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Hospital Mortality for Patients With Bacteremia Due to Staphylococcus aureus or Pseudomonas aeruginosa
Hospital Mortality for Patients With Bacteremia Due to Staphylococcus aureus or Pseudomonas aeruginosa* Stephen Osmon, MD; Suzanne Ward, RN; Victoria J. Fraser, MD; and Marin H. Kollef, MD, FCCP
Study objectives: To evaluate the relationship between hospital mortality and bloodstream infections due to Staphylococcus aureus or Pseudomonas aeruginosa. Design: Prospective cohort study. Setting: A 1,400-bed, university-affiliated urban teaching hospital. Patients: Between December 2001 and September 2002, 314 patients with bacteremia due to S aureus or P aeruginosa were prospectively evaluated. Intervention: Prospective patient surveillance and data collection. Results: Thirteen patients (4.1%) received inadequate initial antibiotic treatment. Fifty-four patients (17.2%) died during hospitalization. Hospital mortality was statistically greater for patients with bloodstream infections due to P aeruginosa (n ⴝ 49) compared to methicillinsensitive S aureus (MSSA) [n ⴝ 117; 30.6% vs 16.2%, p ⴝ 0.036] and methicillin-resistant S aureus (MRSA) [n ⴝ 148; 30.6% vs 13.5%, p ⴝ 0.007]. Multiple logistic regression analysis identified the lack of response to initial medical treatment (adjusted odds ratio [AOR], 2.69; 95% confidence interval [CI], 1.83 to 3.94; p ⴝ 0.010) and endocarditis (AOR, 4.62; 95% CI, 2.45 to 8.73; p ⴝ 0.016) as independent determinants of hospital mortality. Patients with bloodstream infections due to P aeruginosa were statistically more likely to be nonresponders to early medical treatment compared to patients with MSSA (73.5% vs 11.1%, p < 0.001) and MRSA (73.5% vs 16.9%, p < 0.001) bloodstream infections. Conclusions: These data suggest that bloodstream infections due to P aeruginosa have a greater risk of hospital mortality compared to bloodstream infections due to S aureus despite adequate antibiotic treatment. (CHEST 2004; 125:607– 616) Key words: bacteremia; outcomes; Pseudomonas aeruginosa; Staphylococcus aureus Abbreviations: AOR ⫽ adjusted odds ratio; APACHE ⫽ acute physiology and chronic health evaluation; CI ⫽ confidence interval; Fio2 ⫽ fraction of inspired oxygen; HMO ⫽ health maintenance organization; MRSA ⫽ methicillin-resistant Staphylococcus aureus; MSSA ⫽ methicillin-sensitive Staphylococcus aureus; PPO ⫽ preferred provider organization
bloodstream infections are serious infecB acterial tions associated with significant mortality and health-care costs.1 The coexistence of pathogens *From the Pulmonary and Critical Care Division (Drs. Osmon and Kollef, and Ms. Ward), Division of Infectious Diseases (Dr. Fraser), Washington University School of Medicine, St. Louis, MO. This work was supported by funding from the Centers of Disease Control and Prevention Cooperative Agreement, grant No. U50/ CCU717925, and the Barnes-Jewish Hospital Foundation. Manuscript received May 16, 2003; revision accepted August 8, 2003. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). Correspondence to: Marin H. Kollef, MD, FCCP, Washington University School of Medicine, 660 South Euclid Ave, Campus Box 8052, St. Louis, MO 63110; e-mail: kollefm@msnotes. wustl.edu www.chestjournal.org
with increasing resistance to multiple antibiotics and patient populations characterized by increasingly complex medical problems, including immunosuppression, has contributed to an increase in bloodstream infections, particularly those caused by antibiotic-resistant bacteria.2– 6 Staphylococcus aureus and Pseudomonas aeruginosa are common and important causes of bloodstream infection due to their increasing antimicrobial resistance and presence of virulence factors associated with excess mortality.7–11 Given the current trend of greater severity of illness among hospitalized patients, it can be expected that bacteremia due to S aureus or P aeruginosa will be associated with greater morbidity and mortality, particularly when inadequate antimicrobial treatment is administered.12 Due to the clinical importance of bloodstream CHEST / 125 / 2 / FEBRUARY, 2004
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infections due to S aureus and P aeruginosa, we performed a prospective cohort study that had two main goals. First, we wanted to compare the relative occurrence of bloodstream infections due to methicillin-sensitive S aureus (MSSA), methicillin-resistant S aureus (MRSA), and P aeruginosa at BarnesJewish Hospital. Our second goal was to determine the relationship between bloodstream infections with these pathogens and hospital mortality. Materials and Methods Study Location and Patients This study was conducted at a university-affiliated, urban teaching hospital: Barnes-Jewish Hospital (1,400 beds). During a 10-month period (December 2001 to September 2002), all hospitalized patients with positive blood culture findings for S aureus or P aeruginosa were eligible for this investigation. This study was approved by the Washington University School of Medicine Human Studies Committee. Study Design and Data Collection A prospective cohort study design was employed with the main outcome measure being hospital mortality. We also assessed secondary outcomes including the lengths of hospitalization and intensive care, the number of acquired organ system derangements, and clinical response to medical treatment of bloodstream infections. For all study patients, the following characteristics were prospectively recorded by one of the investigators: age, gender, race, health insurance status, premorbid lifestyle scores,13 ratio of the Po2 to the inspired concentration of oxygen, severity of illness based on APACHE (acute physiology and chronic health evaluation) II scores,14 and the presence of congestive heart failure, COPD, underlying malignancy, immunosuppression, and seropositivity for the HIV. Specific processes of medical care examined during hospital stay included the administration of antacids, sucralfate, histamine type-2 receptor antagonists, or corticosteroids, the need for mechanical ventilation, and the use of vasopressors. Variables describing the bloodstream infections and their treatment were also examined including the organism associated with bacteremia (P aeruginosa, MRSA, and MSSA), location where the infection was acquired, type of bloodstream infection (primary vs secondary), whether the bloodstream infections were catheter associated, administration of antibiotics prior to the occurrence of bloodstream infections, endocarditis, adequacy of antibiotic treatment, clinical response to initial medical treatment of the bloodstream infections, treatment with vancomycin and antibiotics directed against Gram-negative bacteria, and duration of antibiotic treatment in the hospital setting. One of the investigators (S.W.) made daily rounds in the hospital to identify eligible patients. A daily computerized list of all patients with positive blood culture findings was generated by the Microbiology Laboratory at Barnes-Jewish Hospital, which allowed identification of potential study patients. Patients entered into the study were prospectively followed up until they were discharged from the hospital or died. All patients with positive blood culture findings for S aureus or P aeruginosa were prospectively and independently reviewed by one of the investigators (M.H.K.) to confirm the diagnosis of bloodstream infection and the response to medical treatment using the criteria described later. Patients could not be entered into the study more than once. 608
Definitions All definitions were selected prospectively as part of the original study design. The premorbid lifestyle score has been defined previously: 0 ⫽ employed without restriction; 1 ⫽ independent, fully ambulatory; 2 ⫽ restricted activities, able to live on one’s own and go outside the home to do basic necessities, severe limitation in exercise ability; 3 ⫽ housebound, cannot get out of the house unassisted, cannot live alone or do heavy chores; and 4 ⫽ bed/chair bound.13 We calculated APACHE II scores on the basis of clinical data available from the first 24-h period following identification of a positive blood culture finding.14 The organ system failure index was modified from that used by Rubin and coworkers.15 One point was given for organ dysfunction acquired after the occurrence of a bloodstream infection. Renal dysfunction was defined as a twofold increase in baseline creatinine level or an absolute increase in baseline creatinine level of 176.8 mol/L (2.0 mg/dL); hepatic dysfunction, an increase in total bilirubin level to ⬎ 34.2 mol/L (2.0 mg/dL); pulmonary dysfunction, as one of the following: (1) a requirement for mechanical ventilation for a diagnosis of pneumonia, COPD, asthma, or pulmonary edema (cardiogenic or noncardiogenic), (2) Pao2 ⬍ 60 mm Hg while receiving a fraction of inspired oxygen of ⱖ 0.50, or (3) the use of at least 10 cm H2O of positive end-expiratory pressure; hematologic dysfunction, the presence of disseminated intravascular coagulation, a leukocyte count of ⬍ 1,000/L (1.0 ⫻ 109/L), or a platelet count of ⬍ 75 ⫻ 103/L (75 ⫻ 109/L); neurologic dysfunction, a new focal deficit (such as hemiparesis after cerebral infarction) or a new generalized process (for example, seizures or coma); GI dysfunction, GI hemorrhage requiring transfusion, new ileus, or diarrhea lasting ⬎ 24 h and unrelated to previous bowel surgery; and cardiac dysfunction, defined as acute myocardial infarction, cardiac arrest, or the new onset of congestive heart failure. Patients with immunosuppression were defined as those receiving corticosteroids (at least 10 mg of prednisone, or equivalent corticosteroid, per day for ⬎ 14 days prior to the onset of bloodstream infection), HIV infection, chemotherapy within the past 45 days before hospital admission, neutropenia (absolute neutrophil count ⬍ 500 L), or organ transplant requiring immunosuppressive therapy. Community-acquired bloodstream infections were defined according to the presence of a positive blood culture finding obtained within 48 h of hospital admission and the absence of criteria for a health-care–acquired bloodstream infection. Health-care–acquired bloodstream infections were defined by a positive blood culture finding obtained within 48 h of hospital admission and one of the following criteria16: (1) IV therapy at home; wound care or specialized nursing care through a health-care agency, family, or friends; or self-administered IV medical therapy in the 30 days before the bloodstream infection; (2) attendance at a hospital or hemodialysis clinic or IV chemotherapy in the 30 days before the bloodstream infection; (3) hospitalization in an acute-care hospital for ⱖ 2 days in the 90 days before the bloodstream infection; and (4) residence in a nursing home or long-term care facility. Similar temporal cutoffs for separating community-acquired infections from hospital-acquired infections have been proposed by other investigators.17 The antimicrobial guidelines for BarnesJewish Hospital during the study period suggested empiric treatment of suspected bloodstream infections with a combination of an antistaphylococcal drug (vancomycin for methicillinresistant staphylococci) and at least one antibiotic, usually cefepime, with Gram-negative activity. For patients at increased risk for infection with antibiotic-resistant Gram-negative bacteria (eg, P aeruginosa and Acinetobacter species), two antibiotics directed against Gram-negative bacteria were initially required, one of which could be an aminoglycoside. Initial empiric treatClinical Investigations in Critical Care
