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Time to blood culture positivity in Staphylococcus aureus bacteremia: Association with 30-day mortality
Journal of Infection (2010) 61, 197e204
www.elsevierhealth.com/journals/jinf
Time to blood culture positivity in Staphylococcus aureus bacteremia: Association with 30-day mortality Joseph Kim a,*, Daniel B. Gregson a,b,c, Terry Ross c,d, Kevin B. Laupland a,b,c,d a
Division of Infectious Diseases, University of Calgary, 3500-26 Avenue NE, Calgary, AB, Canada T1Y 6J4 Department of Pathology and Laboratory Medicine, University of Calgary, 3535 Research Road NW, Calgary, AB, Canada T2L 2K8 c Calgary Laboratory Services, 3535 Research Road NW, Calgary, AB, Canada T2L 2K8 d Centre for Anti-Microbial Resistance, 3535 Research Road NW, Calgary, AB, Canada T2L 2K8 b
Accepted 7 June 2010 Available online 12 June 2010
KEYWORDS Staphylococcus aureus; Bacteremia; Time to positivity
Summary Objectives: Time to blood culture positivity (TTP) has been suggested as a prognostic factor for adverse clinical outcome. This study describes the relationship between TTP and clinical outcome in all patients with Staphylococcus aureus bacteremia (SAB) in a large Canadian health region. Methods: We performed a retrospective study of all first episodes of SAB occurring in the former Calgary Health Region (population w1.2 million) from July 1, 2006 to December 31, 2008. Results: Overall, 684 cases of SAB were evaluated. The median TTP was 16 h and 31/684 (5%) cases had TTP at >48 h. Time to positivity was shorter for methicillin-susceptible Staphylococcus aureus compared with methicillin-resistant S. aureus (MRSA) and for endovascular sources compared with other sources of infection. The overall 30-day case-fatality rate was 18% (124/ 684). Patients with delayed TTP (>48 h) suffered the highest case-fatality rate (39%) compared to those with earlier TTP (17%; P Z 0.002). Multivariable logistic regression modeling showed that age, nosocomial acquisition, MRSA, focus of infection, liver disease, and TTP 12 and >48 h were associated with 30-day mortality. Conclusion: Although uncommon, delayed TTP may be associated with increased mortality. Empiric antimicrobial therapy should continue beyond 48 h in patients at high risk for SAB. ª 2010 The British Infection Society. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Rm. 3A 151, Rockyview General Hospital, 7007-14 ST. SW, Calgary, AB, Canada T2V 1P9. Tel.: þ1 403 943 3255; fax: þ1 403 212 1235. E-mail address: [email protected] (J. Kim). 0163-4453/$36 ª 2010 The British Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2010.06.001
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Introduction Staphylococcus aureus is a ubiquitous but serious bacterial pathogen and is the second most common cause of bloodstream infections.1e3 Despite the availability of potent antimicrobial therapy in the last several decades, S. aureus bacteremia (SAB) is still associated with considerable morbidity and mortality.4 All-cause mortality associated with SAB is estimated to be approximately 20%.5e7 Several important clinical and epidemiologic factors have been examined to prognosticate adverse outcomes associated with SAB.8e11 Time to blood culture positivity (TTP), defined as time between onset of incubation and growth detection using an automated blood culture system, has been suggested as a surrogate marker for quantification of bacterial load12,13 and for adverse outcome in bloodstream infections.14,15 Whether earlier TTP in SAB translates into adverse clinical outcomes is still unclear. Only three studies have reported the relationship between TTP and clinical outcome in all SAB and indicated that earlier TTP is associated with increased mortality.16e18 However, these previous studies have each been single-centered and have been limited by small sample sizes or conducted in select populations. The purpose of this study was to describe the relationship between TTP and clinical outcome in all patients with SAB in a large Canadian health region.
Methods Study setting and protocol Prior to restructuring with Alberta Health Services in April 2009, the Calgary Health Region (CHR) encompassed the cities of Calgary and Airdrie and a large surrounding area (population 1.2 million) in the province of Alberta, Canada. With the exception of liver, heart, or lung transplantation, CHR administered all healthcare to its residents. All persons identified in the CHR with SAB between July 1, 2006 and December 31, 2008 were included in the study. The Conjoint Health Research Ethics Board at the University of Calgary (Calgary, Alberta, Canada) approved this study. Surveillance for S. aureus bacteremia was conducted by the Calgary Laboratory Services (CLS), a large regional laboratory that receives all blood samples submitted for culture from hospitals, long-term care facilities, and clinics in the CHR. Calgary Laboratory Services began routine reporting of TTP beginning in July 2006. Clinical data was obtained for all patients admitted to any of the four major acute-care hospitals (representing >95% of CHR admissions) by use of data from the regional corporate data warehouse. Data collected included demographic (age, gender), epidemiologic (nosocomial or community-onset), microbiological (antimicrobial resistance, TTP), clinical (source of infection, predisposing conditions), and outcome (length of hospitalization, 30-day mortality) variables. Long-term mortality data was obtained through linkage with the Death Registration Database maintained by Alberta Vital Statistics and the Alberta Health and Wellness registry of insured persons. Alberta Health and Wellness has information on all
J. Kim et al. residents of Alberta eligible for publically funded healthcare coverage (>99% of the population).
Definitions S. aureus bacteremia was defined as the isolation of S. aureus from 1 set of blood culture bottles. Among patients with multiple positive cultures, only the first episode of isolation within 365 days of methicillin-susceptible S. aureus (MSSA) or methicillin-resistant S. aureus (MRSA) was included in the analysis. Nosocomial bacteremias were those of which the first positive culture result was obtained 48 h after hospital admission or <48 h after discharge. Community-onset infections were those of which the first positive culture result was obtained <48 h after admission or 48 h after discharge from the hospital. These infections were further classified as health-care associated and community-acquired infections by use of the modification of definitions proposed by Freidman et al.7,19 Primary diagnosis of the source of S. aureus infection was categorized as previously described.20 An ICD-10 derived Charlson weighted index of co-morbidity (CWI) score was used to classify the severity of underlying co-morbid conditions.21,22
Microbiological methods All blood cultures were obtained by trained phelobotomists or registered nurses by use of a standardized sterile technique. Upon receipt, the blood culture bottles were placed in BacT/ALERT 3D blood culture system (bioMe ´rieux, France) at any time of the day. Each blood culture set consisted of an aerobic and anaerobic bottle with a volume of 10 mL per bottle. Time to positivity was defined as the first bottle in a set to be flagged positive. If multiple sets were inoculated in the same 24-hour period, the earliest time at which a bottle was flagged positive was used as the TTP. All isolates were confirmed to be S. aureus and tested for antimicrobial susceptibility by use of standard techniques according to Clinical and Laboratory Standards Institute (CLSI) guidelines.23 Methicillin-resistant S. aureus strains were confirmed by the presence of mecA gene by using multiplex polymerase chain reaction (PCR) assay.24
Statistical analysis Analysis was performed using Stata software (version 11.0; Stata Corporation). Non-normally distributed variables were reported as median values with interquartile ranges (IQRs) and were compared using the rank-sum test for pairs or the median test for multiple groups. Differences in proportions among categorical data were compared using the chi-square test. Risk was expressed as relative risks (RR) with 95% confidence intervals for univariate analysis. A multivariable logistic regression model was developed to assess factors associated with 30-day mortality. Time to positivity and all variables found to be significant to the p < 0.1 level in univariate analysis was included in the initial model. Backward stepwise variable elimination was then performed to develop the most parsimonious model. Interactions between TTP and each of the variables in the
Time to blood culture positivity in S. aureus bacteremia model were tested. Model calibration and discrimination was assessed by the HosmereLemeshow goodness of fit test and the area under the receiver operator characteristic curve. For all statistical comparisons, P < 0.05 was considered to denote statistical significance.
