn Smithc a
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MD, MSc, FRCPC, Associate Clinical Professor, Divisions of Critical Care Medicine and Infectious Diseases, Faculty of Medicine and Dentistry, University of Alberta. Address: 2-124 Clinical Sciences Building, 8440 112 Street, Edmonton, AB, T6G 2B7, CANADA; [email protected] b MD, Department of Medical Microbiology & Immunology, Faculty of Medicine and Dentistry, University of Alberta. Address: 2B3 Walter Mackenzie Centre, 8440 112 Street, Edmonton, AB, T6G 2H7, CANADA; [email protected] c MD, MSc, FRCPC, Associate Professor, Division of Infectious Diseases, Faculty of Medicine and Dentistry, University of Alberta. Address: 1-124 Clinical Sciences Building, 8440 112 Street, Edmonton, AB, T6G 2B7, CANADA; [email protected]
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Address correspondence to: Wendy Sligl Divisions of Critical Care Medicine and Infectious Diseases University of Alberta 2-124 Clinical Sciences Building 8440-112 Street Edmonton, AB, Canada T6G 2B7 Phone 780-492-8311 Fax 780-492-1500 E-mail: [email protected]
Reprints not required Work performed at University of Alberta Category: Original Article Conflicts of Interest and Source of Funding: None declared for all authors.
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We describe the epidemiology and outcomes of ICU-acquired gramnegative bacteremia. Resistance to ciprofloxacin and piperacillin/tazobactam was common.
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Carbapenem resistance among pseudomonal isolates was surprisingly high. Most patients received adequate empiric antimicrobial therapy.
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Coronary disease, immunosuppression and antimicrobial therapy predicted mortality.
ABSTRACT
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Objectives: To describe the epidemiology, antimicrobial susceptibilities, treatment and outcomes of ICU-acquired gram-negative bacteremia.
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Methods: Patients with ICU-acquired gram-negative bacteremia from 2004-2012 were retrospectively reviewed. Independent predictors of mortality were examined using multivariable Cox regression.
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Results: Seventy-eight ICU-acquired gram-negative bacteremias occurred in 74 patients. Infection rate was 0.97/1000 patient days. Mean patient age was 55 years, 62% were male. Most common admission diagnoses were respiratory failure (34%) and sepsis/septic shock (45%). Mortality was 35% at 30-days.
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The most common source of bacteremia was pneumonia (33%). Of 83 gramnegative isolates, Escherichia coli (20%), and Pseudomonas aeruginosa (18%) were most common. For aerobic isolates, susceptibilities to ciprofloxacin (61%) and piperacillin/tazobactam (68%) were low. For pseudomonal isolates, susceptibilities to ciprofloxacin (53%), piperacillin/tazobactam (67%) and imipenem (53%) were equally disappointing. Adequate empiric antimicrobial therapy was prescribed in 85% bacteremias. On multivariable analysis, adequate empiric therapy (adjusted hazard ratio [aHR] 0.38, 95%CI 0.16-0.89), immune suppression (aHR 3.4; 95%CI 1.4-8.3) and coronary artery disease (aHR 4.5; 95%CI 1.7-11.9) were independently associated with 30-day mortality. Conclusions: ICU-acquired gram-negative bacteremia is associated with high mortality. Resistance to ciprofloxacin, piperacillin/tazobactam, and carbapenems was common. Coronary artery disease, immune suppression and inadequate empiric antimicrobial therapy were independently associated with increased mortality.
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Key words: bacteremia; gram negative; critical care; intensive care; nosocomial infection; antimicrobial resistance
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Word counts and numbers: Abstract – 201 Manuscript – 3016 References – 40 Tables – 4 Figures – 3
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INTRODUCTION Despite considerable preventative efforts, hospital-acquired infections
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continue to contribute to substantial morbidity and mortality 1 occurring in approximately 4% of hospitalized patients 2. An estimated 250,000 nosocomial
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bloodstream infections occur each year in the United States 3 with approximately 30% due to gram-negative bacilli. Mortality rates in gram-negative sepsis are
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high, and can be up to 50% depending on patient factors, as well as timing and
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appropriateness of empiric antimicrobial therapy 4-7.
