- Email: [email protected]
Bloodstream infections in patients with kidney disease: risk factors for poor outcome and mortality
Journal of Hospital Infection 85 (2013) 196e205 Available online at www.sciencedirect.com
Journal of Hospital Infection journal homepage: www.elsevierhealth.com/journals/jhin
Bloodstream infections in patients with kidney disease: risk factors for poor outcome and mortality ˜oz a, c, d, M. Kestler a, D. Arroyo b, M. Guembe a, *, L. Rojas a, P. Mun ´ixems a, c, d, E. Verde b, E. Bouza a, c, d M. Rodrı´guez-Cre a
Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Maran˜o´n, Madrid, Spain Department of Nephrology, Hospital General Universitario Gregorio Maran˜o´n, Madrid, Spain c Universidad Complutense de Madrid, Department of Medicine, Madrid, Spain d Red Espan˜ola de Enfermedades Infecciosas (REIPI), Madrid, Spain b
A R T I C L E
I N F O
Article history: Received 14 May 2012 Accepted 11 July 2013 Available online 31 August 2013 Keywords: Bacteraemia Chronic kidney disease Mortality Peritoneal dialysis Renal transplantation
S U M M A R Y
Background: Information regarding bloodstream infections (BSIs) in patients with kidney diseases is scarce and mainly derived from selected groups of patients. Aim: To assess the characteristics of BSI in an unselected population of patients with kidney disease, including renal transplant recipients and patients with chronic kidney failure who were receiving or not receiving dialysis. Methods: A retrospective cohort study of all patients who presented with BSI in the nephrology department of a large teaching hospital. Clinical records were reviewed according to a pre-established protocol. Standard definitions were used. Findings: In all, 155 episodes of BSI were recorded in 108 patients. The incidence of BSI was 77.3 episodes per 1000 admissions, and 4.5 episodes per 100 patient-years. Haemodialysis patients had the highest incidence of BSI. The distribution of micro-organisms was as follows: Gram-negative, 52.3%; Gram-positive, 46.5%; fungi, 1.2%. Escherichia coli was the most frequently isolated micro-organism (27%). The BSI was classed as bacteraemia of unknown source (29.7%), urinary tract infection (23.2%), vascular access infection (17.4%), and other (29.7%). Eighteen patients (11.6%) developed septic shock or multi-organ failure, and the same proportion had persistent bacteraemia. The crude mortality rate was 14.6%. The risk factors for mortality were high Charlson index, persistent bacteraemia, and absence of fever. Conclusion: Nephrology patients have a high incidence of BSI, particularly patients undergoing haemodialysis. The predominant micro-organisms causing BSI episodes were Gram-negative bacilli. Patients with kidney disease have high BSI-related morbidity and mortality. Risk factors for mortality were high Charlson comorbidity index and persistent BSI. The presence of fever during the BSI episodes was found to be a protective factor. ª 2013 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.
Introduction * Corresponding author. Address: Servicio de Microbiologı´a Clı´nica y Enfermedades Infecciosas, Hospital General Universitario Gregorio Maran ˜o ´n, C/Doctor Esquerdo, 46, 28007 Madrid, Spain. Tel.: þ34 91 586 84 53; fax: þ34 91 504 49 06. E-mail address: [email protected] (M. Guembe).
Nephrology patients are at risk of acquiring infection due to uraemia, vascular access, and the combination of surgery and immunosuppressive therapy, both of which are required for kidney transplantation.1e3
0195-6701/$ e see front matter ª 2013 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jhin.2013.07.009
L. Rojas et al. / Journal of Hospital Infection 85 (2013) 196e205 Bloodstream infections (BSIs) have been reported in particular subgroups of nephrology patients, for example, those undergoing chronic haemodialysis or kidney transplantation.4e7 However, data are scarce for BSI in other subgroups and in unselected nephrology patients. Our objective was to describe retrospectively episodes of BSI occurring in all nephrology patients attending a nephrology department in a large teaching hospital.
Methods Setting Our institution is a 1550-bed hospital serving a population of about 715,000 inhabitants in both urban and rural areas of Madrid. The nephrology department has a large-scale chronic and acute haemodialysis programme and is a centre for kidney transplantation. It also cares for patients with various renal disorders and with different degrees of renal dysfunction, including patients who do not require dialysis. The mean number of patients attending the nephrology department per year during the study period was 987 66 patients, of whom 299 14 (30.3%) were on haemodialysis, 209 84 (21.2%) did not receive dialysis, 36 3 (3.7%) received peritoneal dialysis, and 443 15 (44.9%) were kidney recipients.
Inclusion criteria All patients attending the nephrology department from January 2007 to June 2010 who had one or more episodes of BSI were included in this retrospective cohort study. All episodes with clinically non-significant, contaminated blood cultures were excluded.
Microbiological and clinical data Blood cultures were performed using the BACTEC 9240 system (Becton Dickinson Microbiology Systems, Sparks, MD, USA). Isolates were identified according to standard procedures, and susceptibility testing was performed following the recommendations of the Clinical and Laboratory Standards Institute (CLSI).8
Clinical data obtained from the charts Clinical data retrieved to assess baseline characteristics and the clinical course were: age, sex, pre-existing comorbidities, type of renal disease, immunosuppressive therapy, type of vascular access, and renal function in patients not receiving dialysis. Information was also obtained about the clinical setting (community-acquired, hospital-acquired, or healthcare-related), source of BSI, organs involved, persistent BSI, clinical deterioration, initiation of appropriate treatment, and mortality.
Definitions BSI of unknown source Recovery of clinically significant micro-organisms from blood cultures with no evidence of the clinical source or focal clinical manifestations. Commensal micro-organisms
197
[coagulase-negative staphylococci (CoNS), Corynebacterium sp. (except C. jeikeium), Lactobacillus spp., Bacillus spp., and Propionibacterium spp., or Streptococcus viridans group isolates and C. perfringens] were considered as probable pathogens when they were recovered in two or more blood cultures. Catheter-related bloodstream infection (CRBSI) This was defined according to the Clinical Practice Guidelines for the Diagnosis and Management of Intravascular Catheter-Related Infection of the Infectious Diseases Society of America.9 Persistent BSI Presence of clinically significant positive blood cultures after 3 days of effective antibiotic treatment in a patient with bacteraemia. Complicated BSI Septic shock and multi-organ failure, persistent bacteraemia, or metastatic infections. Nosocomial acquisition Positive blood cultures in samples obtained >72 h after admission, with no evidence of the infection on admission. Healthcare-related Patient hospitalized within the previous 3 months or routinely requiring medical treatment inside or outside the hospital (i.e. dialysis, chemotherapy). Related death Death occurring during the BSI that could not be clearly attributed to another cause. Adequate therapy The organism cultured was sensitive to the antibiotics used. Time to adequate therapy Time between blood culture collection and the beginning of suitable antimicrobial treatment. This period was classified into four groups: <24 h, between 24 and 48 h, between 48 and 72 h, and >72 h. Difficult-to-treat micro-organisms Meticillin-resistant Staphylococcus aureus (MRSA), Gramnegative bacilli producing extended-spectrum b-lactamases (ESBLs), Pseudomonas spp., Acinetobacter spp., and Candida spp.
Statistical analysis The ManneWhitney test was used for the univariate analysis of the patient characteristics compared with different types of renal disease and BSI outcome. Qualitative variables were assessed using the Fisher exact test or the chi-square test. P < 0.05 was considered significant. All statistical tests were two-tailed. A multivariate logistic regression model was used to assess risk factors affecting the outcome of patients with BSI. A forward stepwise approach was followed, including as candidate variables all those that were significant in the univariate analysis (P < 0.1). The results are presented as adjusted odds
198
L. Rojas et al. / Journal of Hospital Infection 85 (2013) 196e205
ratio (OR) with 95% confidence interval (CI). All statistical procedures were performed using SPSS version 15.0 (SPSS Inc., Chicago, IL, USA).
Ethical issues The study was approved by the local Research and Ethics Committee.
Results Incidence of BSI During the study period, 162 BSI episodes were registered in the nephrology department; seven were excluded because of blood culture contamination or because not all the clinical data were recorded. The final sample comprised 155 BSI episodes. The overall incidence of BSI during the study period in the department of nephrology was 77.3 episodes per 1000 admissions and 4.5 episodes per 100 patient-years (12.2 episodes per 100 patients per 1000 days). Haemodialysis patients had the highest incidence of BSI (nine episodes per 100 patient-years), followed by transplant recipients (3.2 episodes), patients on peritoneal dialysis (2.1 episodes), and patients without dialysis (1.2 episodes). The annual incidence is shown in Table I. Although the incidence of BSI tended to increase during the study period, the difference was not statistically significant.
Patient characteristics The main clinical characteristics are detailed in Table II. Most BSI episodes were recorded in haemodialysis patients (93, 60%), followed by kidney recipients (50, 32.3%), patients with acute or chronic renal failure not on dialysis (9, 5.8%), and patients on peritoneal dialysis (3, 1.9%). The median [interquartile range (IQR)] age of the population with BSI was 67 years (56e75). Most patients had a high Charlson comorbidity index [median: 6 (4e8)], and a high proportion of patients (72, 46.8%) were receiving immunosuppressive therapy.
Description of the BSI episodes The type of micro-organism varied with the type of renal disease. The predominant micro-organisms were Gramnegative bacilli (86, 52.8%), followed by Gram-positive cocci (75, 46%) and fungi (2, 1.2%). Escherichia coli was the most frequently isolated micro-organism (44, 27%). Fourteen of the Table I Incidence of bloodstream infection per 1000 admissions in the nephrology department Year
No. of admissions
No. of BSIs
Incidencea of BSI
ORb
95% CI
2007 2008 2009 2010
574 600 591 239
40 43 51 21
69.70 71.66 86.29 87.87
e 1.03 1.24 1.26
e 0.68e1.56 0.83e1.84 0.76e2.09
BSI, bloodstream infection; OR, odds ratio; CI, confidence interval. a Per 1000 admissions per year. b Incidence of BSI compared with incidence of BSI in 2007 (P ¼ 0.62).
86 (8.6%) Gram-negative bacilli were ESBL producers, and polymicrobial BSI was detected in 8 of the 155 (5.2%) episodes. The most frequent BSI was bacteraemia of unknown source (46, 29.7%), followed by urinary tract infection (UTI) (36, 23.2%), vascular access infection (27, 17.4%), and other local infections (46, 29.7%). UTI predominated in kidney transplant recipients and in patients with chronic renal failure not on haemodialysis, whereas patients undergoing haemodialysis had mainly catheter-related BSI. Only 64.5% of the patients (100 episodes) received adequate antibiotic treatment during the first 24 h, and 13.5% of patients (21 episodes) received adequate treatment only 72 h after the blood sample was taken. Patients not on dialysis were given adequate treatment within the first 48 h more frequently (55% vs 19.2%, P ¼ 0.02). A higher proportion of patients receiving immunosuppressive therapy (67/72 on prednisone) due to transplant or autoimmune disease had not received adequate treatment within the first 6 h compared with other patients (66% vs 44.8%, P ¼ 0.01; and 62.5% vs 42.2%, P ¼ 0.01, respectively). Overall, 35.5% (55/155) of patients started appropriate therapy after 24 h. Of these, 34.5% (19/55) corresponded to patients with bacteraemia caused by resistant micro-organisms compared with 22% (22/100) of patients who started appropriate therapy within 24 h (P ¼ 0.09). A higher proportion of BSI caused by difficult-to-treat micro-organisms received treatment after 24 h (46.3% vs 31.6%, P ¼ 0.09), and the mean time to start treatment for BSI caused by difficult-totreat micro-organisms was also higher (52.4 h 129 vs 29.7 79.9, P ¼ 0.08). Patients with a delay to treatment developed an abscess more frequently than patients who received treatment within 24 h (63.6% vs 33.3%, P ¼ 0.04). Eighteen patients (11.6%) had persistent BSI (four with septic shock or multi-organ failure). Twenty-one patients (13.5%) had metastatic infections including endocarditis (12), abscesses (11), and bone or joint infections (3). Four of these patients had endocarditis with abscesses and one had arthritis with lung abscess. Finally, 18 patients (11.6%) developed septic shock or multi-organ failure. Median (IQR) basal creatinine clearance of the patients without dialysis was 36.5 (18e53) mL/min; this decreased to 22.3 (12e39) mL/min during the BSI episode. Three patients needed to start haemodialysis during the BSI episode. Median (IQR) creatinine clearance on the day of discharge was 35.6 (18e55) mL/min.