Results Descriptive epidemiology During the study period, 753 patients had at least one episode of S. aureus bacteremia and 13/753 patients had two episodes for a total of 766 cases. Basic demographic characteristics (age, gender, residency) were available for all but two patients. Microbiological and mortality outcome data were available for all cases. Additional clinical data including source of infection and underlying co-morbidities were available for the 684/766 (89%) cases managed at one of the four major acute-care centers in the CHR. This formed the main study cohort to examine characteristics associated with clinical outcomes. Among the 684 cases of S. aureus bacteremia, 275 (40%) were classified as nosocomial, 238 (35%) as health-care associated community-onset, and 171 (25%) as community-acquired. Of the 238 health-care associated cases, 78 (33%) had been recently managed in an Emergency Department, 35 (15%) seen in a specialized clinic, and 145 (61%) recently hospitalized. In addition, 58 (21%) cases were among dialysis patients, and 48 (20%) among residents of a long-term care facility. Methicillin-resistant S. aureus constituted 191 (28%) cases. The median age of the cohort was 61.5 (IQR, 46.7e75.8) years and 422/684 (62%) cases occurred in males. The majority (488/684; 71%) of patients with SAB had underlying co-morbid conditions. The demographic and clinical data of 684 hospitalized patients are summarized in Table 1.
Determinants of time to positivity The overall median TTP was 16 (IQR, 13e20) hours; 26% (175/684) of cases were positive at 0e12 h, 58% (395/684) at 12e24 h, 12% (83/684) at 24e48 h, and 5% (31/684) at >48 h. The distribution of TTP is shown in Fig. 1. The median TTP was shorter for MSSA isolates (15; IQR, 12e20 h) compared with MRSA isolates (17; IQR, 13e22 h; P Z 0.015). Among 684 cases with primary diagnosis of SAB, median TTP was significantly shorter with endovascular source (11; IQR, 9e13 h) compared with other sources of infection (16; IQR, 13e21 h; P < 0.001). The proportion of TTP categories by primary diagnosis of SAB is shown in Fig. 2.
Clinical outcome The overall median length of hospitalization was 20.6 days (IQR, 9.8e43.6 days). It did not differ significantly between groups stratified by TTP (P Z 0.78). The in-hospital, 30-day, and 90-day all cause case-fatality rates were 21% (141/ 684), 18% (124/684), and 25% (174/684), respectively. Patients who died were older (median age 75 vs. 59 years;
199 P < 0.001) and had a higher median CWI score (3 vs. 2; P Z 0.001). Factors associated with 30-day mortality are shown in Table 2. Patients with heart or liver disease, primary bacteremia or pneumonia had significantly higher death rates compared to those who did not. Although the median TTP was not significantly different among those who died as compared to those who survived to 30 days (16 vs. 16 h; P Z 0.39), patients who had delayed TTP >48 h suffered the highest case-fatality rate (Table 2). By multivariate analysis, older age, nosocomial acquisition, pneumonia, presumed endovascular source, MRSA, and the presence of liver disease were found to be significantly associated with 30-day mortality (Table 3). Compared to patients who had TTP12 h, those with delayed TTP>48 h had a 2.6-fold increase in odds of 30-day mortality.
Discussion This study is the largest to date examining the relationship between TTP and mortality in all patients with SAB. The study cohort included pediatric population as well as adult patients with community-onset and nosocomial SAB at multiple centers within the CHR. We report clinical and microbiological characteristics associated with mortality at 30 days. We also present novel data regarding the association between delayed TTP and increased 30-day mortality. Several findings in our multivariate analysis are worth noting. As in previous studies, older age was associated with increased mortality.5,9e11 Interestingly, the presence of liver disease was also found to be an independent predictor of mortality, while a higher CWI score was not. Liver disease alone has been shown to be a risk factor for SAB,7 but its association with mortality independent of a composite co-morbidity score has not been reported. Our observation contrasts other studies that have attributed increased mortality to the severity of co-morbid conditions using validated scores10,25 and suggests that age may be the primary determinant of adverse clinical outcome in SAB. Our study also confirms prior findings that pneumonia, presumed endovascular source, nosocomial acquisition, and MRSA are independently associated with increased mortality in SAB.5,10,26e28 To our knowledge, there are only three studies with which to compare our findings regarding TTP. First, Khatib et al. conducted a prospective cohort study involving 312 adult patients with SAB in one tertiary-care center.16 The main objective of their study was to correlate TTP with the source of infection and clinical outcomes. The patients were followed for 100 days after the initial SAB episode for clinical outcomes including relapse and death. As in our study, shortest TTP was associated with an endovascular source of infection. By multivariate logistic regression analysis, earlier TTP (defined as 14 h) was an independent predictor of endovascular source of infection, metastatic infection, extended bacteremia, and attributable mortality. However, they did not report other characteristics associated with mortality in their analysis. Although the median age of their patient cohort was similar to ours (60 vs. 62 years), a higher proportion of their patients (97%) had an underlying co-morbid condition with over 50% reporting to
200
J. Kim et al.
Table 1 Demographic and clinical characteristics among 684 patients with Staphylococcus aureus bacteremia categorized by time to positivity. Characteristic
Total
Time to positivity categories (hours)
Total (N Z 684)
0-12 (N Z 175)
>12-24 (N Z 395)
422 (61.7)
109 (62.3)
242 (61.3)
Age 65
61.5 (46.7e75.8) 307 (44.9)
60.6 (47.0e73.6) 71 (40.1)
61.2 (45.8e75.1) 177 (44.8)
Acquisition Nosocomial Health-care associated Community acquired MRSA
275 238 171 191
(40.2) (34.8) (25.0) (27.9)
65 57 53 43
(37.1) (32.6) (30.3) (24.6)
161 138 96 114
(40.8) (34.9) (24.3) (28.9)
35 33 15 25
Source of infection Primary bacteremia Respiratory Soft tissue Bone and joint Endocarditis Intra-abdominal/pelvic CNS Other
283 113 104 94 36 45 4 5
(41.4) (16.5) (15.2) (13.7) (5.3) (6.6) (0.6) (0.7)
82 (46.9) 20 (11.4) 29 (16.6) 11(6.3) 25 (14.3) 5 (2.9) 2 (1.1) 1 (0.6)
160 65 62 64 11 28 1 4
(40.5) (16.5) (15.7) (16.2) (2.8) (7.1) (0.3) (1.0)
29 (34.9) 20 (24.1) 11 (13.3) 15 (18.1) 0 8 (9.6) 0 0
12 (38.7) 8 (25.8) 2 (6.5) 4 (12.9) 0 4 (12.9) 1 (3.2) 0
0.28 0.03 0.49 0.009 <0.001 0.04 0.09 1.0
Co-morbid condition Any CWI 3 Heart disease Stroke COPD Liver disease Renal disease Diabetes Cancer HIV infection
488 252 130 32 70 64 122 169 111 11
(71.3) (36.8) (19.0) (4.7) (10.2) (9.4) (17.8) (24.7) (16.2) (1.6)
277 134 74 10 48 37 54 84 65 9
(70.1) (33.9) (18.7) (2.5) (12.2) (9.4) (13.7) (21.3) (16.5) (1.8)
60 31 15 7 12 6 12 20 12 2
22 (71.0) 16 (51.6) 4 (12.9) 3 (9.7) 1 (3.2) 4 (12.9) 3 (9.7) 11 (35.5) 9 (29.0) 0
0.86 0.14 0.72 0.02 0.02 0.82 <0.001 0.046 0.22 0.77
Gender Male Age, years Median age (IQR), yrs
129 71 37 12 9 17 53 54 25 2
(73.7) (40.6) (21.1) (6.9) (5.1) (9.7) (30.3) (30.9) (14.3) (1.1)
>24-48 (N Z 83)
>48 (N Z 31)
P
54 (65.0)
17 (54.8)
0.78
70.5 (54.9e80.3) 46 (55.4)
60.4 (46.6e79.1) 13 (41.9)
0.33
(42.1) (39.8) (18.1) (30.1)
(72.2) (37.4) (18.1) (8.4) (14.5) (7.2) (14.5) (24.1) (14.5) (2.4)
14 10 7 9
(45.2) (32.2) (22.6) (29.0)
0.16 0.76 0.71 0.18 0.71
Data are presented as n (%), unless otherwise stated. IQR, interquartile range; MRSA, methicillin-resistant Staphylococcus aureus; CNS, central nervous system; CWI, Charlson weighted index of co-morbidity score; COPD, chronic obstructive pulmonary disease; HIV, human immuno-deficiency virus.