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Although intensive care units (ICUs) account for less than 10% of the total number of beds in most hospitals, more than 20-30% of all nosocomial infections
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are acquired in the ICU 2 8, with high rates of antimicrobial resistance 9 10 and
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mortality 7 11 when compared with the general hospital population. Understanding
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the local epidemiology and antimicrobial susceptibility patterns in ICU-acquired gram-negative bacteremia may facilitate development of empiric therapy guidelines, formulary restrictions and/or antimicrobial stewardship programs, resulting in improved patient outcomes.
The aim of our study is to provide up-to-date data on the epidemiology
(including incidence, source, microbial etiology, antimicrobial susceptibilities, and outcomes) of nosocomial gram-negative bacteremia in a population of critically ill patients. We also compare rates, microbiology, antimicrobial susceptibilities and
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appropriateness of empiric therapy over time, in particular compared to data previously published in the same patient population 12.
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MATERIALS AND METHODS
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We conducted a retrospective observational cohort study at the University
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of Alberta Hospital, a 650-bed academic quaternary care referral hospital in Edmonton, Canada and the principal teaching hospital of the University of
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Alberta, Faculty of Medicine and Dentistry. It is a level-one trauma center, the largest solid organ transplantation center in Western Canada, and has a referral
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area of over two million.
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The University of Alberta Hospital contains a 32-bed adult general systems intensive care unit (ICU) that admits general medical, surgical, trauma,
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and solid organ transplant patients. The ICU provides general invasive hemodynamic monitoring and support, mechanical ventilation, renal replacement therapy, as well as extracorporeal liver support. Other specialized support therapies such as extracorporeal membrane oxygenation (ECMO) are provided in the cardiovascular ICU.
This study was conducted as part of a quality improvement study through Infection Prevention and Control and was therefore exempt from ethics submission as per the Research Ethics Board at the University of Alberta.
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Infection Prevention and Control (IPC) prospectively monitors all inpatient populations, including ICU patients, for the development of nosocomial infection(s). Positive blood cultures are identified by the clinical microbiology
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laboratory (BACTEC 9240 Blood Culture System; Becton Dickinson Biosciences) and reviewed by IPC daily. Charts are subsequently reviewed and blood culture
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isolates categorized as contaminants, community-acquired, or nosocomial using
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source is then identified and subcategorized.
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standardized CDC/NHSN criteria 13. For nosocomial bacteremia, the originating
All cases of ICU-acquired gram-negative bacteremia from January 1, 2004
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to December 31, 2012 were reviewed. Demographic data, source of bacteremia,
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causative micro-organisms, antimicrobial susceptibilities, choice of empiric
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antibiotic therapy, ICU and hospital lengths of stay and 30-day mortality rates were collected. Data were subsequently compared to previously published data
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from 1999-2003 in the same patient population 12.
Immune compromise was defined as chronic steroid use (daily equivalent
of 20mg prednisone for ≥1 month per year), solid organ or hematopoietic stem cell transplantation, receipt of chemotherapy within the previous month, neutropenia (absolute neutrophil count <1.0 cells/L) at the time of admission, or HIV/AIDS (CD4 count <200 cells/µL). End-stage renal disease (ESRD) was defined as kidney failure necessitating either peritoneal or intermittent hemodialysis prior to admission. Empiric therapy was deemed effective if
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treatment was with an agent to which the microorganism was ultimately susceptible. Multi-drug resistance in Pseudomonas species was defined as resistance to three or more first line antimicrobials in the following classes: β-
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lactams, carbapenems, aminoglycosides (AGs), and fluoroquinolones.