ment of fungal infections with fluconazole was also recommended in patients at increased risk (eg, previous antibiotic treatment, neutropenia, and multiple invasive devices). The initially prescribed empiric antimicrobial regimens were modified or narrowed within 48 to 72 h based on the results of blood cultures and other culture data. The de-escalation of antimicrobial therapy was monitored by hospital pharmacists in conjunction with primary physician teams.18,19 For purposes of this investigation, inadequate antimicrobial treatment of a bloodstream infection was defined as the microbiological documentation of infection (ie, a positive blood culture result) that was not effectively treated at the time the causative microorganism and its antibiotic susceptibility were known.12,20,21 The microbiology laboratory of the hospital determined antimicrobial susceptibility of clinical isolates following breakpoints established by the National Committee for Clinical Laboratory Standards. Inadequate antimicrobial treatment included the absence of antimicrobial agents directed at a specific class of microorganisms (eg, absence of therapy for MRSA) and the administration of an antimicrobial agent to which the microorganism responsible for the infection was resistant (eg, empiric treatment with a Gram-negative antibiotic for bacteremia subsequently attributed to P aeruginosa that was resistant to the prescribed drug). Circulatory shock was defined as systolic arterial pressures ⬍ 90 mm Hg for at least 1 h despite adequate fluid replacement and ⬎ 5 g/kg of body weight of dopamine or current treatment with epinephrine or norepinephrine. Additionally, urinary output of ⬍ 0.5 mL/kg of body weight for at least 1 h was required for circulatory shock. A clinical response to medical treatment was defined as withdrawal of vasopressors, if required, within 48 h of obtaining a positive blood culture finding or two of the following criteria: decrease in core temperature by ⬎ 1.0°C and ⬍ 38.3°C; improvement in oxygenation as demonstrated by a decrease in the fraction of inspired oxygen (Fio2) by at least 10%; and a decrease in the WBC count by 25% or ⬍ 10,000/L.22 Blood Culture Technique Blood samples were obtained from two peripheral sites by nurses and hospital-trained phlebotomists. Before collecting the blood sample, skin was disinfected with 70% isopropyl alcohol followed by 2% iodine tincture. The antecubital fossa was the preferred sampling site using a sterile needle and syringe. When only one peripheral site was available and the patient had a central vein catheter in place, the second blood culture sample was obtained from the central vein catheter.23 The blood samples from central vein catheters were obtained from needleless caps that were disinfected with 70% isopropyl alcohol, allowed to dry, and wiped with a povidone-iodine pad for 30 s. The excess povidone-iodine was wiped off with sterile gauze prior to obtaining the sample. Three milliliters of blood were aspirated and discarded from both the central vein catheter and peripheral venipuncture. A new syringe was used to aspirate an additional 20 mL of blood. A blood volume of 10 mL was injected into each of two blood culture bottles. Injection of ⱕ 5 mL of blood into a blood culture bottle was not permitted to avoid false-negative results.24 All blood samples were inoculated into aerobic media and processed using the Bactec Blood Culture system (Bactec; Becton Dickinson; Sparks, MD). Statistical Analysis All comparisons were unpaired, and all tests of significance were two-tailed. Continuous variables were compared using the Student t test for normally distributed variables and the Wilcoxon www.chestjournal.org
rank-sum test for nonnormally distributed variables. The 2 or Fisher exact test was used to compare categorical variables. The primary data analysis compared hospital nonsurvivors with survivors. Values are expressed as mean ⫾ SD (continuous variables) or as a percentage of the group from which they were derived (categorical variables). All p values were two tailed; p⬍ 0.05 was considered to indicate statistical significance. We performed multiple logistic-regression analysis using a commercial statistical package.25 Multivariate analysis was performed using models that were judged a priori to be clinically sound.26 This was prospectively determined to be necessary to avoid producing spuriously significant results with multiple comparisons. A Bonferroni adjustment for multiple comparisons yielded a corrected p ⱕ 0.001 (0.05/48), which was used to define statistical significance for univariate comparisons entered into the multivariate analysis. Additional variables were entered into the multivariate model, if p ⬎ 0.001, only if they were judged to be potentially important in determining hospital mortality. A stepwise approach was used to enter new terms into the logistic regression model, where hospital mortality was the dependent outcome variable, and 0.05 was set as the limit for the acceptance or removal of new terms.
Results Patients A total of 314 consecutive patients with bloodstream infections due to S aureus or P aeruginosa were evaluated. This represented 19.0% of all hospitalized patients with a bloodstream infection during the study period (Table 1). The mean age of the patients was 55.8 ⫾ 17.8 years (range, 16 to 93 years), and the mean APACHE II score was 16.9 ⫾ 70.7 (range, 2 to 38). There were 141 men (44.9%) and 173 women (55.1%); 180 patients (57.3%) were white, 124 patients (39.5%) were black, and 10 patients (3.2%) were either Hispanic or Asian American. Two hundred nine patients (66.6%) had either Medicare or Medicaid health-care insurance, 56 patients (17.8%) had private health-care insurance, 33 patients (10.5%) belonged to either a health maintenance organization (HMO) or a preferred provider organization (PPO), and 16 patients (5.1%) were self pay. Patient Characteristics According to Pathogen Patients with bloodstream infections due to MSSA were statistically younger than patients with MRSA infection (Table 2). The distribution of premorbid lifestyle scores was statistically greater for patients with bloodstream infections due to MRSA compared to MSSA and P aeruginosa, respectively. Patients with bacteremia due to P aeruginosa were significantly more likely to have health insurance other than Medicare or Medicaid, greater APACHE II scores, greater rates of underlying malignancy, administration of vasopressors, and mechanical ventilation, compared to patients with bloodstream infecCHEST / 125 / 2 / FEBRUARY, 2004
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Table 1—Pathogens Associated With Bloodstream Infection* Pathogens
Bloodstream Infections, No.
Coagulase-negative staphylococci MRSA Enterococcus faecalis MSSA Escherichia coli Vancomycin-resistant enterococci Klebsiella species Cytomegalovirus Streptococcus viridans P aeruginosa Candida albicans Streptococcus pneumoniae Enterobacter species Torulopsis glabrata Stenotrophomonas maltophilia Group B streptococci Serratia marcescens Bacillus species Acinetobacter species Corynebacterium species Other streptococci species Citrobacter species Other Pseudomonas species Epstein-Barr virus Enterococcus faecium Candida tropicalis Proteus mirabilis Micrococcus species Other enterococci species Group A streptococci Cryptococcus neoformans Alcaligenes xylosoxidans Ehrlichia species Lactobacillus species Streptococcus equii Candida kruisii Aerococcus species Herpes simplex virus type 2 Moraxella species Haemophilus species Candida parapsilosis Clostridium species Coccidioides immitis Bacteroides fragilis Neisseria species Pasteurella multocida Mycobacterium avium Other bacteria Other yeast/fungi Other viruses
195 148 136 117 107 97 94 87 62 49 47 43 41 32 24 23 23 22 21 21 19 16 14 14 14 13 13 12 11 11 10 8 8 8 7 6 6 6 6 6 6 5 4 4 4 4 3 17 5 3
aeruginosa, followed by MSSA and MRSA, respectively. Infection with HIV was also statistically greater for patients with bloodstream infections due to P aeruginosa and MSSA compared to MRSA. Infection Characteristics According to Pathogen Of the 314 patients, 102 patients (32.5%) had community-acquired bloodstream infections, 89 patients (28.3%) had health-care–acquired bloodstream infections, and 123 patients (39.2%) had hospital-acquired bloodstream infections (Table 3). Eighteen of 89 patients with health-care–acquired bloodstream infections (20.2%) resided in a nursing home, 6 patients (6.7%) received home health care, 35 patients (39.3%) received home- or clinic-based IV therapy or dialysis, and 54 patients (60.7%) had been hospitalized in the 90 days before bloodstream infection. Bloodstream infections due to P aeruginosa were statistically more likely to be health care acquired and less likely to be community acquired compared to both MSSA and MRSA. Catheterassociated bloodstream infections were significantly more common with MSSA and MRSA compared to P aeruginosa. Prior exposure to antibiotics, and specifically to vancomycin, was statistically greatest in patients with bloodstream infections due to P aeruginosa, while MRSA bloodstream infections had a greater association with prior antibiotic treatment compared to MSSA. Thirteen patients (4.1%) received inadequate initial antibiotic treatment of bloodstream infections. This was due to lack of initial empiric treatment with an antistaphylococcal penicillin, cephalosporin, or vancomycin for MSSA (n ⫽ 4), lack of initial treatment with vancomycin for MRSA (n ⫽ 7), and isolation of P aeruginosa resistant to the prescribed Gram-negative antibiotics (n ⫽ 2). The number of patients receiving treatment with at least two IV doses of vancomycin for their bloodstream infections was greatest for MRSA, followed by MSSA and P aeruginosa. Total duration of antibiotic treatment in the hospital setting was similar for MRSA and P aeruginosa, while both were statistically greater than the duration of treatment for MSSA bacteremia.
*Represents bloodstream infections during the study period in individual patients.
Patient Characteristic According to Hospital Mortality
tions attributed to MSSA and MRSA. Patients with bloodstream infections due to MSSA had statistically lower rates of congestive heart failure and COPD compared to patients with MRSA infection, while overall immunosuppression was statistically greatest for patients with bloodstream infections due to P
Hospital nonsurvivors were statistically older, more likely to be white, to have underlying congestive heart failure or malignancy, and to have a lower Pao2/Fio2 compared to hospital survivors (Table 4). Additionally, hospital nonsurvivors more often required vasopressors, stress ulcer prophylaxis, mechanical ventilation, and intensive care compared to hospital survivors.
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Clinical Investigations in Critical Care
Table 2—Patient Characteristics According to Microorganism*
Characteristics Age, yr Gender Male Female Race White Black Other Insurance status Medicare/Medicaid Self pay Private HMO/PPO Lifestyle score 0 1 2 3 4 APACHE II score Pao2/Fio2 COPD Congestive heart failure Underlying malignancy HIV positive Immunosuppressed Received corticosteroids Vasopressors Circulatory shock Stress ulcer prophylaxis Mechanical ventilation Intensive care Primary hospital service Medicine Surgery Transplant Other Surgery type None Emergent Nonemergent
p Values
MSSA (n ⫽ 117)
MRSA (n ⫽ 148)
P aeruginosa (n ⫽ 19)
52.5 ⫾ 17.7
58.1 ⫾ 17.8
57.0 ⫾ 17.1
0.012
0.135
0.717
58 (49.6) 59 (50.4)
80 (54.1) 68 (45.9)
35 (71.4) 14 (28.6)
0.468
0.010
0.032
62 (53.0) 51 (43.6) 4 (3.4)
84 (56.8) 61 (41.2) 3 (2.0)
34 (69.4) 12 (24.5) 3 (6.1)
0.693
0.063
0.055
74 (63.2) 9 (7.7) 23 (19.7) 11 (9.4)
113 (76.4) 6 (4.1) 16 (10.8) 13 (8.8)
22 (44.9) 1 (2.0) 17 (34.7) 9 (18.4)
0.085
0.025
⬍ 0.001
28 (23.9) 33 (28.2) 35 (29.9) 15 (12.8) 6 (5.1) 16.1 ⫾ 7.7 271 ⫾ 155 7 (6.0) 33 (28.2) 33 (28.2) 9 (7.7) 42 (35.9) 16 (13.7) 23 (19.7) 17 (14.5) 67 (57.3) 28 (23.9) 46 (39.3)
19 (12.8) 32 (21.6) 43 (29.1) 21 (14.2) 33 (22.3) 16.5 ⫾ 7.4 303 ⫾ 195 30 (20.3) 67 (45.3) 37 (25.0) 3 (2.0) 32 (21.6) 18 (12.2) 35 (23.6) 27 (18.2) 112 (75.7) 45 (30.4) 66 (44.6)
5 (10.2) 11 (22.4) 24 (49.0) 6 (12.2) 3 (6.1) 20.0 ⫾ 8.2 247 ⫾ 183 7 (14.3) 15 (30.6) 23 (46.9) 7 (14.3) 27 (55.1) 9 (18.4) 20 (40.8) 20 (40.8) 31 (63.3) 23 (46.9) 27 (55.1)
0.001
0.120
0.042
0.631 0.420 0.001 0.004 0.557 0.028 0.010 0.715 0.435 0.951 0.001 0.241 0.388
0.003 0.591 0.079 0.755 0.020 0.189 0.022 0.441 0.005 0.002 0.473 0.005 0.062
0.005 0.248 0.353 0.071 0.004 0.003 ⬍ 0.001 0.274 0.020 0.001 0.091 0.035 0.202
95 (81.2) 14 (12.0) 1 (0.9) 7 (6.0)
105 (70.9) 43 (29.1) 0 (0.0) 0 (0.0)
30 (61.2) 14 (28.6) 4 (8.2) 1 (2.0)
⬍ 0.001
0.002
0.001
93 (79.5) 11 (9.4) 13 (11.1)
108 (73.0) 16 (10.8) 24 (16.2)
32 (65.3) 8 (16.3) 9 (18.4)
0.425
0.154
0.515
MSSA vs MRSA
MSSA vs P aeruginosa
MRSA vs P aeruginosa
*Data are presented as mean ⫾ SD or No. (%).