Mortality and risk factors The crude mortality rate was 14.2% and attributable mortality was 11.6%. Possible risk factors related to poor outcome and mortality are summarized in Tables III and IV, respectively. The statistically significant factors associated with complicated BSI detected by the univariate analysis were: male gender, high comorbidity index and an ultimately fatal disease according to the McCabe and Jackson classification, coronary disease, stroke, chronic obstructive pulmonary disease, collagen vascular disease and solid tumour, having a BSI with MRSA or CRBSI Klebsiella sp., absence of fever, and lack of drainage of the infectious focus. The risk factors associated with mortality detected in the univariate analysis were older age, high comorbidity index, infection with MRSA, absence of fever, persistent BSI, metastatic infection, and a history of myocardial infarction, stroke
L. Rojas et al. / Journal of Hospital Infection 85 (2013) 196e205
199
Table II Characteristics and outcome of patients with bloodstream infection according to their renal disease Characteristics Mean rates of BSI per 100 patient-years Median age (IQR) Male sex McCabe and Jackson index Rapidly fatal Ultimately fatal Non-fatal Median (IQR) Charlson index Type of renal insufficiency Glomerulonephritis Diabetic nephropathy Polycystic renal disease Nephrosclerosis Chronic pyelonephritis Obstructive uropathy Vasculitis Interstitial nephritis Ischaemic nephropathy Unknown Underlying conditions Chronic heart failure Myocardial infarction Diabetes mellitus Peripheral vascular disease Solid tumour COPD Liver disease Stroke Peptic ulcer disease Collagenosis Dementia Haematological malignancy Immunosuppressive therapy Source of BSI Unknown source Urinary Vascular access Catheter Prosthetic AVG AVF Cystic infections Soft tissue Pneumonia Intra-abdominal Boneejoint Others Acquisition Community Nosocomial Healthcare-related Micro-organisms
Global (N ¼ 155)
RI without HD (N ¼ 9)
RI with HD (N ¼ 93)
RI with PD (N ¼ 3)
R Tx (N ¼ 50)
P
4.5
1.2
9
2.1
3.2
<0.01
67 (56e75) 95 (61.3)
68 (56e77) 5 (55.6)
73 (59e76) 60 (64.5)
66 (60e66) 2 (66.7)
63 (47e69) 28 (56)
<0.01ε 0.76 0.02ε
1 (0.6) 34 (21.9) 120 (77.4) 6 (4e8)
0 1 (11.1) 8 (88.9) 7 (4e8.5)
1 (1.1) 31 (33.7) 62 (66.7) 7 (5e9)
0 30 (32.6) 3 (100) 6 (5e8)
0 3 (6) 47 (94) 4 (2e5)
36 (23.2) 32 (20.6) 26 (16.8) 3 (1.9) 2 (1.3) 7 (4.5) 9 (5.8) 9 (5.8) 5 (3.2) 26 (16.8)
4 1 1 0 0 0 0 1 1 1
19 (20.4) 24 (25.8) 15 (16.1) 1 (1.1) 1 (1.1) 3 (3.2) 4 (4.3) 7 (7.5) 4 (4.3) 15 (16.3)
1 (33.3) 1 (33.3) 0 0 0 0 1 (33.3) 0 0 0
10 (20) 6 (12) 10 (20) 2 (4) 1 (2) 4 (8) 4 (8) 1 (2) 0 10 (20)
79 21 51 37
4 (44.4) 0 2 (22.2) 1 (11.1)
59 15 36 28
(63.4) (16.1) (38.7) (30.1)
1 (33.3) 1 (33.3) 1 (33.3) 0
15 (30) 5 (10) 12 (24) 8 (16)
31 (20) 29 (18.7) 22 (14.2) 22 (14.2) 16 (10.3) 12 (7.7) 2 (1.3) 1 (0.6)
2 0 3 0 1 5 0 0
21 (22.6) 22 (23.7) 14 (15.1) 17 (18.3) 10 (10.8) 5 (5.4) 2 (2.2) 1 (1.1)
1 (33.3) 2 (66.7) 0 0 0 0 0 0
7 5 5 5 5 2 0 0
72 (46.8)
6 (66.7)
15 (16.1)
1 (33.3)
50 (100)
<0.01a.g,ε
46 (29.7) 36 (23.2) 27 (17.4) 20 (12.9) 6 (3.9) 1 (0.6) 17 (11) 11 (7.1) 9 (5.8) 5 (3.2) 2 (1.3) 2 (1.3)
1 4 0 0 0 0 0 1 2 0 0 1
30 (32.3) 7 (7.5) 27 (29) 20 (21.5) 6 (6.5) 1 (1.1) 13 (14) 7 (7.5) 3 (3.2) 5 (5.4) 1 (1.1) 0
1 (33.3) 1 (33.3) 0 0 0 0 0 1 (33.3) 0 0 0 0
14 (28) 24 (48) 0 0 0 0 4 (8) 2 (4) 4 (8) 0 1 (2) 1 (2)
0.60 0.00a,ε
23 (14.8) 53 (34.2) 79 (51) (N ¼ 163)
4 (44.4) 4 (44.4) 1 (11.1) (N ¼ 9)
0 27 (29) 66 (71) (N ¼ 100)
1 (33.3) 0 2 (66.7) (N ¼ 3)
18 (36) 22 (44) 10 (20) (N ¼ 51)
<0.01ε,g 0.66
(51) (13.5) (32.9) (23.9)
(44.4) (11.1) (11.1)
(11.1) (11.1) (11.1)
(22.2) (33.3) (11.1) (55.6)
(11.1) (44.4)
(11.1) (22.2)
(11.1)
(14) (10) (10) (10) (10) (4)
0.01ε 0.32 0.26 0.30 0.60 0.01b,ε 0.26 0.14 0.95 <0.01a,g 0.72 0.88
0.43 0.25 0.10 0.94 0.33 0.41 <0.01a,d,ε
(continued on next page)
200
L. Rojas et al. / Journal of Hospital Infection 85 (2013) 196e205
Table II (continued ) Characteristics Gram-positive Staphylococcus aureus MSSA MRSA CoNS Enterococcus spp.a Streptococcus spp.b Otherc Corynebacterium spp. Listeria spp. Gram-negative Escherichia coli Klebsiella spp. Enterobacter spp. Proteus spp. Pseudomonas spp. Otherd ESBL-producing Fungi Candida spp. Polymicrobial Presence of fever Maximum clinical deterioration Sepsis Severe sepsis Septic shock MOF Persistent BSI Non-withdrawn blood cultures Metastatic infections Abscess Endocarditis Boneejoint Time (hours) to starting appropriate treatment Mean (SD) <24 24e48 48e72 >72 Median (IQR) hospital stay (days) Mortality Crude Related
Global (N ¼ 155)
RI without HD (N ¼ 9) (33.3)
RI with HD (N ¼ 93)
RI with PD (N ¼ 3)
55 (55) 28 (28) 22 (22) 6 (6) 11 (11) 10 (10) 4 (4) 0 1 (1) 1 (1) 44 (44) 25 (25) 8 (8) 0 2 (2) 4 (4) 5 (5) 8 (8)
1 0 0 0 0 0 0 1 0 0 2 1 0 0 0 0 1 1
0.02ε 0.01ε 0.10 0.27 0.24 0.73 0.64 <0.01d 0.88 0.88 0.05ε 0.65 0.78 0.08 0.84 0.04ε 0.17 0.52
3 0 0 0 2 0 1 0 0 0 6 4 0 0 0 2 0 1
2 (1.2) 8 (5.2) 125 (80.6)
0 0 6 (66.7)
1 (1) 7 (7) 75 (80.6)
0 0 2 (66.7)
1 (2) 1 (2) 42 (84)
117 (75.5) 20 (12.9) 8 (5.2) 10 (6.5) 18 (11.6) 42 (27.1)
5 1 2 1 1 5
(55.6) (11.1) (22.2) (11.1) (11.1) (55.6)
65 (69.9) 15 (16.1) 4 (4.3) 9 (9.7) 14 (15.1) 20 (21.5)
2 0 1 0 1 1
45 (90) 4 (8) 1 (2) 0 2 (4) 16 (32)
21 (13.5) 11 (7.1) 12 (7.7) 3 (1.9)
2 (22.2) 2 (22.2) 1 (11.1) 0
17 (18.3) 7 (7.5) 9 (9.7) 3 (3.2)
0 0 0 0
2 (4) 2 (4) 2 (4) 0
0.08 0.60 0.25 0.56 0.20
36 (92) 100 (64.5) 22 (14.2) 12 (7.7) 21 (13.5) 18 (12e30)
56 (61.6) 4 (44.4) 0 2 (22.2) 3 (33.3) 11 (7e38)
22 (39.5) 66 (71) 11 (11.8) 6 (6.5) 10 (10.8) 18 (12e29)
12 (20.8) 2 (66.7) 1 (33.3) 0 0 20 (2e20)
58 (147) 28 (56) 10 (20) 4 (8) 8 (16) 17.5 (13e32)
0.17 0.19 0.19 0.40 0.20 0.65
22 (14.2) 18 (11.6)
3 (33.3) 3 (33.3)
16 (17.2) 14 (15.1)
1 (33.3) 1 (33.3)
2 (4) 0
0.04g,ε 0.01g,ε
(11.1)
(66.7) (44.4)
(22.2) (11.1)
(33.3)
(66.7) (33.3)
(33.3) (33.3)
(66.7) (33.3) (33.3) (33.3)
16 (31.3) 5 (9.8) 5 (9.8) 0 2 (3.9) 5 (9.8) 4 (7.8) 0 0 0 34 (66.7) 14 (27.5) 4 (7.8) 3 (5.9) 2 (3.9) 8 (15.7) 3 (5.9) 4 (7.8)
P
75 (46) 33 (20.3) 27 (16.6) 6 (3.7) 15 (9.2) 15 (9.2) 9 (5.5) 1 (0.6) 1 (0.6) 1 (0.6) 86 (52.8) 44 (27) 12 (7.4) 3 (1.9) 4 (2.5) 14 (8.6) 9 (5.5) 14 (8.6)
(22.2)
(33.3)
R Tx (N ¼ 50)
0.94 0.43 0.60 0.02g,ε
0.10
AVF, arteriovenous fistula; AVG, arteriovenous graft; BSI, bloodstream infection; CoNS, coagulase-negative staphylococci; COPD, chronic obstructive pulmonary disease; ESBL, extended-spectrum beta-lactamase; HCR, healthcare-related; HD, haemodialysis; IQR, interquartile range; MOF, multi-organ failure; MSSA, meticillin-sensitive Staphylococcus aureus; MRSA, meticillin-resistant Staphylococcus aureus; PD, peritoneal dialysis; RI, renal insufficiency; R Tx, renal transplant recipient; SD, standard deviation. a RI without HD vs RI with HD (P < 0.05); bRI without HD vs PD (P < 0.05); gRI without HD vs R Tx (P < 0.05); dRI with HD vs PD (P < 0.05); εRI with HD vs R Tx (P < 0.05). a E. faecalis (13), E. faecium (2). b S. pneumoniae (5), S. bovis (1), S. pyogenes (1), S. viridans (2). c Micrococcus species (1). d Acinetobacter lwoffi (1), Alcaligenes faecalis (1), Aeromonas hydrophila (1), Burkholderia pickettii (1), Citrobacter freundii (1), Morganella morganii (1), Group B Salmonella (1), Stenotrophomonas maltophilia (1), Serratia marcescens (1).