have cardiac disease compared with our patient cohort where 71% had an underlying co-morbid condition and 19% cardiac disease. Moreover, the rate of MRSA at 52% was much higher than that observed in our study (28%). The second study was a retrospective case-control study by Marra et al. where 91 cases of SAB admitted to an adult tertiary-care center were evaluated. In addition to TTP (dichotomized into 12 h and >12 h), detailed clinical characteristics including patient location (ward vs. intensive care unit), antimicrobial use, and presence of neutropenia, and organ failure were assessed for association with in-hospital mortality.17 The median TTP observed in their study was much lower at 12 h compared to the median TTP of 16 h in our study. In contrast to our study, they found no significant difference in TTP between MSSA and MRSA. They also used CWI score to quantify the severity of underlying co-morbid conditions and showed that there was
a significant difference in the proportion of patients who had CWI score 3 between the TTP categories. The reported overall mortality of 14% was lower than observed in our study. By multivariate analysis, a seven-fold increase in odds of in-hospital mortality was observed among 44 patients with TTP 12 h compared with 47 patients with TTP > 12 h. Failure of at least one organ system, CWI score 3, and MRSA were also reported as independent predictors of mortality. In contrast to our study findings, older age, nosocomial acquisition, and endovascular source of infection were not associated with increased mortality. Interestingly, inadequate empiric antimicrobial therapy was not a predictor of mortality. Finally, a single-centered retrospective analysis of 146 patients with SAB was done by Sowden et al.18 In their brief report, complete details regarding underlying co-morbid illnesses and the sources of infection were not provided. A
60 0
20
40
Frequency
80
100
120
Time to blood culture positivity in S. aureus bacteremia
0
10
20
30
40
50
60
70
80
90
100
Time to Positivity (hours)
Figure 1 Distribution of time to blood culture positivity in 684 episodes of Staphylococcus aureus bacteremia
higher overall 30-day mortality of 23.3% was reported. By multivariate analysis, TTP 12 h and the presence of comorbid illnesses as defined by CWI score was also associated with increased 30-day mortality, while adequate antibiotic therapy within 24 h was protective. No specific underlying co-morbid illness or source of infection was associated with increased mortality. Their analysis, however, was limited only to community-acquired cases of MSSA bacteremia. All of the previous studies reported a significant association between earlier TTP (using cutoff times of 14 or 12 h) and mortality. One of the hypotheses for this observation has been the correlation between higher bacterial load and earlier TTP.12,13 It has been extrapolated that earlier TTP, reflecting a more severe bacteremia, would translate into adverse clinical outcomes including metastatic infection and death.16 Consistent with prior findings, our multivariate analysis also showed that relative to the intermediate TTP
201 (>12e48 h), the odds of 30-day mortality was higher in cases with earlier TTP (12 h). Interestingly, longer TTP (>48 h) was also associated with the highest case-fatality rate at 30 days (similar trends for 90 day mortality). Thus, we observed that there was no linear relationship between TTP and 30-day mortality and identified another patient population at higher risk of death. Our key finding of the association between delayed TTP and increased 30-day mortality has not been reported in previous studies. This may be in part due to their smaller study sample sizes, thus very few cases would have had TTP beyond 48 h. The reasons for our observation are unclear. Patients with delayed TTP had a trend towards greater proportion of CWI score 3 compared with shorter TTP (P Z 0.08). However, other potential confounders such as age, proportion of MRSA, nosocomial infection, and source of infection did not differ significantly between the TTP categories. We could not determine whether those with TTP > 48 h were more likely to have a metastatic focus compared to those with shorter TTP. We could not find any significant difference between those who died with TTP > 48 h and with TTP 48 h related to their clinical characteristics, time to death from blood cultures being drawn, and source of infection (data not shown). A possible explanation for our main finding is that this group represents those patients with low-grade bacteremia, whose clinical presentation may not have been severe. As such, empiric antimicrobial therapy may have been delayed or prematurely stopped once the cultures were reported as negative at 24e48 h. Inappropriate or delayed antimicrobial therapy has been shown to be associated with adverse outcome in SAB.29,30 We did not have data regarding antimicrobial utilization in our study and hence this inference could not be verified. Another reason could be that delayed TTP reflects an occult source of infection and failure to eradicate the source of infection is associated with increased mortality.
Figure 2 Proportion of time to positivity categories by primary diagnosis in 684 patients with Staphylococcus aureus bacteremia. SST, skin and soft tissue; BSI, bloodstream infection; IAB, intrabdominal/pelvic; CNS, central nervous system
202 Table 2
J. Kim et al. Univariate analysis of risk factors for 30-day case-fatality in 684 patients with Staphylococcus aureus bacteremia.