Infection Characteristics According to Hospital Mortality Hospital mortality was statistically greater for bloodstream infections due to P aeruginosa (30.6%) compared to MSSA (16.2%, p ⫽ 0.036) and MRSA (13.5%, p ⫽ 0.007) [Table 5]. Hospital mortality was similar for bloodstream infections due to MSSA and MRSA (16.2% vs 13.5%, p ⫽ 0.534). The hospital mortality was similar for patients with communityacquired (14.7%), health-care–acquired (13.5%), and hospital-acquired (22.0%) bloodstream infections (p ⫽ 0.196). Endocarditis was statistically more common among hospital nonsurvivors. www.chestjournal.org
Clinical Response to Medical Treatment Among the 51 patients classified as nonresponders to medical treatment during the 48 h after obtaining a positive blood culture finding, 36 patients (70.6%) were classified as nonresponders on the basis of continued need for vasopressor support fulfilling the criteria for circulatory shock. A clinical response to initial medical treatment during the 48 h after obtaining a positive blood culture finding was statistically greater for patients with bloodstream infections due to MSSA (88.9% vs 26.5%, p ⬍ 0.001) and MRSA (83.1% vs 26.5%, p ⬍ 0.001) compared to P aeruginosa (Fig 1). Clinical response to initial medCHEST / 125 / 2 / FEBRUARY, 2004
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Table 3—Characteristics of Infection According to Pathogen* p Value Characteristics Infection location Community acquired Health acquired Hospital acquired Bacteremia type Primary Secondary Catheter associated Prior antibiotics Prior vancomycin Endocarditis Adequate treatment Antibiotic change Vancomycin treatment Total antibiotic days, No. Vancomycin days, No. Gram-negative antibiotic days, No.
MSSA (n ⫽ 117)
MRSA (n ⫽ 148)
P aeruginosa (n ⫽ 49)
43 (36.8) 36 (30.8) 38 (32.5)
52 (35.1) 32 (21.6) 64 (43.2)
7 (14.3) 21 (42.9) 21 (42.9)
0.126
0.016
0.003
65 (55.6) 52 (44.4) 19 (16.2) 18 (15.4) 9 (7.7) 6 (5.1) 113 (96.6) 12 (10.3) 97 (82.9) 6.2 ⫾ 7.7 4.4 ⫾ 6.2 4.0 ⫾ 6.5
83 (56.1) 65 (43.9) 22 (14.9) 47 (31.8) 23 (15.5) 8 (5.4) 141 (95.3) 22 (14.9) 137 (92.6) 9.9 ⫾ 9.8 8.4 ⫾ 8.3 5.1 ⫾ 7.2
29 (59.2) 20 (40.8) 0 (0.0) 24 (49.0) 16 (32.7) 1 (2.0) 47 (95.9) 5 (10.2) 31 (63.3) 9.7 ⫾ 11.0 3.1 ⫾ 4.7 9.5 ⫾ 10.8
0.932
0.667
0.704
0.759 0.002 0.052 0.920 0.595 0.265 0.015 0.001 ⬍ 0.001 0.196
0.001 ⬍ 0.001 ⬍ 0.001 0.367 ⬎ 0.999 0.992 0.006 0.022 0.162 ⬍ 0.001
0.003 0.030 0.009 0.456 ⬎ 0.999 0.411 ⬍ 0.001 0.912 ⬍ 0.001 0.002
MSSA vs MRSA
MSSA vs P aeruginosa
MRSA vs P aeruginosa
*Data are presented as No. (%) or mean ⫾ SD.
ical treatment was similar for both MSSA and MRSA (88.9% vs 83.1%, p ⫽ 0.182). Patients responding to medical treatment within 48 h of obtaining blood culture findings had a statistically lower hospital mortality rate compared to nonresponders (12.5% vs 32.4%, p ⬍ 0.001). Nonresponders to initial medical treatment had greater hospital mortality rates among all three pathogen types examined, reaching statistical significance for MSSA and P aeruginosa (Fig 2). Similar results were obtained using cutoffs of 24 h (57 nonresponders) and 72 h (41 nonresponders). Multiple logistic regression analysis identified the lack of response to medical treatment during the 48 h following collection of a positive blood culture finding (adjusted odds ratio [AOR], 2.69; 95% confidence interval [CI], 1.83 to 3.94; p ⫽ 0.010) and endocarditis (AOR, 4.62; 95% CI, 2.45 to 8.73; p ⫽ 0.016) as independent determinants of hospital mortality. Multiple logistic regression analysis also demonstrated that bloodstream infections due to P aeruginosa (AOR, 2.96; 95% CI, 2.38 to 3.69; p ⬍ 0.001) and prior administration of antibiotics (AOR, 2.40; 95% CI, 1.57 to 3.65; p ⫽ 0.038) were independent predictors for the lack of response to initial medical treatment. Secondary Outcomes Patients with bloodstream infections due to P aeruginosa acquired a statistically greater number of organ system derangements compared to patients with bloodstream infections due to MSSA and MRSA (Table 6). Patients with bloodstream infec612
tions due to MSSA had significantly shorter hospital length of stay, ICU length of stay, and duration of mechanical ventilation compared to patients with bloodstream infections due to MRSA and P aeruginosa. Hospital nonsurvivors acquired a statistically greater number of organ system derangements and had significantly longer hospital length of stay compared to hospital survivors.
Discussion Our study demonstrated that bloodstream infections due to S aureus were more common than bloodstream infections due to P aeruginosa. However, bloodstream infections due to P aeruginosa were statistically more likely to be associated with a lack of clinical response to initial medical treatment and a greater risk of hospital mortality. Multiple logistic regression analysis identified the lack of response to initial medical treatment and the presence of endocarditis as variables independently associated with hospital mortality. Multiple logistic regression analysis also found that bloodstream infections due to P aeruginosa and prior administration of antibiotics were independent predictors of nonresponse to initial medical treatment. Additionally, our data support the recent findings of Friedman and coworkers16 and Gaynes27 that health-care–acquired bloodstream infections are an important cause of bacteremia among hospitalized patients. More than 25% of our patients with bloodstream infection due Clinical Investigations in Critical Care
Table 4 —Patient Characteristics According to Hospital Mortality*
Characteristics Age, yr Gender Male Female Race White Black Other Insurance status Medicare/Medicaid Self-pay Private HMO/PPO Lifestyle score 0 1 2 3 4 APACHE II score Pao2/Fio2 COPD Congestive heart failure Underlying malignancy HIV positive Immunosuppressed Received corticosteroids Vasopressors Circulatory shock Stress ulcer prophylaxis Mechanical ventilation Intensive care Primary hospital service Medicine Surgery Transplant Other Surgery type None Emergent Nonemergent
Hospital Nonsurvivors (n ⫽ 54)
Table 5—Characteristics of Infection According to Hospital Mortality*
Hospital Survivors (n ⫽ 260)
p Value
62.6 ⫾ 17.9
54.4 ⫾ 17.5
0.003
25 (46.3) 29 (53.7)
116 (44.6) 144 (55.4)
0.821
36 (66.7) 14 (25.9) 4 (7.4)
144 (55.4) 110 (42.3) 6 (2.3)
0.021
38 (70.4) 4 (7.4) 6 (11.1) 6 (11.1)
171 (65.8) 12 (4.6) 50 (19.2) 27 (10.4)
0.475
4 (7.4) 13 (24.1) 19 (35.2) 11 (20.4) 7 (13.0) 22.0 ⫾ 7.6 222 ⫾ 144 7 (13.0) 28 (51.9) 23 (42.6) 4 (7.4) 20 (37.0) 5 (9.3) 35 (64.8) 37 (68.5) 46 (85.2) 40 (74.1) 46 (85.2)
48 (18.5) 63 (24.2) 83 (31.9) 31 (11.9) 35 (13.5) 18.0 ⫾ 36.1 303 ⫾ 188 37 (14.2) 87 (33.5) 70 (26.9) 15 (5.8) 81 (31.2) 38 (14.6) 29 (11.2) 31 (11.9) 164 (63.1) 56 (21.5) 93 (35.8)
0.213
38 (70.4) 14 (25.9) 2 (3.7) 0 (0.0)
192 (73.8) 57 (21.9) 3 (1.2) 8 (3.1)
0.275
35 (64.8) 9 (16.7) 10 (18.5)
198 (76.2) 26 (10.0) 36 (13.8)
0.419
0.107 0.021 0.807 0.011 0.022 0.646 0.400 0.298 ⬍ 0.001 ⬍ 0.001 0.002 ⬍ 0.001 ⬍ 0.001
Characteristics Organism MSSA MRSA P aeruginosa Infection location Community acquired Health care acquired Hospital acquired Bacteremia type Primary Secondary Catheter associated Prior antibiotics Prior vancomycin Endocarditis Adequate treatment Antibiotic change Vancomycin Vancomycin days, No. Gram-negative antibiotic days, No.