L. Rojas et al. / Journal of Hospital Infection 85 (2013) 196e205
201
Table III Risk factors related to complicated bloodstream infection Risk factors
Male sex Mean SD Charlson index McCabe and Jackson index Rapidly fatal Ultimately fatal Non-fatal Underlying conditions Myocardial infarction COPD Stroke Collagenosis Solid tumour Immunosuppressive therapy Source Unknown source Vascular access Catheter Prosthetic AVG AVF Micro-organism Gram-positive MRSA Gram-negative Klebsiella spp. Time (hours) to starting appropriate treatment Mean SD Non-fever Non-drained infectious focus
Septic shock and MOF No (N ¼ 137)
Yes (N ¼ 18)
82 (59.9) 5.7 3
13 (72.2) 8.1 2.3
1 (0.7) 25 (18.2) 111 (81)
0 9 (50) 9 (50)
16 (11.7) 24 (17.5) 16 (11.7) 8 (5.8) 24 (17.5) 64 (46.7)
5 5 6 4 7 8
(27.8) (27.8) (33.3) (22.2) (38.9) (44.4)
38 (27.7) 24 (17.5) 18 (13.1) 5 (3.6) 1 (0.7)
8 3 2 1 0
(44.4) (16.7) (11.1) (5.6)
66 (48.2) 3 (2.2) 74 (54) 8 (5.8)
9 (50) 3 (16.7) 12 (66.6) 4 (22.2)
35.6 95 36.8 67 23 (16.8) 7 (38.9) 25 (18.2) 8 (44.4)
P
Persistent bloodstream infection No (N ¼ 95)
0.31 63 (66.6) 0.02 6.2 2.9 <0.01 1 (1.1) 21 (22.1) 73 (76.8)
Yes (N ¼ 18) 10 (55.6) 7.1 3.5
0.38 0.24 0.29
0 7 (38.9) 11 (61.1)
0.06 0.29 0.01 0.04 0.03 0.86 0.14 0.14 1 1 0.53 1
14 (14.7) 14 (14.7) 15 (15.8) 7 (7.4) 17 (17.9) 64 (46.7)
4 7 4 2 6 8
37 (38.9) 12 (12.6) 7 (7.4) 4 (4.2) 1 (1.1)
0.81 0.02 0.66 0.01
46 (48.4) 3 (3.2) 51 (53.7) 7 (7.4)
0.96 40 112 0.03 19 (20) 0.01 20 (21.1)
P
(22.2) (38.9) (22.2) (11.1) (33.3) (44.4)
Metastatic infections No (N ¼ 134) 78 (58.2) 5.8 3.2
Yes (N ¼ 21) 17 (81) 7.1 1.9
0.047 0.07 0.04
1 (0.7) 0 25 (18.7) 9 (42.9) 108 (80.6) 12 (57.1) 15 (11.2) 24 (17.9) 18 (13.4) 9 (6.7) 28 (20.9) 65 (48.5)
6 5 4 3 3 7
(28.6) (23.8) (19) (14.3) (14.3) (33.3)
2 (11.1) 10 (55.6) 9 (50) 1 (5.6) 0
0.5 0.02 0.5 0.63 0.14 0.85 <0.01 0.03 <0.01 <0.01 0.59 1
37 (27.6) 18 (13.4) 13 (9.7) 4 (3) 1 (0.7)
9 9 7 2 0
(42.9) (42.9) (33.3) (9.5)
15 (83.4) 3 (16.7) 3 (16.7) 0
0.02 0.05 <0.01 0.60
58 (43.2) 4 (3) 83 (61.9) 11 (8.2)
17 (81) 2 (9.5) 3 (14.3) 1 (4.8)
27.3 48 4 (22.2) 2 (11.1)
P
0.62 0.83 0.51
36.9 97 28.6 42.3 23 (17.2) 7 (33.3) 25 (18.7) 8 (38.1)
0.03 0.52 0.5 0.21 0.57 0.20 0.03 0.16 <0.01 <0.01 0.19 1 <0.01 0.19 <0.01 1
0.70 0.08 0.04
MOF, multi-organ failure; SD, standard deviation; COPD, chronic obstructive pulmonary disease; AVG, arteriovenous graft; AVF, arteriovenous fistula; MRSA, meticillin-resistant Staphylococcus aureus.
or solid organ tumour. Multivariate analysis showed that the independent risk factors for mortality were a high Charlson comorbidity index (OR: 1.27; 95% CI: 1.03e1.56; P ¼ 0.02) and a persistent BSI (OR: 5.98; 95% CI: 1.64e21.79; P ¼ 0.007). The presence of fever during the BSI episodes was found to be a protective factor (OR: 0.21; 95% CI: 0.06e0.75; P ¼ 0.017).
Discussion Our study has confirmed that bloodstream infections are fairly widespread in nephrology patients, and haemodialysis patients are particularly at risk. Gram-negative and -positive micro-organisms caused the overwhelming majority of BSI episodes. Surprisingly few yeasts were responsible for infection. The origins and aetiology of the episodes depend on the patient’s underlying clinical condition. A high proportion of patients with BSI did not receive adequate early therapy. Uraemic patients are at higher risk of acquiring bacterial infections than patients without uraemia.10 Mortality associated with BSI in this population ranges between 12% and 22% (14.2% in our hospital), and in our experience the highest mortality occurred in patients with acute or chronic renal
failure who were not on dialysis.11e14 Renal failure is a risk factor for mortality, possibly because of abnormalities of the immune system.1,15e19 This risk is proportional to the level of renal impairment.20 The reported incidence of BSI in general hospitals has varied in recent years from 21.6 to 28.3 episodes per 1000 admissions.21,22 Our institution reported values ranging from 16 to 31.2 episodes per 1000 admissions over a 22-year period.23 The incidence of 77 episodes per 1000 admissions in patients from our nephrology department was twice that of the general population. We were unable to find similar data from nephrology departments in other institutions. Some studies focused on selected groups of patients, such as transplant recipients (2.02 episodes per 200 patients followed per year) or patients on haemodialysis (0.5e27.1 episodes per 100 patientmonths or 6e325 episodes per 100 patient-years).7,24,25 Regarding our results, the incidence rates of BSI among transplant recipients and patients on haemodialysis were 3.2 and 9 episodes per 100 patient-years, respectively, similar to the published literature. The aetiology of BSI in patients with kidney disorders is incompletely described. Some studies show that Gram-positive micro-organisms were associated with BSI in dialysis patients,
202
L. Rojas et al. / Journal of Hospital Infection 85 (2013) 196e205
Table IV Mortality risk factors: univariate analysis Risk factors Mean SD age (years) Male sex Mean SD Charlson index McCabe and Jackson index Rapidly fatal Ultimately fatal Non-fatal Underlying conditions Myocardial infarction Chronic heart failure Diabetes mellitus COPD Liver diseases Stroke Peripheral vascular disease Dementia Collagenosis Peptic ulcer disease Solid tumour Haematological malignancy Type of renal insufficiency RI without dialysis RI with haemodialysis RI with peritoneal dialysis Renal transplant recipient Immunosuppressive therapy Source of BSI Unknown source Vascular access Catheter Prosthetic AVG AVF Pneumonia Urinary Cystic infections Soft tissue Boneejoint Intra-abdominal Acquisition Community Nosocomial Healthcare-related Micro-organisms Staphylococcus aureus MRSA Klebsiella spp. ESBL-producing Candida albicans Polymicrobial Fever Mean SD ( C) No Yes Maximum clinical deterioration Sepsis Severe sepsis Septic shock
Cure (N ¼ 133)
Death (N ¼ 22)
P
63.83 13.2 80 (60.2) 5.59 2.98
70.77 8.7 15 (68.2) 8.36 2.65
0.02 0.47 <0.01 <0.01
0 22 (16.5) 111 (83.5)
1 (4.5) 12 (54.5) 9 (40.9)
15 (11.3) 65 (48.9) 42 (31.6) 24 (18) 19 (14.3) 15 (11.3) 29 (21.8) 2 (1.5) 8 (6) 12 (9) 22 (16.5) 0
6 (27.3) 14 (63.3) 9 (40.9) 5 (22.7) 3 (13.6) 7 (31.8) 8 (36.4) 0 4 (18.2) 4 (18.2) 9 (40.9) 1 (4.5)
0.04 0.20 0.39 0.60 0.94 0.01 0.14 1.00 0.07 0.17 <0.01 0.14
7 (5.3) 76 (57.1) 2 (1.5) 48 (36.1) 62 (46.6)
3 (13.6) 16 (72.7) 1 (4.5) 2 (9.1) 10 (45.5)
38 (28.6) 25 (18.8) 19 (14.3) 5 (3.8) 1 (0.8) 8 (6) 33 (24.8) 17 (12.8) 7 (5.3) 2 (1.5) 3 (2.3)
8 3 2 1 0 1 3 0 4 0 2
0.15 0.17 0.37 0.01 0.92 0.11 0.46 0.77 0.74 1.00 1.00 1.00 0.41 0.13 0.05 1.00 0.15 0.26
22 (16.5) 46 (34.6) 65 (48.9)
1 (4.5) 7 (31.8) 14 (63.6)
26 (19.5) 3 (2.3) 8 (6) 13 (9.8) 1 (0.8) 5 (3.8)
7 3 4 1 1 3
38.4 0.8 22 (16.5) 111 (83.5)
37.9 0.96 8 (36.4) 14 (63.6)
115 (86.5) 16 (12) 2 (1.5)
2 (9.1) 4 (18.2) 6 (27.3)
(36.4) (13.6) (9.1) (4.5) (4.5) (13.6) (18.2) (9.1)
(31.8) (13.6) (18.2) (4.5) (4.5) (13.6)
0.19 0.04 0.07 0.69 0.27 0.09 0.01 0.03 <0.01
L. Rojas et al. / Journal of Hospital Infection 85 (2013) 196e205
203
Table IV (continued ) Risk factors MOF ICU admission Persistent BSI No Yes Non-withdrawn blood cultures Metastatic infections Abscess Endocarditis Boneejoint Non-drained infectious focus Time (hours) to starting appropriate treatment Median SD <24 24e48 48e72 >72
Cure (N ¼ 133)
Death (N ¼ 22)
0 8 (6)
10 (45.5) 8 (36.4)
86 (64.7) 11 (8.3) 36 (27.1) 15 (11.3) 7 (5.3) 9 (6.8) 2 (1.5) 26 (19.5)
9 7 6 6 4 3 1 7
36 96.14 86 (64.7) 21 (15.8) 9 (6.8) 17 (12.8)
33.9 58 14 (63.3) 1 (4.5) 3 (13.6) 4 (18.2)
(40.9) (31.8) (27.3) (27.3) (18.2) (13.6) (4.5) (31.8)
P <0.01 <0.01
0.04 0.05 0.38 0.34 0.19 0.84 0.91 1.00 0.20 0.38 0.50
SD, standard deviation; COPD, chronic obstructive pulmonary disease; RI, renal insufficiency; BSI, bloodstream infection; AVG, arteriovenous graft; AVF, arteriovenous fistula; MRSA, methicillin-resistant Staphylococcus aureus; ESBL, extended-spectrum beta-lactamase; MOF, multiorgan failure; ICU, intensive care unit.
whereas Gram-negative micro-organisms were more frequently associated with BSI in other patients.11,26,27 In our study, Grampositive and Gram-negative micro-organisms were responsible for almost 50% each of the BSI episodes and Candida spp. represented only 1.2% of significant BSI. Other studies of haemodialysis patients showed that candidaemia represented only 1.7e2% of the CRBSI episodes and 2.9% of other arteriovenous fistula infections or vascular prosthesis infections.25,28 Moreno et al. performed a study with transplant patients in whom candidaemia represented 5% of the BSI episodes.24 We are unable to explain this low incidence and are unaware of any protection against candidaemia in uraemic patients.29 The proportion of difficult-to-treat micro-organisms in our study was 26.5%, and this has important implications for the selection of empirical antimicrobial therapy. As reported elsewhere in the literature, vascular access was the main source of BSI in patients undergoing dialysis.2,3 UTIs were an important source of infection in transplant patients and in patients with an indwelling catheter.7,11,24 The proportion of patients receiving haemodialysis with catheter access has increased in recent years from 21% to 36%.30e32 When comparing dialysis patients with an intravascular catheter to those with an arteriovenous fistula (AVF), the risk of infection and mortality was 7.6- and 1.5-fold greater, respectively.33,34 In our study, the frequency of CRBSI was 20fold greater than that of AVF and 14-fold greater than BSI from a vascular prosthesis. Risk factors for UTI were the use of urinary catheters, nephrostomy ureteral stents, obstructive uropathy, and diabetes.35e37 Many urinary catheters are unnecessary, so educational programmes could help to reduce their use and their associated infections.38 We found several risk factors associated with complicated BSI. In general, having a worse comorbidity index was related to complicated BSI. Independent risk factors for septic shock and multi-organ failure were: BSI caused by MRSA or Klebsiella spp., the absence of fever, and having an undrained focus of infection. By contrast, when the source of the BSI was a vascular access
(catheter or prosthetic arteriovenous graft), it was associated with having persistent BSI and metastatic infections. Our study confirmed that symptoms of BSI in nephrology patients were uncommon despite changes in the inflammatory response.40,41 This could be associated with delay in the diagnosis and treatment of BSI.42,43 We also showed that the type of kidney disease (patients with acute or chronic renal failure not on dialysis) and immunosuppressive therapy were associated with a delay in adequate treatment. The presence of fever during BSI episodes was found to be a protective factor (OR: 0.21). This could be explained because the absence of fever could be related to abnormalities of the immune system that are associated with comorbidities. As other authors have reported, our study did not demonstrate that in the general nephrology population treatment delay was a risk factor for mortality.44,45 However, we found that patients without fever e which was associated with more frequent septic shock and multi-organ failure e experienced longer delays in receiving adequate treatment and had higher mortality. This highlights the importance of treating the patient at the time when infection is initially suspected (when the blood culture is taken), rather than waiting for a result before starting to treat. In recent years, several studies have clarified the importance of adequate early antimicrobial therapy for survival.46,47 Different studies have demonstrated that patients with severe septic shock benefited from an early appropriate antimicrobial therapy, as this was the only modifiable factor.48 Kumar et al. showed that survival of patients with septic shock decreased by 6.7% with each hour of delay.48 Shorr et al. demonstrated that initially inappropriate antibiotic therapy occurs in one-third of patients with severe sepsis and septic shock attributable to Gram-negative organisms and was significantly associated with mortality and length of stay.49 Our study found that a high Charlson comorbidity index (OR: 1.27) and a persistent BSI (OR: 5.98) were independent risk factors for mortality. Fowler et al. reported that persistent Staphylococcus aureus bacteraemia was associated with higher
204
L. Rojas et al. / Journal of Hospital Infection 85 (2013) 196e205
mortality.39 This is the first study to demonstrate in nephrology patients that positive follow-up blood cultures at 48e96 h identified patients at higher risk of mortality. This is a warning sign that physicians ought to look for, in order to investigate possible complications and to ensure appropriate treatment. The inadequacy of antimicrobial therapy found in this study is of concern. To help guide a rational choice of empiric antibiotics, there should be regular review of the bacterial aetiology and susceptibility data of the local isolates.50 Another important aspect is that antibacterial dosing in renal replacement therapy depends on a large number of variables which results in considerable inter- and intra-patient heterogeneity in dose requirements.51 The main limitation of the study was its retrospective design. Further studies are needed about the incidence and outcome of BSI in nephrology patients. Educational and preventive measures to avoid intravascular and bladder catheter infections are important.52e55 Knowledge of the local epidemiology is a key issue that can guide selection of empirical therapy in nephrology patients.