Variable
Deaths/no. with variable (%)
Deaths/no. without variable (%)
RR (95%CI)
P
2.8 (1.96e3.95) 0.95 (0.69e1.32)
<0.001 0.76
Demographic Age 65 Male
86/307 (28.0) 75/422 (17.8)
Microbiological MRSA Nosocomial Healthcare-associated Community-acquired
48/191 69/275 37/238 18/171
(25.1) (25.1) (15.6) (10.5)
76/493 55/409 87/446 106/513
(15.4) (13.5) (19.5) (20.7)
1.6 1.9 0.8 0.5
(1.18e2.25) (1.36e2.57) (0.56e1.13) (0.32e0.81)
0.003 <0.001 0.2 0.003
Co-morbid condition Heart disease Stroke COPD Liver disease Renal disease Diabetes Cancer HIV infection CWI 3
33/130 10/32 19/70 20/64 26/122 34/169 21/111 1/11 63/252
(25.4) (31.3) (27.1) (31.3) (21.3) (20.1) (18.9) (9.1) (25.0)
91/554 114/652 105/614 104/620 98/562 90/515 103/573 123/673 61/432
(16.4) (17.5) (17.1) (16.8) (17.4) (17.5) (18.0) (18.3) (14.1)
1.5 1.8 1.6 1.9 1.2 1.2 1.1 0.5 1.8
(1.09e2.19) (1.04e3.07) (1.04e2.42) (1.24e2.79) (0.83e1.80) (0.81e1.64) (0.69e1.61) (0.08e3.25) (1.29e2.43)
0.017 0.049 0.039 0.004 0.31 0.44 0.81 0.43 <0.001
Source of infection Primary bacteremia Soft tissue Bone and joint Respiratory Endocarditis Intra-abdominal/pelvic CNS
63/283 9/104 5/94 32/113 6/36 8/45 1/4
(22.3) (8.7) (5.3) (28.3) (16.7) (17.8) (25.0)
61/401 115/580 119/590 92/571 118/648 116/639 123/680
(15.2) (19.8) (20.2) (16.1) (18.2) (18.2) (18.1)
1.5 0.4 0.3 1.8 0.97 1.0 1.4
(1.07e2.01) (0.23e0.83) (0.11e0.63) (1.24e2.49) (0.43e1.93) (0.51e1.88) (0.25e7.60)
0.018 0.007 <0.001 0.002 0.82 0.95 0.72
Time to positivity TTP 12 h TTP > 12e24 h TTP > 24e48 h TTP > 48 h
37/175 59/395 16/83 12/31
(21.1) (14.9) (19.3) (38.7)
87/509 65/289 108/601 112/653
(17.1) (22.5) (18.0) (17.2)
1.2 0.7 1.1 2.3
(0.88e1.75) (0.48e0.91) (0.67e1.72) (1.41e3.63)
0.23 0.011 0.77 0.002
38/377 (10.1) 49/262 (18.7)
Data are presented as n (%), unless otherwise stated. RR, relative risk; CI, confidence interval; MRSA, methicillin-resistant Staphylococcus aureus; COPD, chronic obstructive pulmonary disease; HIV, human immuno-deficiency virus; CWI, Charlson weighted index of comorbidity score; CNS, central nervous system; TTP, time to positivity.
Our study had several limitations. Although a larger sample size and all age cohorts were included in the study, we were not able to ascertain detailed clinical information. The determination of primary diagnoses was done by ICD codes and could not be prospectively confirmed with use of standardized tests such as an echocardiogram for the diagnosis of endocarditis. In addition, we could not separate those who had catheter-related SAB from those without a focus among primary bacteremia cases. Our inability to make this distinction may have had an impact on overall mortality rates among TTP categories since SAB with a removable focus will likely have a more favorable outcome if the focus is removed.31 It is possible that many of the patients with TTP between 12 and 48 h could have had catheter-related SAB, which may explain the lower 30-day mortality rate. However, the overall proportions of primary bacteremia diagnosis did not differ significantly between the TTP categories. While it is the recommended protocol to obtain blood cultures prior to initiation of
antimicrobial treatment in our health region, we could not exclude those cases where empiric antimicrobial therapy was initiated prior to blood cultures being drawn, which would have impacted the time to blood culture positivity. Finally, this was a retrospective study. In conclusion, we confirm that certain patient and microbiological characteristics are associated with a higher risk of death in SAB. Moreover, delayed TTP may be associated with increased 30-day mortality in SAB. This may have important clinical implications. Negative blood culture results at 24e48 h should not prompt immediate discontinuation of empiric antimicrobial treatment in patients with suspected SAB. Further prospective studies are needed to evaluate optimal therapeutic options for patients with SAB and high risk of adverse outcome.
Funding No external funding was received in support of this study.
Time to blood culture positivity in S. aureus bacteremia Table 3 Logistic regression modeling of factors associated with 30-day mortality. Factor
OR (95%CI)
P
Age (per decade) Nosocomial
1.58 (1.38e1.82) 1.87 (1.19e2.92)
<0.001 0.006
Diagnosis Other Pneumonia Endocarditis/primary bacteremia Co-morbid condition Liver disease
1 (reference) 3.31 (1.75e6.27) 1.98 (1.14e3.45)
<0.001 0.016
3.14 (1.62e6.09)
0.001
Methicillin sensitivity MSSA MRSA
1.0 (reference) 1.66 (1.06e2.61)
0.028
Time to positivity 12 h >12e48 h >48 h
1.0 (reference) 0.57 (0.35e0.93) 2.57 (1.02e6.48)
0.023 0.045
The model (n Z 684) had good calibration (HosmereLemeshow goodness of fit p Z 0.41) and discrimination (area under receiver operator characteristic curve 0.776). OR, odds ratio; CI, confidence interval; MSSA, methicillin-sensitive Staphylococcus aureus; MRSA, methicillin-resistant Staphylococcus aureus.
Conflict of interest None of the authors have professional, personal, or financial conflicts of interest to report.
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203 8. Mylotte JM, Aeschlimann JR, Rotella DL. Staphylococcus aureus bacteremia: factors predicting hospital mortality. Infect Control Hosp Epidemiol 1996;17:165e8. 9. McClelland RS, Fowler VG, Sanders LL, Gottlieb G, Kong LK, Sexton D, et al. Staphylococcus aureus bacteremia among elderly vs. younger adult patients: comparison of clinical features and mortality. Arch Intern Med 1999;159:1244e7. 10. Mylotte JM, Tayara A. Staphylococcus aureus bacteremia: predictors of 30-day mortality in a large cohort. Clin Infect Dis 2000;31:1170e4. 11. Jensen AG, Wachmann CH, Espersen F, Scheibel J, Skinhøj P, Frimodt-Møller N. Treatment and outcome of Staphylococcus aureus bacteremia: a prospective study of 278 cases. Arch Intern Med 2002;162:25e32. 12. Blot F, Schmidt E, Nitenberg G, Tancrede C, Leclercq B, Laplanche A, et al. Earlier positivity of central-venous- versus peripheral-blood cultures is highly predictive of catheter-related sepsis. J Clin Microbiol 1998;36:105e9. 13. Rogers MS, Oppenheim BA. The use of continuous monitoring blood culture systems in the diagnosis of catheter related sepsis. J Clin Pathol 1998;51:635e7. 14. Norris CF, Smith-Whitley K, McGowan KL. Positive blood cultures in sickle cell disease: time to positivity and clinical outcome. J Pediatr Hematol Oncol 2003;25:390e5. 15. Ruimy R, Armand-Lefevre L, Andremont A. Short time to positivity in blood culture with clustered gram-positive cocci on direct smear examination is highly predictive of Staphylococcus aureus. Am J Infect Control 2005;33:304e6. 16. Khatib R, Riederer K, Saeed S, Johnson LB, Fakih MG, Sharma M, et al. Time to positivity in Staphylococcus aureus bacteremia: possible correlation with the source and outcome of infection. Clin Infect Dis 2005;41:594e8. 17. Marra AR, Edmond MB, Forbes BA, Wenzel RP, Bearman GM. Time to blood culture positivity as a predictor of clinical outcome of Staphylococcus aureus bloodstream infection. J Clin Microbiol 2006;44:1342e6. 18. Sowden D, Anstey C, Faddy M. Blood culture time to positivity as a predictor of mortality in community acquired methicillinsusceptible Staphylococcus aureus bacteremia. J Infect: 295e6, 10.1016/j.jinf.2008.01.011, 2008;56. 19. Friedman ND, Kaye KS, Stout JE, McGarry SA, Trivette SL, Briggs JP, et al. Health careeassociated bloodstream infections in adults: a reason to change the accepted definition of community-acquired infections. Ann Intern Med 2002;137:791e7. 20. Laupland KB, Church DL, Mucenski M, Sutherland LR, Davies HD. Population-based study of the epidemiology of and the risk factors for invasive Staphylococcus aureus infections. J Infect Dis 2003;187:1452e9. 21. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 40:373e83. 22. Quan H, Sundararajan V, Halfon P, Fong A, Burnand B, Luthi JC, et al. Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data. Med Care 2005;43:1130e9. 23. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing. 17th informational supplement. CLSI document MS 100-S17. Wayne, PA: CLSI; 2007. 24. Vannuffel P, Gigi J, Ezzedine H, Vandercam B, Delmee M, Wauters G, et al. Specific detection of methicillin-resistant Staphylococcus aureus species by multiplex PCR. J Clin Microbiol 1995;33:2864e7. 25. Lesens O, Methlin C, Hansmann Y, Remy V, Martinot M, Bergin C, et al. Role of comorbidity in mortality related to Staphylococcus aureus bacteremia: a prospective study using the Charlson weighted index of comorbidity. Infect Control Hosp Epidemiol 2003;24:890e6.