Hospital Nonsurvivors (n ⫽ 54)
Hospital Survivors (n ⫽ 260)
p Value
19 (35.2) 20 (37.0) 15 (27.8)
98 (37.7) 128 (49.2) 34 (13.1)
0.022
15 (27.8) 12 (22.2) 27 (50.0)
87 (33.5) 77 (29.6) 96 (36.9)
0.196
30 (55.6) 24 (44.4) 6 (11.1) 20 (37.0) 10 (18.5) 6 (11.1) 50 (92.6) 10 (18.5) 43 (79.6) 5.5 ⫾ 6.4 7.8 ⫾ 7.4
147 (56.5) 113 (43.5) 35 (13.5) 69 (26.5) 38 (14.6) 9 (3.5) 251 (96.5) 29 (11.2) 222 (85.4) 7.5 ⫾ 7.7 9.9 ⫾ 12.0
0.895 0.641 0.119 0.468 0.016 0.168 0.135 0.289 0.102 0.165
*Data are presented as No. (%) or mean ⫾ SD.
antimicrobial regimens lacking activity against the infecting microorganism(s) causing serious infections (eg, hospital-acquired pneumonia or bloodstream infections) are associated with greater hospital mortality. More recently, the same finding has been demonstrated for patients with severe sepsis.28 Inadequate antimicrobial treatment has been shown to be the most important risk factor for mortality among
*Data are presented as mean ⫾ SD or No. (%).
to S aureus or P aeruginosa were classified as having health-care–acquired infections. Despite the common occurrence of bloodstream infections among hospitalized patients, few studies5,6,21 have attempted to compare the influence of bloodstream infections due to specific pathogens on hospital mortality. Our study is unique in examining this association among patients with bloodstream infections having a low prevalence of inadequate antimicrobial treatment. Overall, 95.9% of our patients with bloodstream infections received adequate initial antibiotic treatment. Previous investigations12,18 –21 have shown that the administration of www.chestjournal.org
Figure 1. The clinical response to initial medical treatment determined within 48 h of obtaining blood culture findings for patients with bloodstream infections due to MSSA, MRSA, and P aeruginosa. CHEST / 125 / 2 / FEBRUARY, 2004
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Figure 2. Hospital mortality for patients with bloodstream infections due to MSSA, MRSA, and P aeruginosa according to whether or not they responded to initial medical treatment.
hospitalized patients with bloodstream infections.21 These studies suggest that appropriate antimicrobial treatment for patients with bloodstream infections, including appropriate dosing and interval of administration, is one of the most important determinants of clinical outcome that the physician can directly influence.12 The low prevalence of inadequate antimicrobial treatment in our study population allowed us to more directly compare the influence of bloodstream infections due to S aureus and P aeruginosa on hospital mortality. Previous investigators29 have shown that hospital mortality is greater among patients with MRSA bacteremia compared to MSSA bacteremia despite the lack of evidence to suggest that MRSA strains are more virulent than MSSA strains. Potential explanations for this include the greater severity of illness among patients with MRSA infections compared to MSSA, the greater administration of inadequate antibiotic treatment to patients with MRSA infections, and the limitations of vancomycin as an anti-
staphylococcal antibiotic.21,29 In our study, we found no difference in the hospital mortality between MRSA and MSSA bacteremia. Potential explanations for this lack of mortality difference are the similar severity of illness among patients with MRSA and MSSA as assessed by APACHE II scores (Table 2) and the administration of adequate initial antimicrobial treatment to ⬎ 95% of patients with staphylococcal bacteremia (Table 3). We found that the lack of response to initial medical treatment was the most important predictor of mortality in our study. Other investigators11,21,30,31 have identified predictors of mortality for patients with bloodstream infections that are consistent with our findings including the presence of septic shock and the need for vasopressor support. However, our study observed a relatively low mortality rate for patients with bloodstream infections due to S aureus compared to the rates described in these previous studies. This may, in part, be due to our current institutional practice of recommending treatment with vancomycin for patients with suspected bloodstream infection until the culture results exclude the possibility of MRSA. The more routine use of empiric vancomycin for patients with suspected bloodstream infection was developed, in part, by our prior experience demonstrating that approximately 50% of our bloodstream infections due to S aureus were methicillin resistant.21 In that population of medical ICU patients with bloodstream infections due to S aureus, ⬎ 30% received inadequate initial antimicrobial treatment and their overall hospital mortality rate was ⬎ 35%.21 Our hospital antibiotic policies also recommend limiting the administration of empiric antibiotic treatment based on culture results and the response to treatment.18 Support that this guideline was followed is demonstrated by the observation that ⬎ 60% of our patients with bloodstream infections due to P aeruginosa received initial treatment with vancomycin in addition to antibiotics directed against Gram-negative bacteria. However, among patients
Table 6 —Secondary Clinical Outcomes* p Value Variables
MSSA (n ⫽ 117)
MRSA (n ⫽ 148)
Acquired organ system 1.4 ⫾ 1.4 1.5 ⫾ 1.4 derangements, No. Hospital length of stay, d 13.2 ⫾ 13.5 22.1 ⫾ 24.9 ICU length of stay, d 9.1 ⫾ 8.9 15.9 ⫾ 17.7 Duration of mechanical 7.4 ⫾ 8.7 21.4 ⫾ 21.4 ventilation, d
P aeruginosa MSSA vs MSSA vs P (n ⫽ 49) MRSA aeruginosa
Hospital MRSA vs P Nonsurvivors aeruginosa (n ⫽ 54)
2.2 ⫾ 1.6
0.468
⬍ 0.001
0.002
26.2 ⫾ 39.5 17.8 ⫾ 25.1 19.2 ⫾ 30.7
0.001 0.017 0.001
0.002 0.034 0.041
0.390 0.684 0.716
3.1 ⫾ 1.3
Hospital Survivors (n ⫽ 260)
p Value
1.3 ⫾ 1.2
⬍ 0.001
25.6 ⫾ 38.0 18.1 ⫾ 21.1 15.0 ⫾ 21.4 13.5 ⫾ 15.3 15.8 ⫾ 26.2 16.9 ⫾ 18.8
0.043 0.686 0.828
*Data are presented as mean ⫾ SD. 614
Clinical Investigations in Critical Care
found to have a positive blood culture findings for P aeruginosa, without concurrent evidence of infection due to S aureus, the average duration of vancomycin administration was 3.1 days (Table 3). This suggests that vancomycin was discontinued following recognition of P aeruginosa as the pathogen accounting for bloodstream infection. It is important to note that our study does not prove a causal relationship between bloodstream infections and hospital mortality. However, our analysis suggests that the prevention of bloodstream infections and improvements in the management of patients with bloodstream infections, especially those not responding to initial treatment (eg, patients with septic shock requiring vasopressors) may reduce mortality. The prevention of infections is increasingly being recognized as an important issue because of the escalating emergence of antimicrobial resistance among community-acquired and hospitalacquired pathogens.32 There have been numerous studies performed suggesting that many hospitalacquired infections are preventable by employing readily available processes and interventions. These studies have focused on the use of protocols or educational programs to improve infection control practices,33 vaccines directed against high-risk pathogens such as S aureus and P aeruginosa,34 and the application of novel antimicrobial drugs and devices to prevent infections.35 Interestingly, none of our study patients were treated with drotrecogin alfa, which has been shown to reduce mortality in patients with severe sepsis.36 The application of this and other emerging treatments for some categories of patients with bloodstream infections would be expected to improve outcomes.37,38 Our study has several limitations. First, it was performed within a single hospital with a low prevalence of inadequate antimicrobial treatment of bloodstream infections. Therefore, the results may not be generalizable to other hospitals. Second, we only examined patients with bloodstream infections due to P aeruginosa and S aureus. It is possible that bloodstream infections associated with other pathogens could have produced different results. Third, we arbitrarily selected a cutoff of 48 h to determine the response to initial medical therapy. This seems reasonable given the results of our multivariate analysis demonstrating this to be the best predictor of hospital mortality. Fourth, we may have misclassified some patients as to the origin of their bloodstream infections (community acquired vs healthcare acquired) based on the definitions employed and the available clinical data examined. Finally, the criteria we employed for determining a response to the initial medical therapy could be influenced by factors not specifically aimed at the treatment of www.chestjournal.org
bloodstream infections (eg, the use of antipyretic agents to decrease body temperature). In summary, we showed that bloodstream infections due to P aeruginosa had a greater hospital mortality compared to bloodstream infections due to S aureus. Bloodstream infections due to P aeruginosa were also more likely to be associated with a lack of response to initial medical therapy. Despite the low prevalence of inadequate antimicrobial treatment in this study, bloodstream infections caused by S aureus and P aeruginosa appeared to be an important determinant of outcome. Future clinical and research efforts should be aimed at the development of improved strategies for the prevention and treatment of bloodstream infections due to S aureus and P aeruginosa in order to reduce hospital mortality. Additionally, methods allowing earlier identification of the pathogen causing bloodstream infection may allow more directed medical therapy based on the risk of mortality. ACKNOWLEDGMENT: The authors thank Ms. Linda Brockman for assistance in preparing the manuscript, and Robyn Schaiff, PharmD, Scott Micek, PharmD, and Way Huey, PharmD, for their clinical efforts.