Acknowledgements We thank T. O’Boyle for help with the preparation of the manuscript. Conflict of interest statement None declared. Funding sources This study was partially financed by the Infectious Diseases programme of Fundacio ´n BBVAeFundacio ´n Carolina through the research fellowship granted to L. Rojas.
References 1. Vanholder R, Ringoir S. Infectious morbidity and defects of phagocytic function in end-stage renal disease: a review. J Am Soc Nephrol 1993;3:1541e1554. 2. Powe NR, Jaar B, Furth SL, Hermann J, Briggs W. Septicemia in dialysis patients: incidence, risk factors, and prognosis. Kidney Int 1999;55:1081e1090. 3. Minnaganti VR, Cunha BA. Infections associated with uremia and dialysis. Infect Dis Clin North Am 2001;15:385e406. 4. Ansell D, Roderick P, Steenkamp R, Tomson CR. UK Renal Registry 12th Annual Report (December 2009): Chapter 7: Survival and causes of death of UK adult patients on renal replacement therapy in 2008: national and centre-specific analyses. Nephron Clin Pract 2010;155:c117ec144. 5. Johnson DW, Dent H, Hawley CM, et al. Associations of dialysis modality and infectious mortality in incident dialysis patients in Australia and New Zealand. Am J Kidney Dis 2009;53:290e297. 6. Aslam N, Bernardini J, Fried L, Burr R, Piraino B. Comparison of infectious complications between incident hemodialysis and peritoneal dialysis patients. Clin J Am Soc Nephrol 2006;1:1226e1233. 7. Linares L, Garcia-Goez JF, Cervera C, et al. Early bacteremia after solid organ transplantation. Transplant Proc 2009;41:2262e2264. 8. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing; twentieth informational supplement. Wayne, PA: CLSI; 2010. 9. Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis 2009;49:1e45.
10. National Institutes of Diabetes and Digestive and Kidney Diseases. United States renal data system, USRDS, Atlas of chronic kidney disease in the United States. Bethesda, MD: National Institutes of Health; 2007. 11. James MT, Laupland KB, Tonelli M, Manns BJ, Culleton BF, Hemmelgarn BR. Risk of bloodstream infection in patients with chronic kidney disease not treated with dialysis. Arch Intern Med 2008;168:2333e2339. 12. Vanholder R, Van Biesen W. Incidence of infectious morbidity and mortality in dialysis patients. Blood Purif 2002;20:477e480. 13. Sarnak MJ, Jaber BL. Mortality caused by sepsis in patients with end-stage renal disease compared with the general population. Kidney Int 2000;58:1758e1764. 14. Hoen B, Paul-Dauphin A, Hestin D, Kessler M. EPIBACDIAL: a multicenter prospective study of risk factors for bacteremia in chronic hemodialysis patients. J Am Soc Nephrol 1998; 9:869e876. 15. Hoste EA, Clermont G, Kersten A, et al. RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis. Crit Care 2006;10:R73. 16. Miceli A, Bruno VD, Capoun R, et al. Mild renal dysfunction in patients undergoing cardiac surgery as a new risk factor for EuroSCORE. Heart 2011;97:362e365. 17. Vaz Perez A, Otawa K, Zimmermann AV, et al. The impact of impaired renal function on mortality in patients with acutely decompensated chronic heart failure. Eur J Heart Fail 2010;12:122e128. 18. Vanholder R, Ringoir S, Dhondt A, Hakim R. Phagocytosis in uremic and hemodialysis patients: a prospective and cross sectional study. Kidney Int 1991;39:320e327. 19. Vanholder R, Argiles A, Baurmeister U, et al. Uremic toxicity: present state of the art. Int J Artif Organs 2001;24:695e725. 20. Hedley AJ, Roberts MA, Hayward PA, et al. Impact of chronic kidney disease on patient outcome following cardiac surgery. Heart Lung Circ 2010;19:453e459. 21. Franco A, Casallo S, Marcos F, Sanchez M, Gil M, Martinez de la Casa A. Study on bacteremia in the service of Internal Medicine of a group 2 hospital. Analysis of recent three years. An Med Interna 2005;22:217e221. 22. Al-Rawajfah OM, Stetzer F, Beauchamp Hewitt J. Incidence of and risk factors for nosocomial bloodstream infections in adults in the United States, 2003. Infect Control Hosp Epidemiol 2009;30:1036e1044. 23. Rodriguez-Cre ´ixems M, Alcala ´ L, Mun ˜oz P, Cercenado E, Vicente T, Bouza E. Bloodstream infections: evolution and trends in the microbiology workload, incidence, and etiology, 1985e2006. Medicine 2008;87:234e249. 24. Moreno A, Cervera C, Gavalda J, et al. Bloodstream infections among transplant recipients: results of a nationwide surveillance in Spain. Am J Transplant 2007;7:2579e2586. 25. Klevens RM, Edwards JR, Andrus ML, Peterson KD, Dudeck MA, Horan TC. Dialysis Surveillance Report: National Healthcare Safety Network (NHSN) e data summary for 2006. Semin Dial 2008;21:24e28. 26. Keane WF, Shapiro FL, Raij L. Incidence and type of infections occurring in 445 chronic hemodialysis patients. Trans Am Soc Artif Intern Organs 1977;23:41e47. 27. Beathard GA. Management of bacteremia associated with tunnelede cuffed hemodialysis catheters. J Am Soc Nephrol 1999;10: 1045e1049. 28. Sychev D, Maya ID, Allon M. Clinical outcomes of dialysis catheterrelated candidemia in hemodialysis patients. Clin J Am Soc Nephrol 2009;4:1102e1105. 29. Miller TE, Findon G. Host resistance to Candida albicans in uraemia. J Med Microbiol 1984;17:181e187. 30. Pisoni RL, Young EW, Dykstra DM, et al. Vascular access use in Europe and the United States: results from the DOPPS. Kidney Int 2002;61:305e316.
L. Rojas et al. / Journal of Hospital Infection 85 (2013) 196e205 31. Mendelssohn DC, Ethier J, Elder SJ, Saran R, Port FK, Pisoni RL. Haemodialysis vascular access problems in Canada: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS II). Nephrol Dial Transplant 2006;21:721e728. 32. Ethier J, Mendelssohn DC, Elder SJ, et al. Vascular access use and outcomes: an international perspective from the Dialysis Outcomes and Practice Patterns Study. Nephrol Dial Transplant 2008;23:3219e3226. 33. Grothe C, da Silva Belasco AG, de Cassia Bittencourt AR, Vianna LA, de Castro Cintra Sesso R, Barbosa DA. Incidence of bloodstream infection among patients on hemodialysis by central venous catheter. Rev Lat Am Enfermagem 2010;18:73e80. 34. Astor BC, Eustace JA, Powe NR, Klag MJ, Fink NE, Coresh J. Type of vascular access and survival among incident hemodialysis patients: the Choices for Healthy Outcomes in Caring for ESRD (CHOICE) Study. J Am Soc Nephrol 2005;16:1449e1455. 35. Drinka PJ. Complications of chronic indwelling urinary catheters. J Am Med Dir Assoc 2006;7:388e392. 36. Ranganathan M, Akbar M, Ilham MA, Chavez R, Kumar N, Asderakis A. Infective complications associated with ureteral stents in renal transplant recipients. Transplant Proc 2009;41:162e164. 37. Silva A, Rodig N, Passerotti CP, et al. Risk factors for urinary tract infection after renal transplantation and its impact on graft function in children and young adults. J Urol 2010;184:1462e1467. 38. Meddings J, Rogers MA, Macy M, Saint S. Systematic review and meta-analysis: reminder systems to reduce catheter-associated urinary tract infections and urinary catheter use in hospitalized patients. Clin Infect Dis 2010;51:550e560. 39. Fowler Jr VG, Olsen MK, Corey GR, et al. Clinical identifiers of complicated Staphylococcus aureus bacteremia. Arch Intern Med 2003;163:2066e2072. 40. Lewis SL. Fever: thermal regulation and alterations in end stage renal disease patients. ANNA J 1992;19:13e18. 41. Jones PG, Kauffman CA, Port FK, Kluger MJ. Fever in uremia: production of leukocytic pyrogen by chronic dialysis patients. Am J Kidney Dis 1985;6:241e244. 42. Pien BC, Sundaram P, Raoof N, et al. The clinical and prognostic importance of positive blood cultures in adults. Am J Med 2010;123:819e828. 43. Burlaud A, Mathieu D, Falissard B, Trivalle C. Mortality and bloodstream infections in geriatrics units. Arch Gerontol Geriatr 2010;51:e106e109.
205
44. Valles J, Alvarez-Lerma F, Palomar M, et al. Health-care-associated bloodstream infections at admission to the ICU. Chest 2011;139:810e815. 45. Corona A, Bertolini G, Lipman J, Wilson AP, Singer M. Antibiotic use and impact on outcome from bacteraemic critical illness: the BActeraemia Study in Intensive Care (BASIC). J Antimicrob Chemother 2010;65:1276e1285. 46. Shime N, Kosaka T, Fujita N. The importance of a judicious and early empiric choice of antimicrobial for methicillin-resistant Staphylococcus aureus bacteraemia. Eur J Clin Microbiol Infect Dis 2010;29:1475e1479. 47. Erbay A, Idil A, Gozel MG, Mumcuoglu I, Balaban N. Impact of early appropriate antimicrobial therapy on survival in Acinetobacter baumannii bloodstream infections. Int J Antimicrob Agents 2009;34:575e579. 48. 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. Crit Care Med 2006;34:1589e1596. 49. Shorr AF, Micek ST, Welch EC, Doherty JA, Reichley RM, Kollef MH. Inappropriate antibiotic therapy in Gram-negative sepsis increases hospital length of stay. Crit Care Med 2011;39:46e51. 50. Alexandraki I, Sullivan R, Zaiden R, et al. Blood culture isolates in hemodialysis vascular catheter-related bacteremia. Am J Med Sci 2008;336:297e302. 51. Choi G, Gomersall CD, Tian Q, Joynt GM, Freebairn R, Lipman J. Principles of antibacterial dosing in continuous renal replacement therapy. Crit Care Med 2009;37:2268e2282. 52. Nazarko L. Reducing the risk of catheter-related urinary tract infection. Br J Nurs 2008;17: 1002, 1004, 1006 passim. 53. Verdier R, Parer S, Jean-Pierre H, Dujols P, Picot MC. Impact of an infection control program in an intensive care unit in France. Infect Control Hosp Epidemiol 2006;27:60e66. 54. Ackad A, Simonian GT, Steel K, et al. A journey in reversing practice patterns: a multidisciplinary experience in implementing DOQI guidelines for vascular access. Nephrol Dial Transplant 2005;20:1450e1455. 55. Stevenson KB, Hannah EL, Lowder CA, et al. Epidemiology of hemodialysis vascular access infections from longitudinal infection surveillance data: predicting the impact of NKF-DOQI clinical practice guidelines for vascular access. Am J Kidney Dis 2002;39:549e555.