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Statistical analysis
Epidemiologic data was reported including descriptive statistics such as
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proportions, percentages, means or medians. Characteristics for subjects dead or alive were compared using t-tests or Mann-Whitney U tests (as appropriate
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based on their distribution) for continuous variables. Chi-square or Fisher’s exact
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tests were used for categorical variables.
We then constructed Kaplan-Meier survival curves and performed log-rank
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tests for variables associated with mortality on univariate analysis.
Multivariable Cox regression modeling was subsequently performed to
identify variables independently associated with 30-day mortality. APACHE II was included for clinical significance. Otherwise variables identified to be significantly associated with increased mortality (p<0.1) on univariate analyses were entered into the model. There were no proportional hazards violations, which we tested using time covariate interaction terms. Results are presented as adjusted hazard
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ratios (aHR) and 95% confidence intervals (CI). All statistical tests were twosided and p-values <0.05 were considered statistically significant.
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Statistical analyses were performed using SPSS statistical software
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version 22.0 (IBM Corp. Released 2013. IBM SPSS Statistics. Armonk, NY).
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RESULTS
There were 11,602 admissions to the general systems ICU from January
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1, 2004 to December 31, 2012. A total of 78 episodes of ICU-acquired gram-
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negative bacteremia occurred in 74 patients, resulting in overall infection rates of
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6.7 per 1000 ICU admissions or 9.7 per 10,000 patient days. These rates were similar to those observed in our previous study (6.9 per 1000 ICU admissions
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and 11.3 per 10,000 patient days). Annual infection rates fluctuated by year from 1.6-9.6 per 1000 admissions and 2.3-15.0 per 10,000 patient days consistent with expected year-to-year variation.
The mean patient age was 55 years (range 18-85 years; SD 15.8) and
46/74 (62.2%) were male. A large number of patients [26/74 (35%)] were immune compromised. Additional specific patient demographics can be found in Table 1.
The majority of patients were admitted with medical diagnoses [51/72 (69%)].
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Admitting diagnoses included: respiratory failure 25/74 (34%), sepsis or septic shock 33/74 (45%), liver transplantation 7/74 (10%), and trauma/major
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burns 5/75 (7%). Mean APACHE II score was 25 (SD 8.3) at the time of
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admission and 73/78 (94%) patients required invasive mechanical ventilation.
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The most common source of bacteremia was pneumonia in 26/78 (33%) patients, as was observed in our previous study. Other common sources included
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gastrointestinal tract (not endoscopy related) [17/78 (22%)] and catheter-related bloodstream infections [10/78 (13%)]; see Figure 1. A decrease in catheter-
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related bloodstream infections was observed from 1999-2003 to 2004-2012 (22%
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vs. 13%, respectively).
Bacterial species identified can be found in Figure 2. In summary, the
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most common bacterial pathogen was Escherichia coli 17/83 (21%), followed by Pseudomonas aeruginosa 15/83 (18%) and Klebsiella species (13/83; 16%). The majority of isolates were aerobic gram-negative bacilli (71/83 [86%]) of which 49/83 (59%) were Enterobacteriaceae. Glucose non-fermenting organisms (Pseudomonas and Stenotrophomonas) accounted for 21/83 (25%) of bacteremias.
Multi-drug resistant (MDR) pathogens were isolated in 14/83 (17%) of cases including extended spectrum beta-lactamase producers (ESBLs; 5/83
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[5%]), carbapenem-resistant Enterobacteriaceae (CRE; 2/83 (2%) and MDRPseudomonas (7/83 [8%]).
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The majority [63/78 (81%)] of infections were monomicrobial. In fifteen polymicrobial infections, three were with another gram-negative organism, 10
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with gram-positive organisms, and two events in which additional gram-negative
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and gram-positive organisms were identified.