References 1 Weinstein MP, Towns ML, Quartey SM, et al. The clinical significance of positive blood cultures in the 1990s: a prospective comprehensive evaluation of the microbiology, epidemiology, and outcome of bacteremia and fungemia in adults. Clin Infect Dis 1997; 24:584 – 602 2 Vincent JL, Bihari DJ, Suter PM, et al. The prevalence of nosocomial infection in intensive care units in Europe results of the European Prevalence of Infection in Intensive Care (EPIC) Study. JAMA 1995; 274:639 – 644 3 Richards MJ, Edwards JR, Culver DH, et al. Nosocomial infections in medical intensive care units in the United States: National Nosocomial Infections Surveillance System. Crit Care Med 1999; 27:887– 892 4 Schiappa DA, Hayden MK, Matushek MG, et al. Ceftazidime-resistant Klebsiella pneumoniae and Escherichia coli bloodstream infection: a case-control and molecular epidemiologic investigation. J Infect Dis 1996; 174:529 –536 5 Bryan CS, Reynolds KL, Brenner ER. Analysis of 1,186 episodes of Gram-negative bacteremia in non-university hospitals: the effects of antimicrobial therapy. Rev Infect Dis 1983; 5:629 – 638 6 Caballero-Granado FJ, Cisneros JM, Luque R, et al. Comparative study of bacteremias caused by Enterococcus spp. with and without high-level resistance to gentamicin. J Clin Microbiol 1998; 36:520 –525 7 Hauser AR, Cobb E, Bodi M, et al. Type III protein secretion is associated with poor clinical outcomes in patients with ventilator-associated pneumonia caused by Pseudomonas aeruginosa. Crit Care Med 2002; 30:521–528 8 Roy-Burman A, Savel RH, Racine S, et al. Type III protein secretion is associated with death in lower respiratory and systemic Pseudomonas aeruginosa infections. J Infect Dis 2001; 183:1767–1774 9 Vidal F, Mensa J, Almela M, et al. Epidemiology and outcome of Pseudomonas aeruginosa bacteremia, with special emphaCHEST / 125 / 2 / FEBRUARY, 2004
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sis on the influence of antibiotic treatment: analysis of 189 episodes. Arch Intern Med 1996; 156:2121–2126 Steinberg JP, Clark CC, Hackman BO. Nosocomial and community-acquired Staphylococcus aureus bacteremias from 1980 to 1993: impact of intravascular devices and methicillin resistance. Clin Infect Dis 1996; 23:255–259 Conterno LO, Wey SB, Castelo A. Risk factors for mortality in Staphylococcus aureus bacteremia. Infect Control Hosp Epidemiol 1998; 19:32–37 Kollef MH. Inadequate antimicrobial treatment: an important determinant of outcome for hospitalized patients. Clin Infect Dis 2000; 31:S131–S138 Menzies R, Gibbons W, Goldberg P. Determinants of weaning and survival among patients with COPD who require mechanical ventilation for acute respiratory failure. Chest 1989; 95:398 – 405 Knaus WA, Draper EA, Wagner DP, et al. APACHE II: a severity of disease classification system. Crit Care Med 1985; 13:818 – 829 Rubin DB, Wiener-Kronish JP, Murray JF, et al. Elevated von Willebrand factor antigen is an early plasma predictor of acute lung injury in nonpulmonary sepsis syndrome. J Clin Invest 1990; 86:474 – 480 Friedman ND, Kaye KS, Stout JE, et al. Health-care associated bloodstream infection in adults: a reason to change the accepted definition of community-acquired infections. Ann Intern Med 2002; 137:791–797 Garner JS, Jarvis WR, Emori TG, et al. CDC definitions for nosocomial infections, 1988. Am J Infect Control 1988; 16:128 –140 Ibrahim EH, Ward S, Sherman G, et al. Experience with a clinical guideline for the treatment of ventilator-associated pneumonia. Crit Care Med 2001; 29:1109 –1115 Iregui M, Ward S, Sherman G, et al. Clinical importance of delays in the initiation of appropriate antibiotic treatment for ventilator-associated pneumonia. Chest 2002; 122:262–268 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; 115:462– 474 Ibrahim EH, Sherman G, Ward S, et al. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest 2000; 118: 146 –155 Kollef MH, Gronski TJ, Ward S, et al. Predictors of lung infection among hospitalized patients undergoing bronchoalveolar lavage. Respir Care 1997; 42:935–945 Beutz M, Sherman G, Mayfield J, et al. Clinical utility of blood cultures drawn from central vein catheters and periph-
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eral venipuncture in critically ill medical patients. Chest 2003; 123:854 – 861 Weinstein MP, Mirrett S, Wilson ML, et al. Controlled evaluation of 5 versus 10 milliliters of blood cultured in aerobic BacT/Alert blood culture bottles. J Clin Microbiol 1994; 32:2103–2106 SAS/STAT user’s guide: volume 2. Cary, NC: SAS Institute, 1990; 1071–1126 Concato J, Feinstein AR, Holford TR. The risk of determining risk with multivariable models. Ann Intern Med 1993; 118:201–210 Gaynes R. Health-care associated bloodstream infections: a change in thinking. Ann Intern Med 2002; 137:850 – 851 Garnacho-Montero J, Garcia-Garmendia JL, Barrero-Almodovar AE, et al. Impact of the outcome of adequate empirical antibiotherapy in patients admitted to the ICU by sepsis. Crit Care Med 2003; 31:2742–2751 Cosgrove SE, Sakoulas G, Perencevich EN, et al. Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: a metaanalysis. Clin Infect Dis 2003; 36:53–59 Aliaga L, Mediavilla JD, Cobo F. A clinical index predicting mortality with Pseudomonas aeruginosa bacteremia. J Med Microbiol 2002; 51:615– 619 Jensen AG, Wachmann CH, Espersen F, et al. Treatment and outcome of Staphylococcus aureus bacteremia: a prospective study of 278 cases. Arch Intern Med 2002; 162:25–32 Kollef MH, Fraser VJ. Antibiotic resistance in the intensive care unit. Ann Intern Med 2001; 134:298 –314 Ostrowsky BE, Trick WE, Sohn AH, et al. Control of vancomycin-resistant enterococcus in health care facilities in a region. N Engl J Med 2001; 344:1427–1433 Shinefield H, Black S, Fattom A, et al. Use of a Staphylococcus aureus conjugate vaccine in patients receiving hemodialysis. N Engl J Med 2002; 346:491– 496 Newton T, Still JM, Law E. A comparison of the effect of early insertion of standard latex and silver-impregnated latex Foley catheters on urinary tract infections in burn patients. Infect Control Hosp Epidemiol 2002; 23:217–218 Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344:699 –709 Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368 –1377 Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002; 288:862– 871
Clinical Investigations in Critical Care
Study objectives: To evaluate the relationship between hospital mortality and bloodstream infections due to Staphylococcus aureus or Pseudomonas aeruginosa. Design: Prospective cohort study. Setting: A 1,400-bed, university-affiliated urban teaching hospital. Patients: Between December 2001 and September 2002, 314 patients with bacteremia due to S aureus or P aeruginosa were prospectively evaluated. Intervention: Prospective patient surveillance and data collection. Results: Thirteen patients (4.1%) received inadequate initial antibiotic treatment. Fifty-four patients (17.2%) died during hospitalization. Hospital mortality was statistically greater for patients with bloodstream infections due to P aeruginosa (n ⴝ 49) compared to methicillinsensitive S aureus (MSSA) [n ⴝ 117; 30.6% vs 16.2%, p ⴝ 0.036] and methicillin-resistant S aureus (MRSA) [n ⴝ 148; 30.6% vs 13.5%, p ⴝ 0.007]. Multiple logistic regression analysis identified the lack of response to initial medical treatment (adjusted odds ratio [AOR], 2.69; 95% confidence interval [CI], 1.83 to 3.94; p ⴝ 0.010) and endocarditis (AOR, 4.62; 95% CI, 2.45 to 8.73; p ⴝ 0.016) as independent determinants of hospital mortality. Patients with bloodstream infections due to P aeruginosa were statistically more likely to be nonresponders to early medical treatment compared to patients with MSSA (73.5% vs 11.1%, p < 0.001) and MRSA (73.5% vs 16.9%, p < 0.001) bloodstream infections. Conclusions: These data suggest that bloodstream infections due to P aeruginosa have a greater risk of hospital mortality compared to bloodstream infections due to S aureus despite adequate antibiotic treatment. (CHEST 2004; 125:607– 616) Key words: bacteremia; outcomes; Pseudomonas aeruginosa; Staphylococcus aureus Abbreviations: AOR ⫽ adjusted odds ratio; APACHE ⫽ acute physiology and chronic health evaluation; CI ⫽ confidence interval; Fio2 ⫽ fraction of inspired oxygen; HMO ⫽ health maintenance organization; MRSA ⫽ methicillin-resistant Staphylococcus aureus; MSSA ⫽ methicillin-sensitive Staphylococcus aureus; PPO ⫽ preferred provider organization
bloodstream infections are serious infecB acterial tions associated with significant mortality and health-care costs.1 The coexistence of pathogens *From the Pulmonary and Critical Care Division (Drs. Osmon and Kollef, and Ms. Ward), Division of Infectious Diseases (Dr. Fraser), Washington University School of Medicine, St. Louis, MO. This work was supported by funding from the Centers of Disease Control and Prevention Cooperative Agreement, grant No. U50/ CCU717925, and the Barnes-Jewish Hospital Foundation. Manuscript received May 16, 2003; revision accepted August 8, 2003. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). Correspondence to: Marin H. Kollef, MD, FCCP, Washington University School of Medicine, 660 South Euclid Ave, Campus Box 8052, St. Louis, MO 63110; e-mail: kollefm@msnotes. wustl.edu www.chestjournal.org
with increasing resistance to multiple antibiotics and patient populations characterized by increasingly complex medical problems, including immunosuppression, has contributed to an increase in bloodstream infections, particularly those caused by antibiotic-resistant bacteria.2– 6 Staphylococcus aureus and Pseudomonas aeruginosa are common and important causes of bloodstream infection due to their increasing antimicrobial resistance and presence of virulence factors associated with excess mortality.7–11 Given the current trend of greater severity of illness among hospitalized patients, it can be expected that bacteremia due to S aureus or P aeruginosa will be associated with greater morbidity and mortality, particularly when inadequate antimicrobial treatment is administered.12 Due to the clinical importance of bloodstream CHEST / 125 / 2 / FEBRUARY, 2004
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infections due to S aureus and P aeruginosa, we performed a prospective cohort study that had two main goals. First, we wanted to compare the relative occurrence of bloodstream infections due to methicillin-sensitive S aureus (MSSA), methicillin-resistant S aureus (MRSA), and P aeruginosa at BarnesJewish Hospital. Our second goal was to determine the relationship between bloodstream infections with these pathogens and hospital mortality. Materials and Methods Study Location and Patients This study was conducted at a university-affiliated, urban teaching hospital: Barnes-Jewish Hospital (1,400 beds). During a 10-month period (December 2001 to September 2002), all hospitalized patients with positive blood culture findings for S aureus or P aeruginosa were eligible for this investigation. This study was approved by the Washington University School of Medicine Human Studies Committee. Study Design and Data Collection A prospective cohort study design was employed with the main outcome measure being hospital mortality. We also assessed secondary outcomes including the lengths of hospitalization and intensive care, the number of acquired organ system derangements, and clinical response to medical treatment of bloodstream infections. For all study patients, the following characteristics were prospectively recorded by one of the investigators: age, gender, race, health insurance status, premorbid lifestyle scores,13 ratio of the Po2 to the inspired concentration of oxygen, severity of illness based on APACHE (acute physiology and chronic health evaluation) II scores,14 and the presence of congestive heart failure, COPD, underlying malignancy, immunosuppression, and seropositivity for the HIV. Specific processes of medical care examined during hospital stay included the administration of antacids, sucralfate, histamine type-2 receptor antagonists, or corticosteroids, the need for mechanical ventilation, and the use of vasopressors. Variables describing the bloodstream infections and their treatment were also examined including the organism associated with bacteremia (P aeruginosa, MRSA, and MSSA), location where the infection was acquired, type of bloodstream infection (primary vs secondary), whether the bloodstream infections were catheter associated, administration of antibiotics prior to the occurrence of bloodstream infections, endocarditis, adequacy of antibiotic treatment, clinical response to initial medical treatment of the bloodstream infections, treatment with vancomycin and antibiotics directed against Gram-negative bacteria, and duration of antibiotic treatment in the hospital setting. One of the investigators (S.W.) made daily rounds in the hospital to identify eligible patients. A daily computerized list of all patients with positive blood culture findings was generated by the Microbiology Laboratory at Barnes-Jewish Hospital, which allowed identification of potential study patients. Patients entered into the study were prospectively followed up until they were discharged from the hospital or died. All patients with positive blood culture findings for S aureus or P aeruginosa were prospectively and independently reviewed by one of the investigators (M.H.K.) to confirm the diagnosis of bloodstream infection and the response to medical treatment using the criteria described later. Patients could not be entered into the study more than once. 608