Journal of Hospital Infection journal homepage: www.elsevierhealth.com/journals/jhin
Bloodstream infections in patients with kidney disease: risk factors for poor outcome and mortality ˜oz a, c, d, M. Kestler a, D. Arroyo b, M. Guembe a, *, L. Rojas a, P. Mun ´ixems a, c, d, E. Verde b, E. Bouza a, c, d M. Rodrı´guez-Cre a
Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Maran˜o´n, Madrid, Spain Department of Nephrology, Hospital General Universitario Gregorio Maran˜o´n, Madrid, Spain c Universidad Complutense de Madrid, Department of Medicine, Madrid, Spain d Red Espan˜ola de Enfermedades Infecciosas (REIPI), Madrid, Spain b
A R T I C L E
I N F O
Article history: Received 14 May 2012 Accepted 11 July 2013 Available online 31 August 2013 Keywords: Bacteraemia Chronic kidney disease Mortality Peritoneal dialysis Renal transplantation
S U M M A R Y
Background: Information regarding bloodstream infections (BSIs) in patients with kidney diseases is scarce and mainly derived from selected groups of patients. Aim: To assess the characteristics of BSI in an unselected population of patients with kidney disease, including renal transplant recipients and patients with chronic kidney failure who were receiving or not receiving dialysis. Methods: A retrospective cohort study of all patients who presented with BSI in the nephrology department of a large teaching hospital. Clinical records were reviewed according to a pre-established protocol. Standard definitions were used. Findings: In all, 155 episodes of BSI were recorded in 108 patients. The incidence of BSI was 77.3 episodes per 1000 admissions, and 4.5 episodes per 100 patient-years. Haemodialysis patients had the highest incidence of BSI. The distribution of micro-organisms was as follows: Gram-negative, 52.3%; Gram-positive, 46.5%; fungi, 1.2%. Escherichia coli was the most frequently isolated micro-organism (27%). The BSI was classed as bacteraemia of unknown source (29.7%), urinary tract infection (23.2%), vascular access infection (17.4%), and other (29.7%). Eighteen patients (11.6%) developed septic shock or multi-organ failure, and the same proportion had persistent bacteraemia. The crude mortality rate was 14.6%. The risk factors for mortality were high Charlson index, persistent bacteraemia, and absence of fever. Conclusion: Nephrology patients have a high incidence of BSI, particularly patients undergoing haemodialysis. The predominant micro-organisms causing BSI episodes were Gram-negative bacilli. Patients with kidney disease have high BSI-related morbidity and mortality. Risk factors for mortality were high Charlson comorbidity index and persistent BSI. The presence of fever during the BSI episodes was found to be a protective factor. ª 2013 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.
Introduction * Corresponding author. Address: Servicio de Microbiologı´a Clı´nica y Enfermedades Infecciosas, Hospital General Universitario Gregorio Maran ˜o ´n, C/Doctor Esquerdo, 46, 28007 Madrid, Spain. Tel.: þ34 91 586 84 53; fax: þ34 91 504 49 06. E-mail address: [email protected] (M. Guembe).
Nephrology patients are at risk of acquiring infection due to uraemia, vascular access, and the combination of surgery and immunosuppressive therapy, both of which are required for kidney transplantation.1e3
0195-6701/$ e see front matter ª 2013 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jhin.2013.07.009
L. Rojas et al. / Journal of Hospital Infection 85 (2013) 196e205 Bloodstream infections (BSIs) have been reported in particular subgroups of nephrology patients, for example, those undergoing chronic haemodialysis or kidney transplantation.4e7 However, data are scarce for BSI in other subgroups and in unselected nephrology patients. Our objective was to describe retrospectively episodes of BSI occurring in all nephrology patients attending a nephrology department in a large teaching hospital.
Methods Setting Our institution is a 1550-bed hospital serving a population of about 715,000 inhabitants in both urban and rural areas of Madrid. The nephrology department has a large-scale chronic and acute haemodialysis programme and is a centre for kidney transplantation. It also cares for patients with various renal disorders and with different degrees of renal dysfunction, including patients who do not require dialysis. The mean number of patients attending the nephrology department per year during the study period was 987 66 patients, of whom 299 14 (30.3%) were on haemodialysis, 209 84 (21.2%) did not receive dialysis, 36 3 (3.7%) received peritoneal dialysis, and 443 15 (44.9%) were kidney recipients.
Inclusion criteria All patients attending the nephrology department from January 2007 to June 2010 who had one or more episodes of BSI were included in this retrospective cohort study. All episodes with clinically non-significant, contaminated blood cultures were excluded.
Microbiological and clinical data Blood cultures were performed using the BACTEC 9240 system (Becton Dickinson Microbiology Systems, Sparks, MD, USA). Isolates were identified according to standard procedures, and susceptibility testing was performed following the recommendations of the Clinical and Laboratory Standards Institute (CLSI).8
Clinical data obtained from the charts Clinical data retrieved to assess baseline characteristics and the clinical course were: age, sex, pre-existing comorbidities, type of renal disease, immunosuppressive therapy, type of vascular access, and renal function in patients not receiving dialysis. Information was also obtained about the clinical setting (community-acquired, hospital-acquired, or healthcare-related), source of BSI, organs involved, persistent BSI, clinical deterioration, initiation of appropriate treatment, and mortality.
Definitions BSI of unknown source Recovery of clinically significant micro-organisms from blood cultures with no evidence of the clinical source or focal clinical manifestations. Commensal micro-organisms
197
[coagulase-negative staphylococci (CoNS), Corynebacterium sp. (except C. jeikeium), Lactobacillus spp., Bacillus spp., and Propionibacterium spp., or Streptococcus viridans group isolates and C. perfringens] were considered as probable pathogens when they were recovered in two or more blood cultures. Catheter-related bloodstream infection (CRBSI) This was defined according to the Clinical Practice Guidelines for the Diagnosis and Management of Intravascular Catheter-Related Infection of the Infectious Diseases Society of America.9 Persistent BSI Presence of clinically significant positive blood cultures after 3 days of effective antibiotic treatment in a patient with bacteraemia. Complicated BSI Septic shock and multi-organ failure, persistent bacteraemia, or metastatic infections. Nosocomial acquisition Positive blood cultures in samples obtained >72 h after admission, with no evidence of the infection on admission. Healthcare-related Patient hospitalized within the previous 3 months or routinely requiring medical treatment inside or outside the hospital (i.e. dialysis, chemotherapy). Related death Death occurring during the BSI that could not be clearly attributed to another cause. Adequate therapy The organism cultured was sensitive to the antibiotics used. Time to adequate therapy Time between blood culture collection and the beginning of suitable antimicrobial treatment. This period was classified into four groups: <24 h, between 24 and 48 h, between 48 and 72 h, and >72 h. Difficult-to-treat micro-organisms Meticillin-resistant Staphylococcus aureus (MRSA), Gramnegative bacilli producing extended-spectrum b-lactamases (ESBLs), Pseudomonas spp., Acinetobacter spp., and Candida spp.
Statistical analysis The ManneWhitney test was used for the univariate analysis of the patient characteristics compared with different types of renal disease and BSI outcome. Qualitative variables were assessed using the Fisher exact test or the chi-square test. P < 0.05 was considered significant. All statistical tests were two-tailed. A multivariate logistic regression model was used to assess risk factors affecting the outcome of patients with BSI. A forward stepwise approach was followed, including as candidate variables all those that were significant in the univariate analysis (P < 0.1). The results are presented as adjusted odds
198
L. Rojas et al. / Journal of Hospital Infection 85 (2013) 196e205
ratio (OR) with 95% confidence interval (CI). All statistical procedures were performed using SPSS version 15.0 (SPSS Inc., Chicago, IL, USA).
Ethical issues The study was approved by the local Research and Ethics Committee.
Results Incidence of BSI During the study period, 162 BSI episodes were registered in the nephrology department; seven were excluded because of blood culture contamination or because not all the clinical data were recorded. The final sample comprised 155 BSI episodes. The overall incidence of BSI during the study period in the department of nephrology was 77.3 episodes per 1000 admissions and 4.5 episodes per 100 patient-years (12.2 episodes per 100 patients per 1000 days). Haemodialysis patients had the highest incidence of BSI (nine episodes per 100 patient-years), followed by transplant recipients (3.2 episodes), patients on peritoneal dialysis (2.1 episodes), and patients without dialysis (1.2 episodes). The annual incidence is shown in Table I. Although the incidence of BSI tended to increase during the study period, the difference was not statistically significant.
Patient characteristics The main clinical characteristics are detailed in Table II. Most BSI episodes were recorded in haemodialysis patients (93, 60%), followed by kidney recipients (50, 32.3%), patients with acute or chronic renal failure not on dialysis (9, 5.8%), and patients on peritoneal dialysis (3, 1.9%). The median [interquartile range (IQR)] age of the population with BSI was 67 years (56e75). Most patients had a high Charlson comorbidity index [median: 6 (4e8)], and a high proportion of patients (72, 46.8%) were receiving immunosuppressive therapy.
Description of the BSI episodes The type of micro-organism varied with the type of renal disease. The predominant micro-organisms were Gramnegative bacilli (86, 52.8%), followed by Gram-positive cocci (75, 46%) and fungi (2, 1.2%). Escherichia coli was the most frequently isolated micro-organism (44, 27%). Fourteen of the Table I Incidence of bloodstream infection per 1000 admissions in the nephrology department Year
No. of admissions
No. of BSIs
Incidencea of BSI
ORb
95% CI
2007 2008 2009 2010
574 600 591 239
40 43 51 21
69.70 71.66 86.29 87.87
e 1.03 1.24 1.26
e 0.68e1.56 0.83e1.84 0.76e2.09
BSI, bloodstream infection; OR, odds ratio; CI, confidence interval. a Per 1000 admissions per year. b Incidence of BSI compared with incidence of BSI in 2007 (P ¼ 0.62).
86 (8.6%) Gram-negative bacilli were ESBL producers, and polymicrobial BSI was detected in 8 of the 155 (5.2%) episodes. The most frequent BSI was bacteraemia of unknown source (46, 29.7%), followed by urinary tract infection (UTI) (36, 23.2%), vascular access infection (27, 17.4%), and other local infections (46, 29.7%). UTI predominated in kidney transplant recipients and in patients with chronic renal failure not on haemodialysis, whereas patients undergoing haemodialysis had mainly catheter-related BSI. Only 64.5% of the patients (100 episodes) received adequate antibiotic treatment during the first 24 h, and 13.5% of patients (21 episodes) received adequate treatment only 72 h after the blood sample was taken. Patients not on dialysis were given adequate treatment within the first 48 h more frequently (55% vs 19.2%, P ¼ 0.02). A higher proportion of patients receiving immunosuppressive therapy (67/72 on prednisone) due to transplant or autoimmune disease had not received adequate treatment within the first 6 h compared with other patients (66% vs 44.8%, P ¼ 0.01; and 62.5% vs 42.2%, P ¼ 0.01, respectively). Overall, 35.5% (55/155) of patients started appropriate therapy after 24 h. Of these, 34.5% (19/55) corresponded to patients with bacteraemia caused by resistant micro-organisms compared with 22% (22/100) of patients who started appropriate therapy within 24 h (P ¼ 0.09). A higher proportion of BSI caused by difficult-to-treat micro-organisms received treatment after 24 h (46.3% vs 31.6%, P ¼ 0.09), and the mean time to start treatment for BSI caused by difficult-totreat micro-organisms was also higher (52.4 h 129 vs 29.7 79.9, P ¼ 0.08). Patients with a delay to treatment developed an abscess more frequently than patients who received treatment within 24 h (63.6% vs 33.3%, P ¼ 0.04). Eighteen patients (11.6%) had persistent BSI (four with septic shock or multi-organ failure). Twenty-one patients (13.5%) had metastatic infections including endocarditis (12), abscesses (11), and bone or joint infections (3). Four of these patients had endocarditis with abscesses and one had arthritis with lung abscess. Finally, 18 patients (11.6%) developed septic shock or multi-organ failure. Median (IQR) basal creatinine clearance of the patients without dialysis was 36.5 (18e53) mL/min; this decreased to 22.3 (12e39) mL/min during the BSI episode. Three patients needed to start haemodialysis during the BSI episode. Median (IQR) creatinine clearance on the day of discharge was 35.6 (18e55) mL/min.