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Overall aerobic gram-negative and pseudomonal susceptibilities are shown in Table 2. Of all aerobic isolates tested, susceptibilities to ciprofloxacin
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[40/66 (61%)] and piperacillin/tazobactam [44/65 (68%)] were low. Similar
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numbers were observed for Enterobacteriaceae alone. For pseudomonal
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isolates, susceptibility to ciprofloxacin (8/15 [53%]), piperacillin/tazobactam [10/15 (67%)], and imipenem [8/15 (53%)] were equally disappointing. Changes
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in antimicrobial susceptibilities over time are demonstrated in Figure 3. Comparison of the two study periods demonstrates 1) sustained resistance to ciprofloxacin (in both aerobic isolates as well as Pseudomonas alone) in 30-50% of isolates, 2) increased resistance to piperacillin/tazobactam in aerobic isolates (from 11% to 32%) and in Pseudomonal isolates alone (0% to 33%), and 3) substantially increased carbapenem resistance in Pseudomonas (9% to 47% for imipenem). Surprisingly, only 2/6 (33%) strains of Stenotrophomonas maltophilia were susceptible to trimethoprim/sulfamethoxazole (TMP/SMX).
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Empiric therapy was appropriate in 66/78 (85%) of aerobic gram-negative bacteremias and 11/15 (73%) of pseudomonal bacteremias. Most commonly prescribed empiric antibiotics were piperacillin/tazobactam [31/78 (40%)] and
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anti-pseudomonal carbapenems [29/78 (37%)]. After excluding cases of
Stenotrophomonas maltophilia, for which empiric therapy is not common or
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standard of care, effective empiric coverage increased to 63/72 (88%). In the six
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cases of Stenotrophomonas maltophilia bacteremia, three (50%) patients
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received adequate empiric therapy.
Crude 30-day mortality was 26/74 (35%) and hospital mortality was 36/74
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(49%). Our previous data demonstrated higher mortality rates (53% and 60%,
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respectively). Comparing rates over time, there was a trend to decreased 30-day
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mortality (p=0.07) only (p=0.3 for in-hospital mortality). Median ICU length of stay (LOS) was 20.5 days (IQR 7-33) while hospital LOS was substantially longer
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[49.5 days (IQR 25.3-109)]. Median ICU LOS following the first date of bacteremia was 6.5 days (IQR 2-20).
On univariate analysis (see Table 3), immune suppression, steroid use,
and adequate empiric antimicrobial therapy were associated with mortality. We observed a trend to increased mortality with pseudomonal bacteremia and coronary artery disease.
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On multivariable analysis (see Table 4) adequate empiric antimicrobial therapy [aHR 0.38 (95%CI 0.16-0.89; p=0.03)], immune suppression [aHR 3.44
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1.70-11.85; p=0.003)] were associated with 30-day mortality.
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(95%CI 1.43-8.27; p=0.006)], and coronary artery disease [aHR 4.48 (95%CI
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DISCUSSION
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The incidence of ICU-acquired gram-negative bacteremia in our general systems ICU has been stable over the past one and a half decades. Catheter-
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related bloodstream infections, however, have decreased over time likely due to
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major preventative efforts (zero tolerance) including a prevention bundle
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introduced in 2006, as well as increased education and awareness.
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Similar to our previous study, we identified a large cohort of immune
suppressed patients, which is not surprising for a quaternary care ICU with expertise in solid organ transplantation. In fact 13/74 (18%) of our patients were post-operative liver transplant recipients. In this subgroup, we demonstrated higher risk-adjusted mortality. Several studies have demonstrated similarly poor outcomes in immunocompromised critically ill patients who develop sepsis 1 14 including liver transplant patients with gram-negative sepsis 15 16.
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The most common source of ICU-acquired gram-negative bacteremia was pneumonia in both study periods, as has been observed in a number of other studies 12 17 18. We also observed consistently high rates of Pseudomonal
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infection (22% and 18% of all isolates for both study periods). Multi-drug resistant (MDR) organisms were common (17% of all isolates) and included extended
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spectrum beta-lactamase (ESBL) producers, carbapenem-resistant
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Enterobacteriaceae (CREs), and MDR-Pseudomonal infections.