204 26. Conterno LO, Wey SB, Castelo A. Risk factors for mortality in Staphylococcus aureus bacteremia. Infect Control Hosp Epidemiol 1998;19:32e7. 27. Cosgrove SE, Sakoulas G, Perencevich EN, Schwaber MJ, Karchmer AW, Carmeli Y. Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: a meta-analysis. Clin Infect Dis 2003;36:53e9. 28. Turnidge JD, Kotsanas D, Munckhof W, Roberts S, Bennett CM, Nimmo GR, et al. Staphylococcus aureus bacteraemia: a major cause of mortality in Australia and New Zealand. Med J Aust 2009;191:368e73.
J. Kim et al. 29. Lodise TP, McKinnon PS, Swiderski L, Rybak MJ. Outcomes analysis of delayed antibiotic treatment for hospital-acquired Staphylococcus aureus bacteremia. Clin Infect Dis 2003;36:1418e23. 30. Khatib R, Saeed S, Sharma M, Riederer K, Fakih MG, Johnson LB. Impact of initial antibiotic choice and delayed appropriate treatment on the outcome of Staphylococcus aureus bacteremia. Eur J Clin Microbiol Infect Dis 2006;25:181e5. 31. Mermel L, Allon M, Bouza E, Craven DE, Flynn P, O’Grady NP, 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.
www.elsevierhealth.com/journals/jinf
Time to blood culture positivity in Staphylococcus aureus bacteremia: Association with 30-day mortality Joseph Kim a,*, Daniel B. Gregson a,b,c, Terry Ross c,d, Kevin B. Laupland a,b,c,d a
Division of Infectious Diseases, University of Calgary, 3500-26 Avenue NE, Calgary, AB, Canada T1Y 6J4 Department of Pathology and Laboratory Medicine, University of Calgary, 3535 Research Road NW, Calgary, AB, Canada T2L 2K8 c Calgary Laboratory Services, 3535 Research Road NW, Calgary, AB, Canada T2L 2K8 d Centre for Anti-Microbial Resistance, 3535 Research Road NW, Calgary, AB, Canada T2L 2K8 b
Accepted 7 June 2010 Available online 12 June 2010
KEYWORDS Staphylococcus aureus; Bacteremia; Time to positivity
Summary Objectives: Time to blood culture positivity (TTP) has been suggested as a prognostic factor for adverse clinical outcome. This study describes the relationship between TTP and clinical outcome in all patients with Staphylococcus aureus bacteremia (SAB) in a large Canadian health region. Methods: We performed a retrospective study of all first episodes of SAB occurring in the former Calgary Health Region (population w1.2 million) from July 1, 2006 to December 31, 2008. Results: Overall, 684 cases of SAB were evaluated. The median TTP was 16 h and 31/684 (5%) cases had TTP at >48 h. Time to positivity was shorter for methicillin-susceptible Staphylococcus aureus compared with methicillin-resistant S. aureus (MRSA) and for endovascular sources compared with other sources of infection. The overall 30-day case-fatality rate was 18% (124/ 684). Patients with delayed TTP (>48 h) suffered the highest case-fatality rate (39%) compared to those with earlier TTP (17%; P Z 0.002). Multivariable logistic regression modeling showed that age, nosocomial acquisition, MRSA, focus of infection, liver disease, and TTP 12 and >48 h were associated with 30-day mortality. Conclusion: Although uncommon, delayed TTP may be associated with increased mortality. Empiric antimicrobial therapy should continue beyond 48 h in patients at high risk for SAB. ª 2010 The British Infection Society. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Rm. 3A 151, Rockyview General Hospital, 7007-14 ST. SW, Calgary, AB, Canada T2V 1P9. Tel.: þ1 403 943 3255; fax: þ1 403 212 1235. E-mail address: [email protected] (J. Kim). 0163-4453/$36 ª 2010 The British Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2010.06.001
198
Introduction Staphylococcus aureus is a ubiquitous but serious bacterial pathogen and is the second most common cause of bloodstream infections.1e3 Despite the availability of potent antimicrobial therapy in the last several decades, S. aureus bacteremia (SAB) is still associated with considerable morbidity and mortality.4 All-cause mortality associated with SAB is estimated to be approximately 20%.5e7 Several important clinical and epidemiologic factors have been examined to prognosticate adverse outcomes associated with SAB.8e11 Time to blood culture positivity (TTP), defined as time between onset of incubation and growth detection using an automated blood culture system, has been suggested as a surrogate marker for quantification of bacterial load12,13 and for adverse outcome in bloodstream infections.14,15 Whether earlier TTP in SAB translates into adverse clinical outcomes is still unclear. Only three studies have reported the relationship between TTP and clinical outcome in all SAB and indicated that earlier TTP is associated with increased mortality.16e18 However, these previous studies have each been single-centered and have been limited by small sample sizes or conducted in select populations. The purpose of this study was to describe the relationship between TTP and clinical outcome in all patients with SAB in a large Canadian health region.
Methods Study setting and protocol Prior to restructuring with Alberta Health Services in April 2009, the Calgary Health Region (CHR) encompassed the cities of Calgary and Airdrie and a large surrounding area (population 1.2 million) in the province of Alberta, Canada. With the exception of liver, heart, or lung transplantation, CHR administered all healthcare to its residents. All persons identified in the CHR with SAB between July 1, 2006 and December 31, 2008 were included in the study. The Conjoint Health Research Ethics Board at the University of Calgary (Calgary, Alberta, Canada) approved this study. Surveillance for S. aureus bacteremia was conducted by the Calgary Laboratory Services (CLS), a large regional laboratory that receives all blood samples submitted for culture from hospitals, long-term care facilities, and clinics in the CHR. Calgary Laboratory Services began routine reporting of TTP beginning in July 2006. Clinical data was obtained for all patients admitted to any of the four major acute-care hospitals (representing >95% of CHR admissions) by use of data from the regional corporate data warehouse. Data collected included demographic (age, gender), epidemiologic (nosocomial or community-onset), microbiological (antimicrobial resistance, TTP), clinical (source of infection, predisposing conditions), and outcome (length of hospitalization, 30-day mortality) variables. Long-term mortality data was obtained through linkage with the Death Registration Database maintained by Alberta Vital Statistics and the Alberta Health and Wellness registry of insured persons. Alberta Health and Wellness has information on all