Definitions All definitions were selected prospectively as part of the original study design. The premorbid lifestyle score has been defined previously: 0 ⫽ employed without restriction; 1 ⫽ independent, fully ambulatory; 2 ⫽ restricted activities, able to live on one’s own and go outside the home to do basic necessities, severe limitation in exercise ability; 3 ⫽ housebound, cannot get out of the house unassisted, cannot live alone or do heavy chores; and 4 ⫽ bed/chair bound.13 We calculated APACHE II scores on the basis of clinical data available from the first 24-h period following identification of a positive blood culture finding.14 The organ system failure index was modified from that used by Rubin and coworkers.15 One point was given for organ dysfunction acquired after the occurrence of a bloodstream infection. Renal dysfunction was defined as a twofold increase in baseline creatinine level or an absolute increase in baseline creatinine level of 176.8 mol/L (2.0 mg/dL); hepatic dysfunction, an increase in total bilirubin level to ⬎ 34.2 mol/L (2.0 mg/dL); pulmonary dysfunction, as one of the following: (1) a requirement for mechanical ventilation for a diagnosis of pneumonia, COPD, asthma, or pulmonary edema (cardiogenic or noncardiogenic), (2) Pao2 ⬍ 60 mm Hg while receiving a fraction of inspired oxygen of ⱖ 0.50, or (3) the use of at least 10 cm H2O of positive end-expiratory pressure; hematologic dysfunction, the presence of disseminated intravascular coagulation, a leukocyte count of ⬍ 1,000/L (1.0 ⫻ 109/L), or a platelet count of ⬍ 75 ⫻ 103/L (75 ⫻ 109/L); neurologic dysfunction, a new focal deficit (such as hemiparesis after cerebral infarction) or a new generalized process (for example, seizures or coma); GI dysfunction, GI hemorrhage requiring transfusion, new ileus, or diarrhea lasting ⬎ 24 h and unrelated to previous bowel surgery; and cardiac dysfunction, defined as acute myocardial infarction, cardiac arrest, or the new onset of congestive heart failure. Patients with immunosuppression were defined as those receiving corticosteroids (at least 10 mg of prednisone, or equivalent corticosteroid, per day for ⬎ 14 days prior to the onset of bloodstream infection), HIV infection, chemotherapy within the past 45 days before hospital admission, neutropenia (absolute neutrophil count ⬍ 500 L), or organ transplant requiring immunosuppressive therapy. Community-acquired bloodstream infections were defined according to the presence of a positive blood culture finding obtained within 48 h of hospital admission and the absence of criteria for a health-care–acquired bloodstream infection. Health-care–acquired bloodstream infections were defined by a positive blood culture finding obtained within 48 h of hospital admission and one of the following criteria16: (1) IV therapy at home; wound care or specialized nursing care through a health-care agency, family, or friends; or self-administered IV medical therapy in the 30 days before the bloodstream infection; (2) attendance at a hospital or hemodialysis clinic or IV chemotherapy in the 30 days before the bloodstream infection; (3) hospitalization in an acute-care hospital for ⱖ 2 days in the 90 days before the bloodstream infection; and (4) residence in a nursing home or long-term care facility. Similar temporal cutoffs for separating community-acquired infections from hospital-acquired infections have been proposed by other investigators.17 The antimicrobial guidelines for BarnesJewish Hospital during the study period suggested empiric treatment of suspected bloodstream infections with a combination of an antistaphylococcal drug (vancomycin for methicillinresistant staphylococci) and at least one antibiotic, usually cefepime, with Gram-negative activity. For patients at increased risk for infection with antibiotic-resistant Gram-negative bacteria (eg, P aeruginosa and Acinetobacter species), two antibiotics directed against Gram-negative bacteria were initially required, one of which could be an aminoglycoside. Initial empiric treatClinical Investigations in Critical Care
ment of fungal infections with fluconazole was also recommended in patients at increased risk (eg, previous antibiotic treatment, neutropenia, and multiple invasive devices). The initially prescribed empiric antimicrobial regimens were modified or narrowed within 48 to 72 h based on the results of blood cultures and other culture data. The de-escalation of antimicrobial therapy was monitored by hospital pharmacists in conjunction with primary physician teams.18,19 For purposes of this investigation, inadequate antimicrobial treatment of a bloodstream infection was defined as the microbiological documentation of infection (ie, a positive blood culture result) that was not effectively treated at the time the causative microorganism and its antibiotic susceptibility were known.12,20,21 The microbiology laboratory of the hospital determined antimicrobial susceptibility of clinical isolates following breakpoints established by the National Committee for Clinical Laboratory Standards. Inadequate antimicrobial treatment included the absence of antimicrobial agents directed at a specific class of microorganisms (eg, absence of therapy for MRSA) and the administration of an antimicrobial agent to which the microorganism responsible for the infection was resistant (eg, empiric treatment with a Gram-negative antibiotic for bacteremia subsequently attributed to P aeruginosa that was resistant to the prescribed drug). Circulatory shock was defined as systolic arterial pressures ⬍ 90 mm Hg for at least 1 h despite adequate fluid replacement and ⬎ 5 g/kg of body weight of dopamine or current treatment with epinephrine or norepinephrine. Additionally, urinary output of ⬍ 0.5 mL/kg of body weight for at least 1 h was required for circulatory shock. A clinical response to medical treatment was defined as withdrawal of vasopressors, if required, within 48 h of obtaining a positive blood culture finding or two of the following criteria: decrease in core temperature by ⬎ 1.0°C and ⬍ 38.3°C; improvement in oxygenation as demonstrated by a decrease in the fraction of inspired oxygen (Fio2) by at least 10%; and a decrease in the WBC count by 25% or ⬍ 10,000/L.22 Blood Culture Technique Blood samples were obtained from two peripheral sites by nurses and hospital-trained phlebotomists. Before collecting the blood sample, skin was disinfected with 70% isopropyl alcohol followed by 2% iodine tincture. The antecubital fossa was the preferred sampling site using a sterile needle and syringe. When only one peripheral site was available and the patient had a central vein catheter in place, the second blood culture sample was obtained from the central vein catheter.23 The blood samples from central vein catheters were obtained from needleless caps that were disinfected with 70% isopropyl alcohol, allowed to dry, and wiped with a povidone-iodine pad for 30 s. The excess povidone-iodine was wiped off with sterile gauze prior to obtaining the sample. Three milliliters of blood were aspirated and discarded from both the central vein catheter and peripheral venipuncture. A new syringe was used to aspirate an additional 20 mL of blood. A blood volume of 10 mL was injected into each of two blood culture bottles. Injection of ⱕ 5 mL of blood into a blood culture bottle was not permitted to avoid false-negative results.24 All blood samples were inoculated into aerobic media and processed using the Bactec Blood Culture system (Bactec; Becton Dickinson; Sparks, MD). Statistical Analysis All comparisons were unpaired, and all tests of significance were two-tailed. Continuous variables were compared using the Student t test for normally distributed variables and the Wilcoxon www.chestjournal.org
rank-sum test for nonnormally distributed variables. The 2 or Fisher exact test was used to compare categorical variables. The primary data analysis compared hospital nonsurvivors with survivors. Values are expressed as mean ⫾ SD (continuous variables) or as a percentage of the group from which they were derived (categorical variables). All p values were two tailed; p⬍ 0.05 was considered to indicate statistical significance. We performed multiple logistic-regression analysis using a commercial statistical package.25 Multivariate analysis was performed using models that were judged a priori to be clinically sound.26 This was prospectively determined to be necessary to avoid producing spuriously significant results with multiple comparisons. A Bonferroni adjustment for multiple comparisons yielded a corrected p ⱕ 0.001 (0.05/48), which was used to define statistical significance for univariate comparisons entered into the multivariate analysis. Additional variables were entered into the multivariate model, if p ⬎ 0.001, only if they were judged to be potentially important in determining hospital mortality. A stepwise approach was used to enter new terms into the logistic regression model, where hospital mortality was the dependent outcome variable, and 0.05 was set as the limit for the acceptance or removal of new terms.
Results Patients A total of 314 consecutive patients with bloodstream infections due to S aureus or P aeruginosa were evaluated. This represented 19.0% of all hospitalized patients with a bloodstream infection during the study period (Table 1). The mean age of the patients was 55.8 ⫾ 17.8 years (range, 16 to 93 years), and the mean APACHE II score was 16.9 ⫾ 70.7 (range, 2 to 38). There were 141 men (44.9%) and 173 women (55.1%); 180 patients (57.3%) were white, 124 patients (39.5%) were black, and 10 patients (3.2%) were either Hispanic or Asian American. Two hundred nine patients (66.6%) had either Medicare or Medicaid health-care insurance, 56 patients (17.8%) had private health-care insurance, 33 patients (10.5%) belonged to either a health maintenance organization (HMO) or a preferred provider organization (PPO), and 16 patients (5.1%) were self pay. Patient Characteristics According to Pathogen Patients with bloodstream infections due to MSSA were statistically younger than patients with MRSA infection (Table 2). The distribution of premorbid lifestyle scores was statistically greater for patients with bloodstream infections due to MRSA compared to MSSA and P aeruginosa, respectively. Patients with bacteremia due to P aeruginosa were significantly more likely to have health insurance other than Medicare or Medicaid, greater APACHE II scores, greater rates of underlying malignancy, administration of vasopressors, and mechanical ventilation, compared to patients with bloodstream infecCHEST / 125 / 2 / FEBRUARY, 2004
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Table 1—Pathogens Associated With Bloodstream Infection* Pathogens
Bloodstream Infections, No.
Coagulase-negative staphylococci MRSA Enterococcus faecalis MSSA Escherichia coli Vancomycin-resistant enterococci Klebsiella species Cytomegalovirus Streptococcus viridans P aeruginosa Candida albicans Streptococcus pneumoniae Enterobacter species Torulopsis glabrata Stenotrophomonas maltophilia Group B streptococci Serratia marcescens Bacillus species Acinetobacter species Corynebacterium species Other streptococci species Citrobacter species Other Pseudomonas species Epstein-Barr virus Enterococcus faecium Candida tropicalis Proteus mirabilis Micrococcus species Other enterococci species Group A streptococci Cryptococcus neoformans Alcaligenes xylosoxidans Ehrlichia species Lactobacillus species Streptococcus equii Candida kruisii Aerococcus species Herpes simplex virus type 2 Moraxella species Haemophilus species Candida parapsilosis Clostridium species Coccidioides immitis Bacteroides fragilis Neisseria species Pasteurella multocida Mycobacterium avium Other bacteria Other yeast/fungi Other viruses
195 148 136 117 107 97 94 87 62 49 47 43 41 32 24 23 23 22 21 21 19 16 14 14 14 13 13 12 11 11 10 8 8 8 7 6 6 6 6 6 6 5 4 4 4 4 3 17 5 3
aeruginosa, followed by MSSA and MRSA, respectively. Infection with HIV was also statistically greater for patients with bloodstream infections due to P aeruginosa and MSSA compared to MRSA. Infection Characteristics According to Pathogen Of the 314 patients, 102 patients (32.5%) had community-acquired bloodstream infections, 89 patients (28.3%) had health-care–acquired bloodstream infections, and 123 patients (39.2%) had hospital-acquired bloodstream infections (Table 3). Eighteen of 89 patients with health-care–acquired bloodstream infections (20.2%) resided in a nursing home, 6 patients (6.7%) received home health care, 35 patients (39.3%) received home- or clinic-based IV therapy or dialysis, and 54 patients (60.7%) had been hospitalized in the 90 days before bloodstream infection. Bloodstream infections due to P aeruginosa were statistically more likely to be health care acquired and less likely to be community acquired compared to both MSSA and MRSA. Catheterassociated bloodstream infections were significantly more common with MSSA and MRSA compared to P aeruginosa. Prior exposure to antibiotics, and specifically to vancomycin, was statistically greatest in patients with bloodstream infections due to P aeruginosa, while MRSA bloodstream infections had a greater association with prior antibiotic treatment compared to MSSA. Thirteen patients (4.1%) received inadequate initial antibiotic treatment of bloodstream infections. This was due to lack of initial empiric treatment with an antistaphylococcal penicillin, cephalosporin, or vancomycin for MSSA (n ⫽ 4), lack of initial treatment with vancomycin for MRSA (n ⫽ 7), and isolation of P aeruginosa resistant to the prescribed Gram-negative antibiotics (n ⫽ 2). The number of patients receiving treatment with at least two IV doses of vancomycin for their bloodstream infections was greatest for MRSA, followed by MSSA and P aeruginosa. Total duration of antibiotic treatment in the hospital setting was similar for MRSA and P aeruginosa, while both were statistically greater than the duration of treatment for MSSA bacteremia.