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Perhaps of most interest, antimicrobial susceptibility patterns demonstrated persistent and increasing resistance over time. Ciprofloxacin
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resistance remained high among pseudomonal isolates making this drug an
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unattractive choice for empiric therapy. Ciprofloxacin resistance in Pseudomonas
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has been steadily increasing over the past decade due to high fluoroquinolone use in both community and hospital settings 19 20, and although recent studies
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suggest resistance may actually be decreasing due to decreased fluoroquinolone use 21, we did not observe this in our data. Ciprofloxacin resistance among all aerobic isolates (including the Enterobacteriaceae) was high, essentially ruling out ciprofloxacin as an option for empiric therapy in ICU-acquired gram-negative bacteremia.
More concerning was the substantial increase in both piperacillin/tazobactam and carbapenem resistance over time. This resistance was demonstrated in all aerobic isolates as well as Pseudomonal isolates alone.
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Other studies have also demonstrated high rates of carbapenem resistance 14 22 23
in Enterobacteriaceae (predominantly Klebsiella pneumoniae) as well as
Pseudomonas aeruginosa, which relates mainly to prior patient antimicrobial
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exposure as well as unit antimicrobial pressure. Although AGs demonstrated the highest activity overall, substantial resistance to these agents was also observed,
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with approximately 17% resistance among aerobic isolates and up to one quarter
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resistance among Pseudomonal isolates.
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We postulate the increasing resistance observed may be due to widespread use as well as longer than necessary, or even unnecessary, courses
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of antimicrobial therapy in critically ill patients in general. The use of
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piperacillin/tazobactam or anti-pseudomonal carbapenems as empiric therapy in
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77% of our cases demonstrates these are preferred agents in our institution. In addition, the increasing incidence of MDR-pathogens such as ESBLs and CREs
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likely contributes to the observed increase in antimicrobial resistance, as these organisms may be inherently resistant to specific antimicrobials (e.g. ESBLs to piperacillin/tazobactam). The incidence of drug-resistant gram negatives has become a global problem for a number of reasons 24-26, particularly in ICUs, and will pose more and more of a challenge in the future given the lack of investment in antimicrobial research and development.
Despite increasing antimicrobial resistance however, most patients (85%) received appropriate empiric therapy. After excluding cases of
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Stenotrophomonas, for which empiric therapy would not be considered standard of care, even higher effective therapy rates (88%) were observed. To compare, a recent study by Shorr et al. observed lower (66%) rates of appropriate therapy in
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patients with gram-negative bacteremia and severe sepsis or septic shock 27.
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Nonetheless, 85% is still suboptimal, as 15% of patients received
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ineffective empiric therapy for a serious, life-threatening infection. The results of this study, however, serve to provide us with the knowledge required to improve
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care. Effectiveness of empiric therapy is indeed an important quality indicator as recent studies have shown that both inadequate empiric therapies, as well as
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delays in therapy, are associated with increased mortality 4 27-32.
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Based on our data, we would recommend empiric therapy with an AG in addition to a carbapenem or ureidopenicillin for ICU-acquired gram-negative
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bacteremia in our centre. However, local epidemiology must be considered in each unit and empiric therapy prescribed based on local susceptibility patterns and patient risk factors. Regarding the short-term safety profile of AGs, the risk of nephro- and oto-toxicity is minimal if administered for 24-48 hours as a bridge to definitive therapy until susceptibility results are available. Despite the low risk of toxicity with one to two doses, many intensivists are still very reluctant to prescribe AGs even short-term, particularly in patients presenting with acute kidney injury. We would strongly argue that the risks of ineffective empiric therapy in patients with ICU-acquired gram-negative bacteremia far exceed the
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risks of short-course AG therapy, and we would urge intensivists to reconsider their prescribing practices. However, when prescribing longer courses of AGs, which can result in toxicity due to cumulative doses, a more careful evaluation of
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risks versus benefits is necessary.