Mortality and risk factors The crude mortality rate was 14.2% and attributable mortality was 11.6%. Possible risk factors related to poor outcome and mortality are summarized in Tables III and IV, respectively. The statistically significant factors associated with complicated BSI detected by the univariate analysis were: male gender, high comorbidity index and an ultimately fatal disease according to the McCabe and Jackson classification, coronary disease, stroke, chronic obstructive pulmonary disease, collagen vascular disease and solid tumour, having a BSI with MRSA or CRBSI Klebsiella sp., absence of fever, and lack of drainage of the infectious focus. The risk factors associated with mortality detected in the univariate analysis were older age, high comorbidity index, infection with MRSA, absence of fever, persistent BSI, metastatic infection, and a history of myocardial infarction, stroke
L. Rojas et al. / Journal of Hospital Infection 85 (2013) 196e205
199
Table II Characteristics and outcome of patients with bloodstream infection according to their renal disease Characteristics Mean rates of BSI per 100 patient-years Median age (IQR) Male sex McCabe and Jackson index Rapidly fatal Ultimately fatal Non-fatal Median (IQR) Charlson index Type of renal insufficiency Glomerulonephritis Diabetic nephropathy Polycystic renal disease Nephrosclerosis Chronic pyelonephritis Obstructive uropathy Vasculitis Interstitial nephritis Ischaemic nephropathy Unknown Underlying conditions Chronic heart failure Myocardial infarction Diabetes mellitus Peripheral vascular disease Solid tumour COPD Liver disease Stroke Peptic ulcer disease Collagenosis Dementia Haematological malignancy Immunosuppressive therapy Source of BSI Unknown source Urinary Vascular access Catheter Prosthetic AVG AVF Cystic infections Soft tissue Pneumonia Intra-abdominal Boneejoint Others Acquisition Community Nosocomial Healthcare-related Micro-organisms
Global (N ¼ 155)
RI without HD (N ¼ 9)
RI with HD (N ¼ 93)
RI with PD (N ¼ 3)
R Tx (N ¼ 50)
P
4.5
1.2
9
2.1
3.2
<0.01
67 (56e75) 95 (61.3)
68 (56e77) 5 (55.6)
73 (59e76) 60 (64.5)
66 (60e66) 2 (66.7)
63 (47e69) 28 (56)
<0.01ε 0.76 0.02ε
1 (0.6) 34 (21.9) 120 (77.4) 6 (4e8)
0 1 (11.1) 8 (88.9) 7 (4e8.5)
1 (1.1) 31 (33.7) 62 (66.7) 7 (5e9)
0 30 (32.6) 3 (100) 6 (5e8)
0 3 (6) 47 (94) 4 (2e5)
36 (23.2) 32 (20.6) 26 (16.8) 3 (1.9) 2 (1.3) 7 (4.5) 9 (5.8) 9 (5.8) 5 (3.2) 26 (16.8)
4 1 1 0 0 0 0 1 1 1
19 (20.4) 24 (25.8) 15 (16.1) 1 (1.1) 1 (1.1) 3 (3.2) 4 (4.3) 7 (7.5) 4 (4.3) 15 (16.3)
1 (33.3) 1 (33.3) 0 0 0 0 1 (33.3) 0 0 0
10 (20) 6 (12) 10 (20) 2 (4) 1 (2) 4 (8) 4 (8) 1 (2) 0 10 (20)
79 21 51 37
4 (44.4) 0 2 (22.2) 1 (11.1)
59 15 36 28
(63.4) (16.1) (38.7) (30.1)
1 (33.3) 1 (33.3) 1 (33.3) 0
15 (30) 5 (10) 12 (24) 8 (16)
31 (20) 29 (18.7) 22 (14.2) 22 (14.2) 16 (10.3) 12 (7.7) 2 (1.3) 1 (0.6)
2 0 3 0 1 5 0 0
21 (22.6) 22 (23.7) 14 (15.1) 17 (18.3) 10 (10.8) 5 (5.4) 2 (2.2) 1 (1.1)
1 (33.3) 2 (66.7) 0 0 0 0 0 0
7 5 5 5 5 2 0 0
72 (46.8)
6 (66.7)
15 (16.1)
1 (33.3)
50 (100)
<0.01a.g,ε
46 (29.7) 36 (23.2) 27 (17.4) 20 (12.9) 6 (3.9) 1 (0.6) 17 (11) 11 (7.1) 9 (5.8) 5 (3.2) 2 (1.3) 2 (1.3)
1 4 0 0 0 0 0 1 2 0 0 1
30 (32.3) 7 (7.5) 27 (29) 20 (21.5) 6 (6.5) 1 (1.1) 13 (14) 7 (7.5) 3 (3.2) 5 (5.4) 1 (1.1) 0
1 (33.3) 1 (33.3) 0 0 0 0 0 1 (33.3) 0 0 0 0
14 (28) 24 (48) 0 0 0 0 4 (8) 2 (4) 4 (8) 0 1 (2) 1 (2)
0.60 0.00a,ε
23 (14.8) 53 (34.2) 79 (51) (N ¼ 163)
4 (44.4) 4 (44.4) 1 (11.1) (N ¼ 9)
0 27 (29) 66 (71) (N ¼ 100)
1 (33.3) 0 2 (66.7) (N ¼ 3)
18 (36) 22 (44) 10 (20) (N ¼ 51)
<0.01ε,g 0.66
(51) (13.5) (32.9) (23.9)
(44.4) (11.1) (11.1)
(11.1) (11.1) (11.1)
(22.2) (33.3) (11.1) (55.6)
(11.1) (44.4)
(11.1) (22.2)
(11.1)
(14) (10) (10) (10) (10) (4)
0.01ε 0.32 0.26 0.30 0.60 0.01b,ε 0.26 0.14 0.95 <0.01a,g 0.72 0.88
0.43 0.25 0.10 0.94 0.33 0.41 <0.01a,d,ε
(continued on next page)
200
L. Rojas et al. / Journal of Hospital Infection 85 (2013) 196e205
Table II (continued ) Characteristics Gram-positive Staphylococcus aureus MSSA MRSA CoNS Enterococcus spp.a Streptococcus spp.b Otherc Corynebacterium spp. Listeria spp. Gram-negative Escherichia coli Klebsiella spp. Enterobacter spp. Proteus spp. Pseudomonas spp. Otherd ESBL-producing Fungi Candida spp. Polymicrobial Presence of fever Maximum clinical deterioration Sepsis Severe sepsis Septic shock MOF Persistent BSI Non-withdrawn blood cultures Metastatic infections Abscess Endocarditis Boneejoint Time (hours) to starting appropriate treatment Mean (SD) <24 24e48 48e72 >72 Median (IQR) hospital stay (days) Mortality Crude Related
Global (N ¼ 155)
RI without HD (N ¼ 9) (33.3)
RI with HD (N ¼ 93)
RI with PD (N ¼ 3)
55 (55) 28 (28) 22 (22) 6 (6) 11 (11) 10 (10) 4 (4) 0 1 (1) 1 (1) 44 (44) 25 (25) 8 (8) 0 2 (2) 4 (4) 5 (5) 8 (8)
1 0 0 0 0 0 0 1 0 0 2 1 0 0 0 0 1 1
0.02ε 0.01ε 0.10 0.27 0.24 0.73 0.64 <0.01d 0.88 0.88 0.05ε 0.65 0.78 0.08 0.84 0.04ε 0.17 0.52
3 0 0 0 2 0 1 0 0 0 6 4 0 0 0 2 0 1
2 (1.2) 8 (5.2) 125 (80.6)
0 0 6 (66.7)
1 (1) 7 (7) 75 (80.6)
0 0 2 (66.7)
1 (2) 1 (2) 42 (84)
117 (75.5) 20 (12.9) 8 (5.2) 10 (6.5) 18 (11.6) 42 (27.1)
5 1 2 1 1 5
(55.6) (11.1) (22.2) (11.1) (11.1) (55.6)
65 (69.9) 15 (16.1) 4 (4.3) 9 (9.7) 14 (15.1) 20 (21.5)
2 0 1 0 1 1
45 (90) 4 (8) 1 (2) 0 2 (4) 16 (32)
21 (13.5) 11 (7.1) 12 (7.7) 3 (1.9)
2 (22.2) 2 (22.2) 1 (11.1) 0
17 (18.3) 7 (7.5) 9 (9.7) 3 (3.2)
0 0 0 0
2 (4) 2 (4) 2 (4) 0
0.08 0.60 0.25 0.56 0.20
36 (92) 100 (64.5) 22 (14.2) 12 (7.7) 21 (13.5) 18 (12e30)
56 (61.6) 4 (44.4) 0 2 (22.2) 3 (33.3) 11 (7e38)
22 (39.5) 66 (71) 11 (11.8) 6 (6.5) 10 (10.8) 18 (12e29)
12 (20.8) 2 (66.7) 1 (33.3) 0 0 20 (2e20)
58 (147) 28 (56) 10 (20) 4 (8) 8 (16) 17.5 (13e32)
0.17 0.19 0.19 0.40 0.20 0.65
22 (14.2) 18 (11.6)
3 (33.3) 3 (33.3)
16 (17.2) 14 (15.1)
1 (33.3) 1 (33.3)
2 (4) 0
0.04g,ε 0.01g,ε
(11.1)
(66.7) (44.4)
(22.2) (11.1)
(33.3)
(66.7) (33.3)
(33.3) (33.3)
(66.7) (33.3) (33.3) (33.3)
16 (31.3) 5 (9.8) 5 (9.8) 0 2 (3.9) 5 (9.8) 4 (7.8) 0 0 0 34 (66.7) 14 (27.5) 4 (7.8) 3 (5.9) 2 (3.9) 8 (15.7) 3 (5.9) 4 (7.8)
P
75 (46) 33 (20.3) 27 (16.6) 6 (3.7) 15 (9.2) 15 (9.2) 9 (5.5) 1 (0.6) 1 (0.6) 1 (0.6) 86 (52.8) 44 (27) 12 (7.4) 3 (1.9) 4 (2.5) 14 (8.6) 9 (5.5) 14 (8.6)
(22.2)
(33.3)
R Tx (N ¼ 50)
0.94 0.43 0.60 0.02g,ε
0.10
AVF, arteriovenous fistula; AVG, arteriovenous graft; BSI, bloodstream infection; CoNS, coagulase-negative staphylococci; COPD, chronic obstructive pulmonary disease; ESBL, extended-spectrum beta-lactamase; HCR, healthcare-related; HD, haemodialysis; IQR, interquartile range; MOF, multi-organ failure; MSSA, meticillin-sensitive Staphylococcus aureus; MRSA, meticillin-resistant Staphylococcus aureus; PD, peritoneal dialysis; RI, renal insufficiency; R Tx, renal transplant recipient; SD, standard deviation. a RI without HD vs RI with HD (P < 0.05); bRI without HD vs PD (P < 0.05); gRI without HD vs R Tx (P < 0.05); dRI with HD vs PD (P < 0.05); εRI with HD vs R Tx (P < 0.05). a E. faecalis (13), E. faecium (2). b S. pneumoniae (5), S. bovis (1), S. pyogenes (1), S. viridans (2). c Micrococcus species (1). d Acinetobacter lwoffi (1), Alcaligenes faecalis (1), Aeromonas hydrophila (1), Burkholderia pickettii (1), Citrobacter freundii (1), Morganella morganii (1), Group B Salmonella (1), Stenotrophomonas maltophilia (1), Serratia marcescens (1).