J. Kim et al. residents of Alberta eligible for publically funded healthcare coverage (>99% of the population).
Definitions S. aureus bacteremia was defined as the isolation of S. aureus from 1 set of blood culture bottles. Among patients with multiple positive cultures, only the first episode of isolation within 365 days of methicillin-susceptible S. aureus (MSSA) or methicillin-resistant S. aureus (MRSA) was included in the analysis. Nosocomial bacteremias were those of which the first positive culture result was obtained 48 h after hospital admission or <48 h after discharge. Community-onset infections were those of which the first positive culture result was obtained <48 h after admission or 48 h after discharge from the hospital. These infections were further classified as health-care associated and community-acquired infections by use of the modification of definitions proposed by Freidman et al.7,19 Primary diagnosis of the source of S. aureus infection was categorized as previously described.20 An ICD-10 derived Charlson weighted index of co-morbidity (CWI) score was used to classify the severity of underlying co-morbid conditions.21,22
Microbiological methods All blood cultures were obtained by trained phelobotomists or registered nurses by use of a standardized sterile technique. Upon receipt, the blood culture bottles were placed in BacT/ALERT 3D blood culture system (bioMe ´rieux, France) at any time of the day. Each blood culture set consisted of an aerobic and anaerobic bottle with a volume of 10 mL per bottle. Time to positivity was defined as the first bottle in a set to be flagged positive. If multiple sets were inoculated in the same 24-hour period, the earliest time at which a bottle was flagged positive was used as the TTP. All isolates were confirmed to be S. aureus and tested for antimicrobial susceptibility by use of standard techniques according to Clinical and Laboratory Standards Institute (CLSI) guidelines.23 Methicillin-resistant S. aureus strains were confirmed by the presence of mecA gene by using multiplex polymerase chain reaction (PCR) assay.24
Statistical analysis Analysis was performed using Stata software (version 11.0; Stata Corporation). Non-normally distributed variables were reported as median values with interquartile ranges (IQRs) and were compared using the rank-sum test for pairs or the median test for multiple groups. Differences in proportions among categorical data were compared using the chi-square test. Risk was expressed as relative risks (RR) with 95% confidence intervals for univariate analysis. A multivariable logistic regression model was developed to assess factors associated with 30-day mortality. Time to positivity and all variables found to be significant to the p < 0.1 level in univariate analysis was included in the initial model. Backward stepwise variable elimination was then performed to develop the most parsimonious model. Interactions between TTP and each of the variables in the
Time to blood culture positivity in S. aureus bacteremia model were tested. Model calibration and discrimination was assessed by the HosmereLemeshow goodness of fit test and the area under the receiver operator characteristic curve. For all statistical comparisons, P < 0.05 was considered to denote statistical significance.
Results Descriptive epidemiology During the study period, 753 patients had at least one episode of S. aureus bacteremia and 13/753 patients had two episodes for a total of 766 cases. Basic demographic characteristics (age, gender, residency) were available for all but two patients. Microbiological and mortality outcome data were available for all cases. Additional clinical data including source of infection and underlying co-morbidities were available for the 684/766 (89%) cases managed at one of the four major acute-care centers in the CHR. This formed the main study cohort to examine characteristics associated with clinical outcomes. Among the 684 cases of S. aureus bacteremia, 275 (40%) were classified as nosocomial, 238 (35%) as health-care associated community-onset, and 171 (25%) as community-acquired. Of the 238 health-care associated cases, 78 (33%) had been recently managed in an Emergency Department, 35 (15%) seen in a specialized clinic, and 145 (61%) recently hospitalized. In addition, 58 (21%) cases were among dialysis patients, and 48 (20%) among residents of a long-term care facility. Methicillin-resistant S. aureus constituted 191 (28%) cases. The median age of the cohort was 61.5 (IQR, 46.7e75.8) years and 422/684 (62%) cases occurred in males. The majority (488/684; 71%) of patients with SAB had underlying co-morbid conditions. The demographic and clinical data of 684 hospitalized patients are summarized in Table 1.
Determinants of time to positivity The overall median TTP was 16 (IQR, 13e20) hours; 26% (175/684) of cases were positive at 0e12 h, 58% (395/684) at 12e24 h, 12% (83/684) at 24e48 h, and 5% (31/684) at >48 h. The distribution of TTP is shown in Fig. 1. The median TTP was shorter for MSSA isolates (15; IQR, 12e20 h) compared with MRSA isolates (17; IQR, 13e22 h; P Z 0.015). Among 684 cases with primary diagnosis of SAB, median TTP was significantly shorter with endovascular source (11; IQR, 9e13 h) compared with other sources of infection (16; IQR, 13e21 h; P < 0.001). The proportion of TTP categories by primary diagnosis of SAB is shown in Fig. 2.
Clinical outcome The overall median length of hospitalization was 20.6 days (IQR, 9.8e43.6 days). It did not differ significantly between groups stratified by TTP (P Z 0.78). The in-hospital, 30-day, and 90-day all cause case-fatality rates were 21% (141/ 684), 18% (124/684), and 25% (174/684), respectively. Patients who died were older (median age 75 vs. 59 years;
199 P < 0.001) and had a higher median CWI score (3 vs. 2; P Z 0.001). Factors associated with 30-day mortality are shown in Table 2. Patients with heart or liver disease, primary bacteremia or pneumonia had significantly higher death rates compared to those who did not. Although the median TTP was not significantly different among those who died as compared to those who survived to 30 days (16 vs. 16 h; P Z 0.39), patients who had delayed TTP >48 h suffered the highest case-fatality rate (Table 2). By multivariate analysis, older age, nosocomial acquisition, pneumonia, presumed endovascular source, MRSA, and the presence of liver disease were found to be significantly associated with 30-day mortality (Table 3). Compared to patients who had TTP12 h, those with delayed TTP>48 h had a 2.6-fold increase in odds of 30-day mortality.
Discussion This study is the largest to date examining the relationship between TTP and mortality in all patients with SAB. The study cohort included pediatric population as well as adult patients with community-onset and nosocomial SAB at multiple centers within the CHR. We report clinical and microbiological characteristics associated with mortality at 30 days. We also present novel data regarding the association between delayed TTP and increased 30-day mortality. Several findings in our multivariate analysis are worth noting. As in previous studies, older age was associated with increased mortality.5,9e11 Interestingly, the presence of liver disease was also found to be an independent predictor of mortality, while a higher CWI score was not. Liver disease alone has been shown to be a risk factor for SAB,7 but its association with mortality independent of a composite co-morbidity score has not been reported. Our observation contrasts other studies that have attributed increased mortality to the severity of co-morbid conditions using validated scores10,25 and suggests that age may be the primary determinant of adverse clinical outcome in SAB. Our study also confirms prior findings that pneumonia, presumed endovascular source, nosocomial acquisition, and MRSA are independently associated with increased mortality in SAB.5,10,26e28 To our knowledge, there are only three studies with which to compare our findings regarding TTP. First, Khatib et al. conducted a prospective cohort study involving 312 adult patients with SAB in one tertiary-care center.16 The main objective of their study was to correlate TTP with the source of infection and clinical outcomes. The patients were followed for 100 days after the initial SAB episode for clinical outcomes including relapse and death. As in our study, shortest TTP was associated with an endovascular source of infection. By multivariate logistic regression analysis, earlier TTP (defined as 14 h) was an independent predictor of endovascular source of infection, metastatic infection, extended bacteremia, and attributable mortality. However, they did not report other characteristics associated with mortality in their analysis. Although the median age of their patient cohort was similar to ours (60 vs. 62 years), a higher proportion of their patients (97%) had an underlying co-morbid condition with over 50% reporting to