Once susceptibilities are confirmed, it is also imperative to narrow and
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discontinue antimicrobial therapy at the earliest time possible to decrease
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adverse impacts on both the individual patient (alterations in microbiome) and the unit microbial ecology. Data from several studies 33-35 suggests that restricting
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antimicrobial use, with respect to duration and breadth, can decrease resistance rates. Clearly, with increasing resistance this needs to be a priority. The
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institution of antimicrobial stewardship programs can be an effective way to
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instituted in all ICUs.
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decrease unnecessary and inappropriate antibiotic use 36 37 and should be
Our observed mortality rates remained high in this patient population, with
35% 30-day mortality. However, when compared to our previous data from 19992003 (30-day mortality 53%), a substantial 18% reduction was observed with a trend to statistical significance. This hopefully reflects improvements in care, but we recognize may also be due to any number of confounders.
Independent predictors of mortality, identified on multivariable analysis, included coronary artery disease, immune suppression and effective empiric
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antimicrobial therapy. Other studies have demonstrated similar results 1 4 14 27-31 38
, including a study that demonstrated an association between reduced coronary
flow reserve and mortality in sepsis 38. Despite an association on univariate
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analysis, Pseudomonal infection was not predictive of mortality on multivariable
analysis. This may be due to lack of power given the relatively small sample size
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of our study, as pseudomonal infection has been clearly associated with inferior
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outcomes in a number of studies 28 31.
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Lastly, it may seem surprising that APACHEII scores did not correlate with mortality in this study, however it is important to recognize that APACHE II scores
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were collected within the first 24 hours of ICU admission, which was temporally
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distinct from the time of ICU-acquired bacteremia (which by definition occurred
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>48 hours after ICU admission). So although we included the APACHE II score in our model for exploratory purposes (as it captures chronic as well as acute
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disease) we were not surprised by the lack of association.
Despite some strengths of our study, we also recognize several
limitations. First, all observational data is inherently at risk of confounding even with rigorous risk-adjustment. In our study, the number of bacteremic events was small (78 total events) with only 26 deaths at 30-days thus we were limited in our ability to risk-adjust and may have been underpowered to detect predictors of mortality. The small size of the study also limited our ability to perform sensitivity analyses. For example, analyses in specific subgroups such as those with
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immune suppression, septic shock, or specific microbial etiologies were not feasible. Although this is a weakness of our study, we are proud to report so few nosocomial bloodstream infections over the past decade as this reflects high
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quality care provided in our institution.
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Second, empiric therapy was deemed to be adequate if treatment was
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prescribed with an effective agent once positive blood culture results were reported (all results are called directly to the bedside nurse at our institution)
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however actual antimicrobial administration times may have varied. Delays in effective antimicrobial administration have been associated with poor outcomes
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in a number of studies 27 30-32 39 40 and clearly could have confounded our results.
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In addition, specific doses of empiric antimicrobial therapies were not collected.
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Antimicrobial under-dosing (due to obesity or inaccurate estimation of creatinine clearance), for example, may have occurred and altered patient outcomes.
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Lastly, the single center design also limits generalizability of our results, particularly given the high proportion of immune suppressed (predominantly solid organ transplant) patients in our population.
CONCLUSIONS
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In conclusion, ICU-acquired gram-negative bacteremia is associated with high mortality. The most common source of ICU-acquired gram-negative bacteremia continues to be pneumonia. Resistance to ciprofloxacin remains high,
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while resistance to piperacillin/tazobactam increased substantially over the past decade. A substantial increase in carbapenem resistance in Pseudomonas
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aeruginosa was also observed. Despite increasing antimicrobial resistance most
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patients received adequate empiric antimicrobial therapy. We would suggest empiric treatment regimens be based on unit-specific data. Coronary artery
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disease, immune suppression and inadequate empiric antimicrobial therapy were
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independently associated with increased 30-day mortality.