L. Rojas et al. / Journal of Hospital Infection 85 (2013) 196e205
201
Table III Risk factors related to complicated bloodstream infection Risk factors
Male sex Mean SD Charlson index McCabe and Jackson index Rapidly fatal Ultimately fatal Non-fatal Underlying conditions Myocardial infarction COPD Stroke Collagenosis Solid tumour Immunosuppressive therapy Source Unknown source Vascular access Catheter Prosthetic AVG AVF Micro-organism Gram-positive MRSA Gram-negative Klebsiella spp. Time (hours) to starting appropriate treatment Mean SD Non-fever Non-drained infectious focus
Septic shock and MOF No (N ¼ 137)
Yes (N ¼ 18)
82 (59.9) 5.7 3
13 (72.2) 8.1 2.3
1 (0.7) 25 (18.2) 111 (81)
0 9 (50) 9 (50)
16 (11.7) 24 (17.5) 16 (11.7) 8 (5.8) 24 (17.5) 64 (46.7)
5 5 6 4 7 8
(27.8) (27.8) (33.3) (22.2) (38.9) (44.4)
38 (27.7) 24 (17.5) 18 (13.1) 5 (3.6) 1 (0.7)
8 3 2 1 0
(44.4) (16.7) (11.1) (5.6)
66 (48.2) 3 (2.2) 74 (54) 8 (5.8)
9 (50) 3 (16.7) 12 (66.6) 4 (22.2)
35.6 95 36.8 67 23 (16.8) 7 (38.9) 25 (18.2) 8 (44.4)
P
Persistent bloodstream infection No (N ¼ 95)
0.31 63 (66.6) 0.02 6.2 2.9 <0.01 1 (1.1) 21 (22.1) 73 (76.8)
Yes (N ¼ 18) 10 (55.6) 7.1 3.5
0.38 0.24 0.29
0 7 (38.9) 11 (61.1)
0.06 0.29 0.01 0.04 0.03 0.86 0.14 0.14 1 1 0.53 1
14 (14.7) 14 (14.7) 15 (15.8) 7 (7.4) 17 (17.9) 64 (46.7)
4 7 4 2 6 8
37 (38.9) 12 (12.6) 7 (7.4) 4 (4.2) 1 (1.1)
0.81 0.02 0.66 0.01
46 (48.4) 3 (3.2) 51 (53.7) 7 (7.4)
0.96 40 112 0.03 19 (20) 0.01 20 (21.1)
P
(22.2) (38.9) (22.2) (11.1) (33.3) (44.4)
Metastatic infections No (N ¼ 134) 78 (58.2) 5.8 3.2
Yes (N ¼ 21) 17 (81) 7.1 1.9
0.047 0.07 0.04
1 (0.7) 0 25 (18.7) 9 (42.9) 108 (80.6) 12 (57.1) 15 (11.2) 24 (17.9) 18 (13.4) 9 (6.7) 28 (20.9) 65 (48.5)
6 5 4 3 3 7
(28.6) (23.8) (19) (14.3) (14.3) (33.3)
2 (11.1) 10 (55.6) 9 (50) 1 (5.6) 0
0.5 0.02 0.5 0.63 0.14 0.85 <0.01 0.03 <0.01 <0.01 0.59 1
37 (27.6) 18 (13.4) 13 (9.7) 4 (3) 1 (0.7)
9 9 7 2 0
(42.9) (42.9) (33.3) (9.5)
15 (83.4) 3 (16.7) 3 (16.7) 0
0.02 0.05 <0.01 0.60
58 (43.2) 4 (3) 83 (61.9) 11 (8.2)
17 (81) 2 (9.5) 3 (14.3) 1 (4.8)
27.3 48 4 (22.2) 2 (11.1)
P
0.62 0.83 0.51
36.9 97 28.6 42.3 23 (17.2) 7 (33.3) 25 (18.7) 8 (38.1)
0.03 0.52 0.5 0.21 0.57 0.20 0.03 0.16 <0.01 <0.01 0.19 1 <0.01 0.19 <0.01 1
0.70 0.08 0.04
MOF, multi-organ failure; SD, standard deviation; COPD, chronic obstructive pulmonary disease; AVG, arteriovenous graft; AVF, arteriovenous fistula; MRSA, meticillin-resistant Staphylococcus aureus.
or solid organ tumour. Multivariate analysis showed that the independent risk factors for mortality were a high Charlson comorbidity index (OR: 1.27; 95% CI: 1.03e1.56; P ¼ 0.02) and a persistent BSI (OR: 5.98; 95% CI: 1.64e21.79; P ¼ 0.007). The presence of fever during the BSI episodes was found to be a protective factor (OR: 0.21; 95% CI: 0.06e0.75; P ¼ 0.017).
Discussion Our study has confirmed that bloodstream infections are fairly widespread in nephrology patients, and haemodialysis patients are particularly at risk. Gram-negative and -positive micro-organisms caused the overwhelming majority of BSI episodes. Surprisingly few yeasts were responsible for infection. The origins and aetiology of the episodes depend on the patient’s underlying clinical condition. A high proportion of patients with BSI did not receive adequate early therapy. Uraemic patients are at higher risk of acquiring bacterial infections than patients without uraemia.10 Mortality associated with BSI in this population ranges between 12% and 22% (14.2% in our hospital), and in our experience the highest mortality occurred in patients with acute or chronic renal
failure who were not on dialysis.11e14 Renal failure is a risk factor for mortality, possibly because of abnormalities of the immune system.1,15e19 This risk is proportional to the level of renal impairment.20 The reported incidence of BSI in general hospitals has varied in recent years from 21.6 to 28.3 episodes per 1000 admissions.21,22 Our institution reported values ranging from 16 to 31.2 episodes per 1000 admissions over a 22-year period.23 The incidence of 77 episodes per 1000 admissions in patients from our nephrology department was twice that of the general population. We were unable to find similar data from nephrology departments in other institutions. Some studies focused on selected groups of patients, such as transplant recipients (2.02 episodes per 200 patients followed per year) or patients on haemodialysis (0.5e27.1 episodes per 100 patientmonths or 6e325 episodes per 100 patient-years).7,24,25 Regarding our results, the incidence rates of BSI among transplant recipients and patients on haemodialysis were 3.2 and 9 episodes per 100 patient-years, respectively, similar to the published literature. The aetiology of BSI in patients with kidney disorders is incompletely described. Some studies show that Gram-positive micro-organisms were associated with BSI in dialysis patients,
202
L. Rojas et al. / Journal of Hospital Infection 85 (2013) 196e205
Table IV Mortality risk factors: univariate analysis Risk factors Mean SD age (years) Male sex Mean SD Charlson index McCabe and Jackson index Rapidly fatal Ultimately fatal Non-fatal Underlying conditions Myocardial infarction Chronic heart failure Diabetes mellitus COPD Liver diseases Stroke Peripheral vascular disease Dementia Collagenosis Peptic ulcer disease Solid tumour Haematological malignancy Type of renal insufficiency RI without dialysis RI with haemodialysis RI with peritoneal dialysis Renal transplant recipient Immunosuppressive therapy Source of BSI Unknown source Vascular access Catheter Prosthetic AVG AVF Pneumonia Urinary Cystic infections Soft tissue Boneejoint Intra-abdominal Acquisition Community Nosocomial Healthcare-related Micro-organisms Staphylococcus aureus MRSA Klebsiella spp. ESBL-producing Candida albicans Polymicrobial Fever Mean SD ( C) No Yes Maximum clinical deterioration Sepsis Severe sepsis Septic shock
Cure (N ¼ 133)
Death (N ¼ 22)
P
63.83 13.2 80 (60.2) 5.59 2.98
70.77 8.7 15 (68.2) 8.36 2.65
0.02 0.47 <0.01 <0.01
0 22 (16.5) 111 (83.5)
1 (4.5) 12 (54.5) 9 (40.9)
15 (11.3) 65 (48.9) 42 (31.6) 24 (18) 19 (14.3) 15 (11.3) 29 (21.8) 2 (1.5) 8 (6) 12 (9) 22 (16.5) 0
6 (27.3) 14 (63.3) 9 (40.9) 5 (22.7) 3 (13.6) 7 (31.8) 8 (36.4) 0 4 (18.2) 4 (18.2) 9 (40.9) 1 (4.5)
0.04 0.20 0.39 0.60 0.94 0.01 0.14 1.00 0.07 0.17 <0.01 0.14
7 (5.3) 76 (57.1) 2 (1.5) 48 (36.1) 62 (46.6)
3 (13.6) 16 (72.7) 1 (4.5) 2 (9.1) 10 (45.5)
38 (28.6) 25 (18.8) 19 (14.3) 5 (3.8) 1 (0.8) 8 (6) 33 (24.8) 17 (12.8) 7 (5.3) 2 (1.5) 3 (2.3)
8 3 2 1 0 1 3 0 4 0 2
0.15 0.17 0.37 0.01 0.92 0.11 0.46 0.77 0.74 1.00 1.00 1.00 0.41 0.13 0.05 1.00 0.15 0.26
22 (16.5) 46 (34.6) 65 (48.9)
1 (4.5) 7 (31.8) 14 (63.6)
26 (19.5) 3 (2.3) 8 (6) 13 (9.8) 1 (0.8) 5 (3.8)
7 3 4 1 1 3
38.4 0.8 22 (16.5) 111 (83.5)
37.9 0.96 8 (36.4) 14 (63.6)
115 (86.5) 16 (12) 2 (1.5)
2 (9.1) 4 (18.2) 6 (27.3)
(36.4) (13.6) (9.1) (4.5) (4.5) (13.6) (18.2) (9.1)
(31.8) (13.6) (18.2) (4.5) (4.5) (13.6)
0.19 0.04 0.07 0.69 0.27 0.09 0.01 0.03 <0.01
L. Rojas et al. / Journal of Hospital Infection 85 (2013) 196e205
203
Table IV (continued ) Risk factors MOF ICU admission Persistent BSI No Yes Non-withdrawn blood cultures Metastatic infections Abscess Endocarditis Boneejoint Non-drained infectious focus Time (hours) to starting appropriate treatment Median SD <24 24e48 48e72 >72
Cure (N ¼ 133)
Death (N ¼ 22)
0 8 (6)
10 (45.5) 8 (36.4)
86 (64.7) 11 (8.3) 36 (27.1) 15 (11.3) 7 (5.3) 9 (6.8) 2 (1.5) 26 (19.5)
9 7 6 6 4 3 1 7
36 96.14 86 (64.7) 21 (15.8) 9 (6.8) 17 (12.8)
33.9 58 14 (63.3) 1 (4.5) 3 (13.6) 4 (18.2)
(40.9) (31.8) (27.3) (27.3) (18.2) (13.6) (4.5) (31.8)
P <0.01 <0.01
0.04 0.05 0.38 0.34 0.19 0.84 0.91 1.00 0.20 0.38 0.50
SD, standard deviation; COPD, chronic obstructive pulmonary disease; RI, renal insufficiency; BSI, bloodstream infection; AVG, arteriovenous graft; AVF, arteriovenous fistula; MRSA, methicillin-resistant Staphylococcus aureus; ESBL, extended-spectrum beta-lactamase; MOF, multiorgan failure; ICU, intensive care unit.
whereas Gram-negative micro-organisms were more frequently associated with BSI in other patients.11,26,27 In our study, Grampositive and Gram-negative micro-organisms were responsible for almost 50% each of the BSI episodes and Candida spp. represented only 1.2% of significant BSI. Other studies of haemodialysis patients showed that candidaemia represented only 1.7e2% of the CRBSI episodes and 2.9% of other arteriovenous fistula infections or vascular prosthesis infections.25,28 Moreno et al. performed a study with transplant patients in whom candidaemia represented 5% of the BSI episodes.24 We are unable to explain this low incidence and are unaware of any protection against candidaemia in uraemic patients.29 The proportion of difficult-to-treat micro-organisms in our study was 26.5%, and this has important implications for the selection of empirical antimicrobial therapy. As reported elsewhere in the literature, vascular access was the main source of BSI in patients undergoing dialysis.2,3 UTIs were an important source of infection in transplant patients and in patients with an indwelling catheter.7,11,24 The proportion of patients receiving haemodialysis with catheter access has increased in recent years from 21% to 36%.30e32 When comparing dialysis patients with an intravascular catheter to those with an arteriovenous fistula (AVF), the risk of infection and mortality was 7.6- and 1.5-fold greater, respectively.33,34 In our study, the frequency of CRBSI was 20fold greater than that of AVF and 14-fold greater than BSI from a vascular prosthesis. Risk factors for UTI were the use of urinary catheters, nephrostomy ureteral stents, obstructive uropathy, and diabetes.35e37 Many urinary catheters are unnecessary, so educational programmes could help to reduce their use and their associated infections.38 We found several risk factors associated with complicated BSI. In general, having a worse comorbidity index was related to complicated BSI. Independent risk factors for septic shock and multi-organ failure were: BSI caused by MRSA or Klebsiella spp., the absence of fever, and having an undrained focus of infection. By contrast, when the source of the BSI was a vascular access
(catheter or prosthetic arteriovenous graft), it was associated with having persistent BSI and metastatic infections. Our study confirmed that symptoms of BSI in nephrology patients were uncommon despite changes in the inflammatory response.40,41 This could be associated with delay in the diagnosis and treatment of BSI.42,43 We also showed that the type of kidney disease (patients with acute or chronic renal failure not on dialysis) and immunosuppressive therapy were associated with a delay in adequate treatment. The presence of fever during BSI episodes was found to be a protective factor (OR: 0.21). This could be explained because the absence of fever could be related to abnormalities of the immune system that are associated with comorbidities. As other authors have reported, our study did not demonstrate that in the general nephrology population treatment delay was a risk factor for mortality.44,45 However, we found that patients without fever e which was associated with more frequent septic shock and multi-organ failure e experienced longer delays in receiving adequate treatment and had higher mortality. This highlights the importance of treating the patient at the time when infection is initially suspected (when the blood culture is taken), rather than waiting for a result before starting to treat. In recent years, several studies have clarified the importance of adequate early antimicrobial therapy for survival.46,47 Different studies have demonstrated that patients with severe septic shock benefited from an early appropriate antimicrobial therapy, as this was the only modifiable factor.48 Kumar et al. showed that survival of patients with septic shock decreased by 6.7% with each hour of delay.48 Shorr et al. demonstrated that initially inappropriate antibiotic therapy occurs in one-third of patients with severe sepsis and septic shock attributable to Gram-negative organisms and was significantly associated with mortality and length of stay.49 Our study found that a high Charlson comorbidity index (OR: 1.27) and a persistent BSI (OR: 5.98) were independent risk factors for mortality. Fowler et al. reported that persistent Staphylococcus aureus bacteraemia was associated with higher
204
L. Rojas et al. / Journal of Hospital Infection 85 (2013) 196e205
mortality.39 This is the first study to demonstrate in nephrology patients that positive follow-up blood cultures at 48e96 h identified patients at higher risk of mortality. This is a warning sign that physicians ought to look for, in order to investigate possible complications and to ensure appropriate treatment. The inadequacy of antimicrobial therapy found in this study is of concern. To help guide a rational choice of empiric antibiotics, there should be regular review of the bacterial aetiology and susceptibility data of the local isolates.50 Another important aspect is that antibacterial dosing in renal replacement therapy depends on a large number of variables which results in considerable inter- and intra-patient heterogeneity in dose requirements.51 The main limitation of the study was its retrospective design. Further studies are needed about the incidence and outcome of BSI in nephrology patients. Educational and preventive measures to avoid intravascular and bladder catheter infections are important.52e55 Knowledge of the local epidemiology is a key issue that can guide selection of empirical therapy in nephrology patients.