*Represents bloodstream infections during the study period in individual patients.
Patient Characteristic According to Hospital Mortality
tions attributed to MSSA and MRSA. Patients with bloodstream infections due to MSSA had statistically lower rates of congestive heart failure and COPD compared to patients with MRSA infection, while overall immunosuppression was statistically greatest for patients with bloodstream infections due to P
Hospital nonsurvivors were statistically older, more likely to be white, to have underlying congestive heart failure or malignancy, and to have a lower Pao2/Fio2 compared to hospital survivors (Table 4). Additionally, hospital nonsurvivors more often required vasopressors, stress ulcer prophylaxis, mechanical ventilation, and intensive care compared to hospital survivors.
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Clinical Investigations in Critical Care
Table 2—Patient Characteristics According to Microorganism*
Characteristics Age, yr Gender Male Female Race White Black Other Insurance status Medicare/Medicaid Self pay Private HMO/PPO Lifestyle score 0 1 2 3 4 APACHE II score Pao2/Fio2 COPD Congestive heart failure Underlying malignancy HIV positive Immunosuppressed Received corticosteroids Vasopressors Circulatory shock Stress ulcer prophylaxis Mechanical ventilation Intensive care Primary hospital service Medicine Surgery Transplant Other Surgery type None Emergent Nonemergent
p Values
MSSA (n ⫽ 117)
MRSA (n ⫽ 148)
P aeruginosa (n ⫽ 19)
52.5 ⫾ 17.7
58.1 ⫾ 17.8
57.0 ⫾ 17.1
0.012
0.135
0.717
58 (49.6) 59 (50.4)
80 (54.1) 68 (45.9)
35 (71.4) 14 (28.6)
0.468
0.010
0.032
62 (53.0) 51 (43.6) 4 (3.4)
84 (56.8) 61 (41.2) 3 (2.0)
34 (69.4) 12 (24.5) 3 (6.1)
0.693
0.063
0.055
74 (63.2) 9 (7.7) 23 (19.7) 11 (9.4)
113 (76.4) 6 (4.1) 16 (10.8) 13 (8.8)
22 (44.9) 1 (2.0) 17 (34.7) 9 (18.4)
0.085
0.025
⬍ 0.001
28 (23.9) 33 (28.2) 35 (29.9) 15 (12.8) 6 (5.1) 16.1 ⫾ 7.7 271 ⫾ 155 7 (6.0) 33 (28.2) 33 (28.2) 9 (7.7) 42 (35.9) 16 (13.7) 23 (19.7) 17 (14.5) 67 (57.3) 28 (23.9) 46 (39.3)
19 (12.8) 32 (21.6) 43 (29.1) 21 (14.2) 33 (22.3) 16.5 ⫾ 7.4 303 ⫾ 195 30 (20.3) 67 (45.3) 37 (25.0) 3 (2.0) 32 (21.6) 18 (12.2) 35 (23.6) 27 (18.2) 112 (75.7) 45 (30.4) 66 (44.6)
5 (10.2) 11 (22.4) 24 (49.0) 6 (12.2) 3 (6.1) 20.0 ⫾ 8.2 247 ⫾ 183 7 (14.3) 15 (30.6) 23 (46.9) 7 (14.3) 27 (55.1) 9 (18.4) 20 (40.8) 20 (40.8) 31 (63.3) 23 (46.9) 27 (55.1)
0.001
0.120
0.042
0.631 0.420 0.001 0.004 0.557 0.028 0.010 0.715 0.435 0.951 0.001 0.241 0.388
0.003 0.591 0.079 0.755 0.020 0.189 0.022 0.441 0.005 0.002 0.473 0.005 0.062
0.005 0.248 0.353 0.071 0.004 0.003 ⬍ 0.001 0.274 0.020 0.001 0.091 0.035 0.202
95 (81.2) 14 (12.0) 1 (0.9) 7 (6.0)
105 (70.9) 43 (29.1) 0 (0.0) 0 (0.0)
30 (61.2) 14 (28.6) 4 (8.2) 1 (2.0)
⬍ 0.001
0.002
0.001
93 (79.5) 11 (9.4) 13 (11.1)
108 (73.0) 16 (10.8) 24 (16.2)
32 (65.3) 8 (16.3) 9 (18.4)
0.425
0.154
0.515
MSSA vs MRSA
MSSA vs P aeruginosa
MRSA vs P aeruginosa
*Data are presented as mean ⫾ SD or No. (%).
Infection Characteristics According to Hospital Mortality Hospital mortality was statistically greater for bloodstream infections due to P aeruginosa (30.6%) compared to MSSA (16.2%, p ⫽ 0.036) and MRSA (13.5%, p ⫽ 0.007) [Table 5]. Hospital mortality was similar for bloodstream infections due to MSSA and MRSA (16.2% vs 13.5%, p ⫽ 0.534). The hospital mortality was similar for patients with communityacquired (14.7%), health-care–acquired (13.5%), and hospital-acquired (22.0%) bloodstream infections (p ⫽ 0.196). Endocarditis was statistically more common among hospital nonsurvivors. www.chestjournal.org
Clinical Response to Medical Treatment Among the 51 patients classified as nonresponders to medical treatment during the 48 h after obtaining a positive blood culture finding, 36 patients (70.6%) were classified as nonresponders on the basis of continued need for vasopressor support fulfilling the criteria for circulatory shock. A clinical response to initial medical treatment during the 48 h after obtaining a positive blood culture finding was statistically greater for patients with bloodstream infections due to MSSA (88.9% vs 26.5%, p ⬍ 0.001) and MRSA (83.1% vs 26.5%, p ⬍ 0.001) compared to P aeruginosa (Fig 1). Clinical response to initial medCHEST / 125 / 2 / FEBRUARY, 2004
611
Table 3—Characteristics of Infection According to Pathogen* p Value Characteristics Infection location Community acquired Health acquired Hospital acquired Bacteremia type Primary Secondary Catheter associated Prior antibiotics Prior vancomycin Endocarditis Adequate treatment Antibiotic change Vancomycin treatment Total antibiotic days, No. Vancomycin days, No. Gram-negative antibiotic days, No.
MSSA (n ⫽ 117)
MRSA (n ⫽ 148)
P aeruginosa (n ⫽ 49)
43 (36.8) 36 (30.8) 38 (32.5)
52 (35.1) 32 (21.6) 64 (43.2)
7 (14.3) 21 (42.9) 21 (42.9)
0.126
0.016
0.003
65 (55.6) 52 (44.4) 19 (16.2) 18 (15.4) 9 (7.7) 6 (5.1) 113 (96.6) 12 (10.3) 97 (82.9) 6.2 ⫾ 7.7 4.4 ⫾ 6.2 4.0 ⫾ 6.5
83 (56.1) 65 (43.9) 22 (14.9) 47 (31.8) 23 (15.5) 8 (5.4) 141 (95.3) 22 (14.9) 137 (92.6) 9.9 ⫾ 9.8 8.4 ⫾ 8.3 5.1 ⫾ 7.2
29 (59.2) 20 (40.8) 0 (0.0) 24 (49.0) 16 (32.7) 1 (2.0) 47 (95.9) 5 (10.2) 31 (63.3) 9.7 ⫾ 11.0 3.1 ⫾ 4.7 9.5 ⫾ 10.8
0.932
0.667
0.704
0.759 0.002 0.052 0.920 0.595 0.265 0.015 0.001 ⬍ 0.001 0.196
0.001 ⬍ 0.001 ⬍ 0.001 0.367 ⬎ 0.999 0.992 0.006 0.022 0.162 ⬍ 0.001
0.003 0.030 0.009 0.456 ⬎ 0.999 0.411 ⬍ 0.001 0.912 ⬍ 0.001 0.002
MSSA vs MRSA
MSSA vs P aeruginosa
MRSA vs P aeruginosa
*Data are presented as No. (%) or mean ⫾ SD.
ical treatment was similar for both MSSA and MRSA (88.9% vs 83.1%, p ⫽ 0.182). Patients responding to medical treatment within 48 h of obtaining blood culture findings had a statistically lower hospital mortality rate compared to nonresponders (12.5% vs 32.4%, p ⬍ 0.001). Nonresponders to initial medical treatment had greater hospital mortality rates among all three pathogen types examined, reaching statistical significance for MSSA and P aeruginosa (Fig 2). Similar results were obtained using cutoffs of 24 h (57 nonresponders) and 72 h (41 nonresponders). Multiple logistic regression analysis identified the lack of response to medical treatment during the 48 h following collection of a positive blood culture finding (adjusted odds ratio [AOR], 2.69; 95% confidence interval [CI], 1.83 to 3.94; p ⫽ 0.010) and endocarditis (AOR, 4.62; 95% CI, 2.45 to 8.73; p ⫽ 0.016) as independent determinants of hospital mortality. Multiple logistic regression analysis also demonstrated that bloodstream infections due to P aeruginosa (AOR, 2.96; 95% CI, 2.38 to 3.69; p ⬍ 0.001) and prior administration of antibiotics (AOR, 2.40; 95% CI, 1.57 to 3.65; p ⫽ 0.038) were independent predictors for the lack of response to initial medical treatment. Secondary Outcomes Patients with bloodstream infections due to P aeruginosa acquired a statistically greater number of organ system derangements compared to patients with bloodstream infections due to MSSA and MRSA (Table 6). Patients with bloodstream infec612
tions due to MSSA had significantly shorter hospital length of stay, ICU length of stay, and duration of mechanical ventilation compared to patients with bloodstream infections due to MRSA and P aeruginosa. Hospital nonsurvivors acquired a statistically greater number of organ system derangements and had significantly longer hospital length of stay compared to hospital survivors.