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ACKNOWLEDGEMENTS
We thank the Infection Control Practitioners at the University of Alberta for
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their collection of data.
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Figure 1 – Sources of bacteremia
Figure 2 – Microbial isolates
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Figure 3 – Comparison of antimicrobial susceptibilities over time
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a. Aerobic isolates
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b. Pseudomonal isolates
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Table 1 – Baseline characteristics
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12 (16) 7 (10) 2 (3) 2 (3) 2 (3) 1 (1) 18 (24) 19 (26) 8 (11) 4 (5) 11 (15) 2 (3) 9 (12) 15 (20) 5 (7) 7 (10) 12 (16) 26 (35) 4 (5) 5 (7) 3 (4) 3 (4) 19 (26) 13 (18) 1 (1) 2 (3) 3 (4) 5 (7) 8 (11)
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51 (69) 23 (31)
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Age, in years (mean, SD) Male sex Admission class Medical Surgical Comorbidities Chronic lung disease COPD Pulmonary fibrosis Asthma Bronchiectasis Neuromuscular disease Diabetes mellitus ESLD HCV infection Autoimmune hepatitis Alcoholic liver disease Primary sclerosing cholangitis Coronary artery disease Hypertension Congestive heart failure Atrial fibrillation Malignancy Immune suppression Steroids Chemotherapy Neutropenia HIV/AIDS Solid organ transplant Liver transplant Lung transplant Heart transplant Renal transplant ESRD Psychiatric disease Admission diagnosis Respiratory failure Sepsis or septic shock Liver transplantation Trauma or major burn APACHE II score (mean, SD) ICU LOS Hospital LOS
N=74 No. (%) 55 (16) 46 (62)
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Variables
25 (34) 33 (45) 7 (10) 5 (7) 25 (8) 20.5 (7-33) 50 (25-109)
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30-day mortality Hospital mortality
26 (35) 36 (49)
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Legend: SD, standard deviation; COPD, chronic obstructive pulmonary disorder; ESLD, end stage liver disease; HCV, hepatitis C virus; HIV, human immunodeficiency virus; AIDS, acquired immunodeficiency syndrome; ESRD, end stage renal disease; APACHE, Acute Physiology and Chronic Health Evaluation; LOS, length of stay.
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Table 2 – Antimicrobial susceptibilities Intermediate 1 (2) 2 (3) 2 (3) 0 (0) 1 (1) 1 (2) 3 (5)
Pseudomonas aeruginosa (N=15) Ceftazidime (N=15) Cefepime (N=5) Ciprofloxacin (N=15) Gentamicin (N=15) Meropenem (N=12) Imipenem (N=15) Piperacillin/tazobactam (N=15) Tobramycin (N=15) Amikacin (N=15) Aztreonam (N=10) Colistin (N=4)
Susceptible 11 (73) 2 (40) 8 (53) 9 (60) 7 (58) 8 (53) 10 (67) 11 (73) 13 (87) 4 (40) 4 (100)
Intermediate 1 (7) 1 (20) 1 (7) 2 (13) 0 (0) 1 (7) 0 (0) 1 (7) 0 (0) 1 (10) 0 (0)
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Resistant 3 (20) 2 (40) 6 (40) 4 (27) 5 (42) 6 (40) 5 (33) 3 (20) 2 (13) 5 (50) 0 (0)
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Resistant 15 (28) 24 (36) 11 (17) 9 (16) 10 (17) 20 (31) 11 (18)
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Susceptible 37 (70) 40 (61) 53 (80) 46 (84) 47 (81) 44 (68) 49 (78)