Acknowledgements We thank T. O’Boyle for help with the preparation of the manuscript. Conflict of interest statement None declared. Funding sources This study was partially financed by the Infectious Diseases programme of Fundacio ´n BBVAeFundacio ´n Carolina through the research fellowship granted to L. Rojas.
References 1. Vanholder R, Ringoir S. Infectious morbidity and defects of phagocytic function in end-stage renal disease: a review. J Am Soc Nephrol 1993;3:1541e1554. 2. Powe NR, Jaar B, Furth SL, Hermann J, Briggs W. Septicemia in dialysis patients: incidence, risk factors, and prognosis. Kidney Int 1999;55:1081e1090. 3. Minnaganti VR, Cunha BA. Infections associated with uremia and dialysis. Infect Dis Clin North Am 2001;15:385e406. 4. Ansell D, Roderick P, Steenkamp R, Tomson CR. UK Renal Registry 12th Annual Report (December 2009): Chapter 7: Survival and causes of death of UK adult patients on renal replacement therapy in 2008: national and centre-specific analyses. Nephron Clin Pract 2010;155:c117ec144. 5. Johnson DW, Dent H, Hawley CM, et al. Associations of dialysis modality and infectious mortality in incident dialysis patients in Australia and New Zealand. Am J Kidney Dis 2009;53:290e297. 6. Aslam N, Bernardini J, Fried L, Burr R, Piraino B. Comparison of infectious complications between incident hemodialysis and peritoneal dialysis patients. Clin J Am Soc Nephrol 2006;1:1226e1233. 7. Linares L, Garcia-Goez JF, Cervera C, et al. Early bacteremia after solid organ transplantation. Transplant Proc 2009;41:2262e2264. 8. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing; twentieth informational supplement. Wayne, PA: CLSI; 2010. 9. Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis 2009;49:1e45.
10. National Institutes of Diabetes and Digestive and Kidney Diseases. United States renal data system, USRDS, Atlas of chronic kidney disease in the United States. Bethesda, MD: National Institutes of Health; 2007. 11. James MT, Laupland KB, Tonelli M, Manns BJ, Culleton BF, Hemmelgarn BR. Risk of bloodstream infection in patients with chronic kidney disease not treated with dialysis. Arch Intern Med 2008;168:2333e2339. 12. Vanholder R, Van Biesen W. Incidence of infectious morbidity and mortality in dialysis patients. Blood Purif 2002;20:477e480. 13. Sarnak MJ, Jaber BL. Mortality caused by sepsis in patients with end-stage renal disease compared with the general population. Kidney Int 2000;58:1758e1764. 14. Hoen B, Paul-Dauphin A, Hestin D, Kessler M. EPIBACDIAL: a multicenter prospective study of risk factors for bacteremia in chronic hemodialysis patients. J Am Soc Nephrol 1998; 9:869e876. 15. Hoste EA, Clermont G, Kersten A, et al. RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis. Crit Care 2006;10:R73. 16. Miceli A, Bruno VD, Capoun R, et al. Mild renal dysfunction in patients undergoing cardiac surgery as a new risk factor for EuroSCORE. Heart 2011;97:362e365. 17. Vaz Perez A, Otawa K, Zimmermann AV, et al. The impact of impaired renal function on mortality in patients with acutely decompensated chronic heart failure. Eur J Heart Fail 2010;12:122e128. 18. Vanholder R, Ringoir S, Dhondt A, Hakim R. Phagocytosis in uremic and hemodialysis patients: a prospective and cross sectional study. Kidney Int 1991;39:320e327. 19. Vanholder R, Argiles A, Baurmeister U, et al. Uremic toxicity: present state of the art. Int J Artif Organs 2001;24:695e725. 20. Hedley AJ, Roberts MA, Hayward PA, et al. Impact of chronic kidney disease on patient outcome following cardiac surgery. Heart Lung Circ 2010;19:453e459. 21. Franco A, Casallo S, Marcos F, Sanchez M, Gil M, Martinez de la Casa A. Study on bacteremia in the service of Internal Medicine of a group 2 hospital. Analysis of recent three years. An Med Interna 2005;22:217e221. 22. Al-Rawajfah OM, Stetzer F, Beauchamp Hewitt J. Incidence of and risk factors for nosocomial bloodstream infections in adults in the United States, 2003. Infect Control Hosp Epidemiol 2009;30:1036e1044. 23. Rodriguez-Cre ´ixems M, Alcala ´ L, Mun ˜oz P, Cercenado E, Vicente T, Bouza E. Bloodstream infections: evolution and trends in the microbiology workload, incidence, and etiology, 1985e2006. Medicine 2008;87:234e249. 24. Moreno A, Cervera C, Gavalda J, et al. Bloodstream infections among transplant recipients: results of a nationwide surveillance in Spain. Am J Transplant 2007;7:2579e2586. 25. Klevens RM, Edwards JR, Andrus ML, Peterson KD, Dudeck MA, Horan TC. Dialysis Surveillance Report: National Healthcare Safety Network (NHSN) e data summary for 2006. Semin Dial 2008;21:24e28. 26. Keane WF, Shapiro FL, Raij L. Incidence and type of infections occurring in 445 chronic hemodialysis patients. Trans Am Soc Artif Intern Organs 1977;23:41e47. 27. Beathard GA. Management of bacteremia associated with tunnelede cuffed hemodialysis catheters. J Am Soc Nephrol 1999;10: 1045e1049. 28. Sychev D, Maya ID, Allon M. Clinical outcomes of dialysis catheterrelated candidemia in hemodialysis patients. Clin J Am Soc Nephrol 2009;4:1102e1105. 29. Miller TE, Findon G. Host resistance to Candida albicans in uraemia. J Med Microbiol 1984;17:181e187. 30. Pisoni RL, Young EW, Dykstra DM, et al. Vascular access use in Europe and the United States: results from the DOPPS. Kidney Int 2002;61:305e316.
L. Rojas et al. / Journal of Hospital Infection 85 (2013) 196e205 31. Mendelssohn DC, Ethier J, Elder SJ, Saran R, Port FK, Pisoni RL. Haemodialysis vascular access problems in Canada: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS II). Nephrol Dial Transplant 2006;21:721e728. 32. Ethier J, Mendelssohn DC, Elder SJ, et al. Vascular access use and outcomes: an international perspective from the Dialysis Outcomes and Practice Patterns Study. Nephrol Dial Transplant 2008;23:3219e3226. 33. Grothe C, da Silva Belasco AG, de Cassia Bittencourt AR, Vianna LA, de Castro Cintra Sesso R, Barbosa DA. Incidence of bloodstream infection among patients on hemodialysis by central venous catheter. Rev Lat Am Enfermagem 2010;18:73e80. 34. Astor BC, Eustace JA, Powe NR, Klag MJ, Fink NE, Coresh J. Type of vascular access and survival among incident hemodialysis patients: the Choices for Healthy Outcomes in Caring for ESRD (CHOICE) Study. J Am Soc Nephrol 2005;16:1449e1455. 35. Drinka PJ. Complications of chronic indwelling urinary catheters. J Am Med Dir Assoc 2006;7:388e392. 36. Ranganathan M, Akbar M, Ilham MA, Chavez R, Kumar N, Asderakis A. Infective complications associated with ureteral stents in renal transplant recipients. Transplant Proc 2009;41:162e164. 37. Silva A, Rodig N, Passerotti CP, et al. Risk factors for urinary tract infection after renal transplantation and its impact on graft function in children and young adults. J Urol 2010;184:1462e1467. 38. Meddings J, Rogers MA, Macy M, Saint S. Systematic review and meta-analysis: reminder systems to reduce catheter-associated urinary tract infections and urinary catheter use in hospitalized patients. Clin Infect Dis 2010;51:550e560. 39. Fowler Jr VG, Olsen MK, Corey GR, et al. Clinical identifiers of complicated Staphylococcus aureus bacteremia. Arch Intern Med 2003;163:2066e2072. 40. Lewis SL. Fever: thermal regulation and alterations in end stage renal disease patients. ANNA J 1992;19:13e18. 41. Jones PG, Kauffman CA, Port FK, Kluger MJ. Fever in uremia: production of leukocytic pyrogen by chronic dialysis patients. Am J Kidney Dis 1985;6:241e244. 42. Pien BC, Sundaram P, Raoof N, et al. The clinical and prognostic importance of positive blood cultures in adults. Am J Med 2010;123:819e828. 43. Burlaud A, Mathieu D, Falissard B, Trivalle C. Mortality and bloodstream infections in geriatrics units. Arch Gerontol Geriatr 2010;51:e106e109.
205
44. Valles J, Alvarez-Lerma F, Palomar M, et al. Health-care-associated bloodstream infections at admission to the ICU. Chest 2011;139:810e815. 45. Corona A, Bertolini G, Lipman J, Wilson AP, Singer M. Antibiotic use and impact on outcome from bacteraemic critical illness: the BActeraemia Study in Intensive Care (BASIC). J Antimicrob Chemother 2010;65:1276e1285. 46. Shime N, Kosaka T, Fujita N. The importance of a judicious and early empiric choice of antimicrobial for methicillin-resistant Staphylococcus aureus bacteraemia. Eur J Clin Microbiol Infect Dis 2010;29:1475e1479. 47. Erbay A, Idil A, Gozel MG, Mumcuoglu I, Balaban N. Impact of early appropriate antimicrobial therapy on survival in Acinetobacter baumannii bloodstream infections. Int J Antimicrob Agents 2009;34:575e579. 48. 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. Crit Care Med 2006;34:1589e1596. 49. Shorr AF, Micek ST, Welch EC, Doherty JA, Reichley RM, Kollef MH. Inappropriate antibiotic therapy in Gram-negative sepsis increases hospital length of stay. Crit Care Med 2011;39:46e51. 50. Alexandraki I, Sullivan R, Zaiden R, et al. Blood culture isolates in hemodialysis vascular catheter-related bacteremia. Am J Med Sci 2008;336:297e302. 51. Choi G, Gomersall CD, Tian Q, Joynt GM, Freebairn R, Lipman J. Principles of antibacterial dosing in continuous renal replacement therapy. Crit Care Med 2009;37:2268e2282. 52. Nazarko L. Reducing the risk of catheter-related urinary tract infection. Br J Nurs 2008;17: 1002, 1004, 1006 passim. 53. Verdier R, Parer S, Jean-Pierre H, Dujols P, Picot MC. Impact of an infection control program in an intensive care unit in France. Infect Control Hosp Epidemiol 2006;27:60e66. 54. Ackad A, Simonian GT, Steel K, et al. A journey in reversing practice patterns: a multidisciplinary experience in implementing DOQI guidelines for vascular access. Nephrol Dial Transplant 2005;20:1450e1455. 55. Stevenson KB, Hannah EL, Lowder CA, et al. Epidemiology of hemodialysis vascular access infections from longitudinal infection surveillance data: predicting the impact of NKF-DOQI clinical practice guidelines for vascular access. Am J Kidney Dis 2002;39:549e555.