Discussion Our study demonstrated that bloodstream infections due to S aureus were more common than bloodstream infections due to P aeruginosa. However, bloodstream infections due to P aeruginosa were statistically more likely to be associated with a lack of clinical response to initial medical treatment and a greater risk of hospital mortality. Multiple logistic regression analysis identified the lack of response to initial medical treatment and the presence of endocarditis as variables independently associated with hospital mortality. Multiple logistic regression analysis also found that bloodstream infections due to P aeruginosa and prior administration of antibiotics were independent predictors of nonresponse to initial medical treatment. Additionally, our data support the recent findings of Friedman and coworkers16 and Gaynes27 that health-care–acquired bloodstream infections are an important cause of bacteremia among hospitalized patients. More than 25% of our patients with bloodstream infection due Clinical Investigations in Critical Care
Table 4 —Patient Characteristics According to Hospital Mortality*
Characteristics Age, yr Gender Male Female Race White Black Other Insurance status Medicare/Medicaid Self-pay Private HMO/PPO Lifestyle score 0 1 2 3 4 APACHE II score Pao2/Fio2 COPD Congestive heart failure Underlying malignancy HIV positive Immunosuppressed Received corticosteroids Vasopressors Circulatory shock Stress ulcer prophylaxis Mechanical ventilation Intensive care Primary hospital service Medicine Surgery Transplant Other Surgery type None Emergent Nonemergent
Hospital Nonsurvivors (n ⫽ 54)
Table 5—Characteristics of Infection According to Hospital Mortality*
Hospital Survivors (n ⫽ 260)
p Value
62.6 ⫾ 17.9
54.4 ⫾ 17.5
0.003
25 (46.3) 29 (53.7)
116 (44.6) 144 (55.4)
0.821
36 (66.7) 14 (25.9) 4 (7.4)
144 (55.4) 110 (42.3) 6 (2.3)
0.021
38 (70.4) 4 (7.4) 6 (11.1) 6 (11.1)
171 (65.8) 12 (4.6) 50 (19.2) 27 (10.4)
0.475
4 (7.4) 13 (24.1) 19 (35.2) 11 (20.4) 7 (13.0) 22.0 ⫾ 7.6 222 ⫾ 144 7 (13.0) 28 (51.9) 23 (42.6) 4 (7.4) 20 (37.0) 5 (9.3) 35 (64.8) 37 (68.5) 46 (85.2) 40 (74.1) 46 (85.2)
48 (18.5) 63 (24.2) 83 (31.9) 31 (11.9) 35 (13.5) 18.0 ⫾ 36.1 303 ⫾ 188 37 (14.2) 87 (33.5) 70 (26.9) 15 (5.8) 81 (31.2) 38 (14.6) 29 (11.2) 31 (11.9) 164 (63.1) 56 (21.5) 93 (35.8)
0.213
38 (70.4) 14 (25.9) 2 (3.7) 0 (0.0)
192 (73.8) 57 (21.9) 3 (1.2) 8 (3.1)
0.275
35 (64.8) 9 (16.7) 10 (18.5)
198 (76.2) 26 (10.0) 36 (13.8)
0.419
0.107 0.021 0.807 0.011 0.022 0.646 0.400 0.298 ⬍ 0.001 ⬍ 0.001 0.002 ⬍ 0.001 ⬍ 0.001
Characteristics Organism MSSA MRSA P aeruginosa Infection location Community acquired Health care acquired Hospital acquired Bacteremia type Primary Secondary Catheter associated Prior antibiotics Prior vancomycin Endocarditis Adequate treatment Antibiotic change Vancomycin Vancomycin days, No. Gram-negative antibiotic days, No.
Hospital Nonsurvivors (n ⫽ 54)
Hospital Survivors (n ⫽ 260)
p Value
19 (35.2) 20 (37.0) 15 (27.8)
98 (37.7) 128 (49.2) 34 (13.1)
0.022
15 (27.8) 12 (22.2) 27 (50.0)
87 (33.5) 77 (29.6) 96 (36.9)
0.196
30 (55.6) 24 (44.4) 6 (11.1) 20 (37.0) 10 (18.5) 6 (11.1) 50 (92.6) 10 (18.5) 43 (79.6) 5.5 ⫾ 6.4 7.8 ⫾ 7.4
147 (56.5) 113 (43.5) 35 (13.5) 69 (26.5) 38 (14.6) 9 (3.5) 251 (96.5) 29 (11.2) 222 (85.4) 7.5 ⫾ 7.7 9.9 ⫾ 12.0
0.895 0.641 0.119 0.468 0.016 0.168 0.135 0.289 0.102 0.165
*Data are presented as No. (%) or mean ⫾ SD.
antimicrobial regimens lacking activity against the infecting microorganism(s) causing serious infections (eg, hospital-acquired pneumonia or bloodstream infections) are associated with greater hospital mortality. More recently, the same finding has been demonstrated for patients with severe sepsis.28 Inadequate antimicrobial treatment has been shown to be the most important risk factor for mortality among
*Data are presented as mean ⫾ SD or No. (%).
to S aureus or P aeruginosa were classified as having health-care–acquired infections. Despite the common occurrence of bloodstream infections among hospitalized patients, few studies5,6,21 have attempted to compare the influence of bloodstream infections due to specific pathogens on hospital mortality. Our study is unique in examining this association among patients with bloodstream infections having a low prevalence of inadequate antimicrobial treatment. Overall, 95.9% of our patients with bloodstream infections received adequate initial antibiotic treatment. Previous investigations12,18 –21 have shown that the administration of www.chestjournal.org
Figure 1. The clinical response to initial medical treatment determined within 48 h of obtaining blood culture findings for patients with bloodstream infections due to MSSA, MRSA, and P aeruginosa. CHEST / 125 / 2 / FEBRUARY, 2004
613
Figure 2. Hospital mortality for patients with bloodstream infections due to MSSA, MRSA, and P aeruginosa according to whether or not they responded to initial medical treatment.
hospitalized patients with bloodstream infections.21 These studies suggest that appropriate antimicrobial treatment for patients with bloodstream infections, including appropriate dosing and interval of administration, is one of the most important determinants of clinical outcome that the physician can directly influence.12 The low prevalence of inadequate antimicrobial treatment in our study population allowed us to more directly compare the influence of bloodstream infections due to S aureus and P aeruginosa on hospital mortality. Previous investigators29 have shown that hospital mortality is greater among patients with MRSA bacteremia compared to MSSA bacteremia despite the lack of evidence to suggest that MRSA strains are more virulent than MSSA strains. Potential explanations for this include the greater severity of illness among patients with MRSA infections compared to MSSA, the greater administration of inadequate antibiotic treatment to patients with MRSA infections, and the limitations of vancomycin as an anti-
staphylococcal antibiotic.21,29 In our study, we found no difference in the hospital mortality between MRSA and MSSA bacteremia. Potential explanations for this lack of mortality difference are the similar severity of illness among patients with MRSA and MSSA as assessed by APACHE II scores (Table 2) and the administration of adequate initial antimicrobial treatment to ⬎ 95% of patients with staphylococcal bacteremia (Table 3). We found that the lack of response to initial medical treatment was the most important predictor of mortality in our study. Other investigators11,21,30,31 have identified predictors of mortality for patients with bloodstream infections that are consistent with our findings including the presence of septic shock and the need for vasopressor support. However, our study observed a relatively low mortality rate for patients with bloodstream infections due to S aureus compared to the rates described in these previous studies. This may, in part, be due to our current institutional practice of recommending treatment with vancomycin for patients with suspected bloodstream infection until the culture results exclude the possibility of MRSA. The more routine use of empiric vancomycin for patients with suspected bloodstream infection was developed, in part, by our prior experience demonstrating that approximately 50% of our bloodstream infections due to S aureus were methicillin resistant.21 In that population of medical ICU patients with bloodstream infections due to S aureus, ⬎ 30% received inadequate initial antimicrobial treatment and their overall hospital mortality rate was ⬎ 35%.21 Our hospital antibiotic policies also recommend limiting the administration of empiric antibiotic treatment based on culture results and the response to treatment.18 Support that this guideline was followed is demonstrated by the observation that ⬎ 60% of our patients with bloodstream infections due to P aeruginosa received initial treatment with vancomycin in addition to antibiotics directed against Gram-negative bacteria. However, among patients
Table 6 —Secondary Clinical Outcomes* p Value Variables
MSSA (n ⫽ 117)
MRSA (n ⫽ 148)
Acquired organ system 1.4 ⫾ 1.4 1.5 ⫾ 1.4 derangements, No. Hospital length of stay, d 13.2 ⫾ 13.5 22.1 ⫾ 24.9 ICU length of stay, d 9.1 ⫾ 8.9 15.9 ⫾ 17.7 Duration of mechanical 7.4 ⫾ 8.7 21.4 ⫾ 21.4 ventilation, d
P aeruginosa MSSA vs MSSA vs P (n ⫽ 49) MRSA aeruginosa
Hospital MRSA vs P Nonsurvivors aeruginosa (n ⫽ 54)
2.2 ⫾ 1.6
0.468
⬍ 0.001
0.002
26.2 ⫾ 39.5 17.8 ⫾ 25.1 19.2 ⫾ 30.7
0.001 0.017 0.001
0.002 0.034 0.041
0.390 0.684 0.716
3.1 ⫾ 1.3
Hospital Survivors (n ⫽ 260)
p Value
1.3 ⫾ 1.2
⬍ 0.001
25.6 ⫾ 38.0 18.1 ⫾ 21.1 15.0 ⫾ 21.4 13.5 ⫾ 15.3 15.8 ⫾ 26.2 16.9 ⫾ 18.8
0.043 0.686 0.828
*Data are presented as mean ⫾ SD. 614
Clinical Investigations in Critical Care
found to have a positive blood culture findings for P aeruginosa, without concurrent evidence of infection due to S aureus, the average duration of vancomycin administration was 3.1 days (Table 3). This suggests that vancomycin was discontinued following recognition of P aeruginosa as the pathogen accounting for bloodstream infection. It is important to note that our study does not prove a causal relationship between bloodstream infections and hospital mortality. However, our analysis suggests that the prevention of bloodstream infections and improvements in the management of patients with bloodstream infections, especially those not responding to initial treatment (eg, patients with septic shock requiring vasopressors) may reduce mortality. The prevention of infections is increasingly being recognized as an important issue because of the escalating emergence of antimicrobial resistance among community-acquired and hospitalacquired pathogens.32 There have been numerous studies performed suggesting that many hospitalacquired infections are preventable by employing readily available processes and interventions. These studies have focused on the use of protocols or educational programs to improve infection control practices,33 vaccines directed against high-risk pathogens such as S aureus and P aeruginosa,34 and the application of novel antimicrobial drugs and devices to prevent infections.35 Interestingly, none of our study patients were treated with drotrecogin alfa, which has been shown to reduce mortality in patients with severe sepsis.36 The application of this and other emerging treatments for some categories of patients with bloodstream infections would be expected to improve outcomes.37,38 Our study has several limitations. First, it was performed within a single hospital with a low prevalence of inadequate antimicrobial treatment of bloodstream infections. Therefore, the results may not be generalizable to other hospitals. Second, we only examined patients with bloodstream infections due to P aeruginosa and S aureus. It is possible that bloodstream infections associated with other pathogens could have produced different results. Third, we arbitrarily selected a cutoff of 48 h to determine the response to initial medical therapy. This seems reasonable given the results of our multivariate analysis demonstrating this to be the best predictor of hospital mortality. Fourth, we may have misclassified some patients as to the origin of their bloodstream infections (community acquired vs healthcare acquired) based on the definitions employed and the available clinical data examined. Finally, the criteria we employed for determining a response to the initial medical therapy could be influenced by factors not specifically aimed at the treatment of www.chestjournal.org
bloodstream infections (eg, the use of antipyretic agents to decrease body temperature). In summary, we showed that bloodstream infections due to P aeruginosa had a greater hospital mortality compared to bloodstream infections due to S aureus. Bloodstream infections due to P aeruginosa were also more likely to be associated with a lack of response to initial medical therapy. Despite the low prevalence of inadequate antimicrobial treatment in this study, bloodstream infections caused by S aureus and P aeruginosa appeared to be an important determinant of outcome. Future clinical and research efforts should be aimed at the development of improved strategies for the prevention and treatment of bloodstream infections due to S aureus and P aeruginosa in order to reduce hospital mortality. Additionally, methods allowing earlier identification of the pathogen causing bloodstream infection may allow more directed medical therapy based on the risk of mortality. ACKNOWLEDGMENT: The authors thank Ms. Linda Brockman for assistance in preparing the manuscript, and Robyn Schaiff, PharmD, Scott Micek, PharmD, and Way Huey, PharmD, for their clinical efforts.
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