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Aerobic isolates (N=71) Ceftriaxone (N=53) Ciprofloxacin (N=66) Gentamicin (N=66) Meropenem (N=55) Imipenem (N=58) Piperacillin/tazobactam (N=65) Tobramycin (N=63)
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Table 3 – Univariate analyses of 30-day mortality (78 bacteremic events) Variable
30-day mortality Deceased
p-value
N=51
N=27
(Chi-Square)
(65%)
(35%)
Age, in years (mean, SD)
54 (16)
56 (16)
Male sex
31 (61)
16 (60)
Admission class
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Alive
0.8 0.9
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0.7
34 (67)
19 (70)
Surgical
17 (33)
8 (30)
Comorbidities Chronic lung disease
7 (14)
COPD
5 (10)
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Medical
5 (18)
0.7
2 (7)
1.0
1 (2)
1 (4)
0.6
Asthma
1 (2)
1 (4)
1.0
Bronchiectasis
1 (2)
1 (4)
1.0
Neuromuscular disease
1 (2)
0 (0)
1.0
14 (28)
5 (19)
0.4
14 (28)
6 (22)
0.6
6 (12)
2 (7)
0.7
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Pulmonary fibrosis
Diabetes mellitus ESLD
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HCV infection Autoimmune hepatitis
3 (11)
0.3
5 (19)
0.5
Primary sclerosing cholangitis
2 (4)
0 (0)
0.5
Coronary artery disease
3 (6)
6 (22)
0.06
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2 (4)
6 (12)
Alcoholic liver disease
Hypertension
8 (16)
8 (30)
0.2
Congestive heart failure
2 (4)
3 (11)
0.3
Atrial fibrillation
4 (8)
3 (11)
0.7
7 (14)
5 (19)
0.7
Malignancy
Immune suppression
13 (26)
15 (56)
0.01
Steroids
1 (2)
4 (15)
0.046
Chemotherapy
2 (4)
3 (11)
0.3
Neutropenia
1 (2)
2 (7)
0.3
HIV/AIDS
2 (4)
1 (4)
1.0
Transplant
12 (24)
8 (30)
0.6
Liver transplant
11 (22)
3 (11)
0.4
Lung transplant
0 (0)
1 (4)
0.4
Heart transplant
1 (2)
1 (4)
1.0
Renal transplant
1 (2)
2 (7)
0.3
4 (8)
2 (7)
1.0
6 (12)
2 (7)
0.7
ESRD Psychiatric disease
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Admission diagnosis 16 (31)
10 (37)
0.6
Sepsis or septic shock
20 (39)
14 (52)
0.3
7 (14)
1 (4)
0.3
4 (8)
1 (4)
0.4
APACHE II score (mean, SD)
24 (8)
26 (9)
0.8
Pseudomonal bacteremia
7 (14)
8 (30)
Adequate empiric therapy
47 (92)
19 (70)
Liver transplantation Trauma or major burn
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Respiratory failure
0.09 0.01
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Legend: SD, standard deviation; COPD, chronic obstructive pulmonary disorder; ESLD, end stage liver disease; HCV, hepatitis C virus; HIV, human immunodeficiency virus; AIDS, acquired immunodeficiency syndrome; ESRD, end stage renal disease; APACHE, Acute Physiology and Chronic Health Evaluation; LOS, length of stay.
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Variable
30-day mortality aHR (95% CI) p-value 1.00 (0.96-1.05) 0.9 0.38 (0.16-0.89) 0.03 3.44 (1.43-8.27) 0.006 4.48 (1.70-11.85) 0.003 1.18 (0.48-2.90) 0.7
APACHE II score Adequate empiric therapy Immune suppression Coronary artery disease Pseudomonal bacteremia
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Table 4 – Multivariable regression analysis of 30-day mortality (78 bacteremic events)
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Legend: aHR, adjusted hazard ratio; APACHE, Acute Physiology and Chronic Health Evaluation
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Figure 2
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Figure 3a
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Figure 3b
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