200
J. Kim et al.
Table 1 Demographic and clinical characteristics among 684 patients with Staphylococcus aureus bacteremia categorized by time to positivity. Characteristic
Total
Time to positivity categories (hours)
Total (N Z 684)
0-12 (N Z 175)
>12-24 (N Z 395)
422 (61.7)
109 (62.3)
242 (61.3)
Age 65
61.5 (46.7e75.8) 307 (44.9)
60.6 (47.0e73.6) 71 (40.1)
61.2 (45.8e75.1) 177 (44.8)
Acquisition Nosocomial Health-care associated Community acquired MRSA
275 238 171 191
(40.2) (34.8) (25.0) (27.9)
65 57 53 43
(37.1) (32.6) (30.3) (24.6)
161 138 96 114
(40.8) (34.9) (24.3) (28.9)
35 33 15 25
Source of infection Primary bacteremia Respiratory Soft tissue Bone and joint Endocarditis Intra-abdominal/pelvic CNS Other
283 113 104 94 36 45 4 5
(41.4) (16.5) (15.2) (13.7) (5.3) (6.6) (0.6) (0.7)
82 (46.9) 20 (11.4) 29 (16.6) 11(6.3) 25 (14.3) 5 (2.9) 2 (1.1) 1 (0.6)
160 65 62 64 11 28 1 4
(40.5) (16.5) (15.7) (16.2) (2.8) (7.1) (0.3) (1.0)
29 (34.9) 20 (24.1) 11 (13.3) 15 (18.1) 0 8 (9.6) 0 0
12 (38.7) 8 (25.8) 2 (6.5) 4 (12.9) 0 4 (12.9) 1 (3.2) 0
0.28 0.03 0.49 0.009 <0.001 0.04 0.09 1.0
Co-morbid condition Any CWI 3 Heart disease Stroke COPD Liver disease Renal disease Diabetes Cancer HIV infection
488 252 130 32 70 64 122 169 111 11
(71.3) (36.8) (19.0) (4.7) (10.2) (9.4) (17.8) (24.7) (16.2) (1.6)
277 134 74 10 48 37 54 84 65 9
(70.1) (33.9) (18.7) (2.5) (12.2) (9.4) (13.7) (21.3) (16.5) (1.8)
60 31 15 7 12 6 12 20 12 2
22 (71.0) 16 (51.6) 4 (12.9) 3 (9.7) 1 (3.2) 4 (12.9) 3 (9.7) 11 (35.5) 9 (29.0) 0
0.86 0.14 0.72 0.02 0.02 0.82 <0.001 0.046 0.22 0.77
Gender Male Age, years Median age (IQR), yrs
129 71 37 12 9 17 53 54 25 2
(73.7) (40.6) (21.1) (6.9) (5.1) (9.7) (30.3) (30.9) (14.3) (1.1)
>24-48 (N Z 83)
>48 (N Z 31)
P
54 (65.0)
17 (54.8)
0.78
70.5 (54.9e80.3) 46 (55.4)
60.4 (46.6e79.1) 13 (41.9)
0.33
(42.1) (39.8) (18.1) (30.1)
(72.2) (37.4) (18.1) (8.4) (14.5) (7.2) (14.5) (24.1) (14.5) (2.4)
14 10 7 9
(45.2) (32.2) (22.6) (29.0)
0.16 0.76 0.71 0.18 0.71
Data are presented as n (%), unless otherwise stated. IQR, interquartile range; MRSA, methicillin-resistant Staphylococcus aureus; CNS, central nervous system; CWI, Charlson weighted index of co-morbidity score; COPD, chronic obstructive pulmonary disease; HIV, human immuno-deficiency virus.
have cardiac disease compared with our patient cohort where 71% had an underlying co-morbid condition and 19% cardiac disease. Moreover, the rate of MRSA at 52% was much higher than that observed in our study (28%). The second study was a retrospective case-control study by Marra et al. where 91 cases of SAB admitted to an adult tertiary-care center were evaluated. In addition to TTP (dichotomized into 12 h and >12 h), detailed clinical characteristics including patient location (ward vs. intensive care unit), antimicrobial use, and presence of neutropenia, and organ failure were assessed for association with in-hospital mortality.17 The median TTP observed in their study was much lower at 12 h compared to the median TTP of 16 h in our study. In contrast to our study, they found no significant difference in TTP between MSSA and MRSA. They also used CWI score to quantify the severity of underlying co-morbid conditions and showed that there was
a significant difference in the proportion of patients who had CWI score 3 between the TTP categories. The reported overall mortality of 14% was lower than observed in our study. By multivariate analysis, a seven-fold increase in odds of in-hospital mortality was observed among 44 patients with TTP 12 h compared with 47 patients with TTP > 12 h. Failure of at least one organ system, CWI score 3, and MRSA were also reported as independent predictors of mortality. In contrast to our study findings, older age, nosocomial acquisition, and endovascular source of infection were not associated with increased mortality. Interestingly, inadequate empiric antimicrobial therapy was not a predictor of mortality. Finally, a single-centered retrospective analysis of 146 patients with SAB was done by Sowden et al.18 In their brief report, complete details regarding underlying co-morbid illnesses and the sources of infection were not provided. A
60 0
20
40
Frequency
80
100
120
Time to blood culture positivity in S. aureus bacteremia
0
10
20
30
40
50
60
70
80
90
100
Time to Positivity (hours)
Figure 1 Distribution of time to blood culture positivity in 684 episodes of Staphylococcus aureus bacteremia
higher overall 30-day mortality of 23.3% was reported. By multivariate analysis, TTP 12 h and the presence of comorbid illnesses as defined by CWI score was also associated with increased 30-day mortality, while adequate antibiotic therapy within 24 h was protective. No specific underlying co-morbid illness or source of infection was associated with increased mortality. Their analysis, however, was limited only to community-acquired cases of MSSA bacteremia. All of the previous studies reported a significant association between earlier TTP (using cutoff times of 14 or 12 h) and mortality. One of the hypotheses for this observation has been the correlation between higher bacterial load and earlier TTP.12,13 It has been extrapolated that earlier TTP, reflecting a more severe bacteremia, would translate into adverse clinical outcomes including metastatic infection and death.16 Consistent with prior findings, our multivariate analysis also showed that relative to the intermediate TTP
201 (>12e48 h), the odds of 30-day mortality was higher in cases with earlier TTP (12 h). Interestingly, longer TTP (>48 h) was also associated with the highest case-fatality rate at 30 days (similar trends for 90 day mortality). Thus, we observed that there was no linear relationship between TTP and 30-day mortality and identified another patient population at higher risk of death. Our key finding of the association between delayed TTP and increased 30-day mortality has not been reported in previous studies. This may be in part due to their smaller study sample sizes, thus very few cases would have had TTP beyond 48 h. The reasons for our observation are unclear. Patients with delayed TTP had a trend towards greater proportion of CWI score 3 compared with shorter TTP (P Z 0.08). However, other potential confounders such as age, proportion of MRSA, nosocomial infection, and source of infection did not differ significantly between the TTP categories. We could not determine whether those with TTP > 48 h were more likely to have a metastatic focus compared to those with shorter TTP. We could not find any significant difference between those who died with TTP > 48 h and with TTP 48 h related to their clinical characteristics, time to death from blood cultures being drawn, and source of infection (data not shown). A possible explanation for our main finding is that this group represents those patients with low-grade bacteremia, whose clinical presentation may not have been severe. As such, empiric antimicrobial therapy may have been delayed or prematurely stopped once the cultures were reported as negative at 24e48 h. Inappropriate or delayed antimicrobial therapy has been shown to be associated with adverse outcome in SAB.29,30 We did not have data regarding antimicrobial utilization in our study and hence this inference could not be verified. Another reason could be that delayed TTP reflects an occult source of infection and failure to eradicate the source of infection is associated with increased mortality.
Figure 2 Proportion of time to positivity categories by primary diagnosis in 684 patients with Staphylococcus aureus bacteremia. SST, skin and soft tissue; BSI, bloodstream infection; IAB, intrabdominal/pelvic; CNS, central nervous system
202 Table 2
J. Kim et al. Univariate analysis of risk factors for 30-day case-fatality in 684 patients with Staphylococcus aureus bacteremia.
Variable
Deaths/no. with variable (%)
Deaths/no. without variable (%)
RR (95%CI)
P
2.8 (1.96e3.95) 0.95 (0.69e1.32)
<0.001 0.76
Demographic Age 65 Male
86/307 (28.0) 75/422 (17.8)
Microbiological MRSA Nosocomial Healthcare-associated Community-acquired
48/191 69/275 37/238 18/171
(25.1) (25.1) (15.6) (10.5)
76/493 55/409 87/446 106/513
(15.4) (13.5) (19.5) (20.7)
1.6 1.9 0.8 0.5
(1.18e2.25) (1.36e2.57) (0.56e1.13) (0.32e0.81)
0.003 <0.001 0.2 0.003
Co-morbid condition Heart disease Stroke COPD Liver disease Renal disease Diabetes Cancer HIV infection CWI 3
33/130 10/32 19/70 20/64 26/122 34/169 21/111 1/11 63/252
(25.4) (31.3) (27.1) (31.3) (21.3) (20.1) (18.9) (9.1) (25.0)
91/554 114/652 105/614 104/620 98/562 90/515 103/573 123/673 61/432
(16.4) (17.5) (17.1) (16.8) (17.4) (17.5) (18.0) (18.3) (14.1)
1.5 1.8 1.6 1.9 1.2 1.2 1.1 0.5 1.8
(1.09e2.19) (1.04e3.07) (1.04e2.42) (1.24e2.79) (0.83e1.80) (0.81e1.64) (0.69e1.61) (0.08e3.25) (1.29e2.43)
0.017 0.049 0.039 0.004 0.31 0.44 0.81 0.43 <0.001
Source of infection Primary bacteremia Soft tissue Bone and joint Respiratory Endocarditis Intra-abdominal/pelvic CNS
63/283 9/104 5/94 32/113 6/36 8/45 1/4
(22.3) (8.7) (5.3) (28.3) (16.7) (17.8) (25.0)
61/401 115/580 119/590 92/571 118/648 116/639 123/680
(15.2) (19.8) (20.2) (16.1) (18.2) (18.2) (18.1)
1.5 0.4 0.3 1.8 0.97 1.0 1.4
(1.07e2.01) (0.23e0.83) (0.11e0.63) (1.24e2.49) (0.43e1.93) (0.51e1.88) (0.25e7.60)
0.018 0.007 <0.001 0.002 0.82 0.95 0.72
Time to positivity TTP 12 h TTP > 12e24 h TTP > 24e48 h TTP > 48 h
37/175 59/395 16/83 12/31
(21.1) (14.9) (19.3) (38.7)
87/509 65/289 108/601 112/653
(17.1) (22.5) (18.0) (17.2)
1.2 0.7 1.1 2.3
(0.88e1.75) (0.48e0.91) (0.67e1.72) (1.41e3.63)
0.23 0.011 0.77 0.002
38/377 (10.1) 49/262 (18.7)
Data are presented as n (%), unless otherwise stated. RR, relative risk; CI, confidence interval; MRSA, methicillin-resistant Staphylococcus aureus; COPD, chronic obstructive pulmonary disease; HIV, human immuno-deficiency virus; CWI, Charlson weighted index of comorbidity score; CNS, central nervous system; TTP, time to positivity.
Our study had several limitations. Although a larger sample size and all age cohorts were included in the study, we were not able to ascertain detailed clinical information. The determination of primary diagnoses was done by ICD codes and could not be prospectively confirmed with use of standardized tests such as an echocardiogram for the diagnosis of endocarditis. In addition, we could not separate those who had catheter-related SAB from those without a focus among primary bacteremia cases. Our inability to make this distinction may have had an impact on overall mortality rates among TTP categories since SAB with a removable focus will likely have a more favorable outcome if the focus is removed.31 It is possible that many of the patients with TTP between 12 and 48 h could have had catheter-related SAB, which may explain the lower 30-day mortality rate. However, the overall proportions of primary bacteremia diagnosis did not differ significantly between the TTP categories. While it is the recommended protocol to obtain blood cultures prior to initiation of
antimicrobial treatment in our health region, we could not exclude those cases where empiric antimicrobial therapy was initiated prior to blood cultures being drawn, which would have impacted the time to blood culture positivity. Finally, this was a retrospective study. In conclusion, we confirm that certain patient and microbiological characteristics are associated with a higher risk of death in SAB. Moreover, delayed TTP may be associated with increased 30-day mortality in SAB. This may have important clinical implications. Negative blood culture results at 24e48 h should not prompt immediate discontinuation of empiric antimicrobial treatment in patients with suspected SAB. Further prospective studies are needed to evaluate optimal therapeutic options for patients with SAB and high risk of adverse outcome.
Funding No external funding was received in support of this study.
Time to blood culture positivity in S. aureus bacteremia Table 3 Logistic regression modeling of factors associated with 30-day mortality. Factor
OR (95%CI)
P
Age (per decade) Nosocomial
1.58 (1.38e1.82) 1.87 (1.19e2.92)
<0.001 0.006
Diagnosis Other Pneumonia Endocarditis/primary bacteremia Co-morbid condition Liver disease
1 (reference) 3.31 (1.75e6.27) 1.98 (1.14e3.45)
<0.001 0.016
3.14 (1.62e6.09)
0.001
Methicillin sensitivity MSSA MRSA
1.0 (reference) 1.66 (1.06e2.61)
0.028
Time to positivity 12 h >12e48 h >48 h
1.0 (reference) 0.57 (0.35e0.93) 2.57 (1.02e6.48)
0.023 0.045
The model (n Z 684) had good calibration (HosmereLemeshow goodness of fit p Z 0.41) and discrimination (area under receiver operator characteristic curve 0.776). OR, odds ratio; CI, confidence interval; MSSA, methicillin-sensitive Staphylococcus aureus; MRSA, methicillin-resistant Staphylococcus aureus.
Conflict of interest None of the authors have professional, personal, or financial conflicts of interest to report.
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