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Timing of antibiotics in septic patients: a prospective cohort study
Journal Pre-proof Timing of antibiotics in septic patients: a prospective cohort study Hyeri Seok, Juhyun Song, Ji Hoon Jeon, Hee Kyoung Choi, Won Suk Choi, Sungwoo Moon, Dae Won Park PII:
S1198-743X(20)30089-6
DOI:
https://doi.org/10.1016/j.cmi.2020.01.037
Reference:
CMI 1933
To appear in:
Clinical Microbiology and Infection
Received Date: 14 November 2019 Revised Date:
30 January 2020
Accepted Date: 31 January 2020
Please cite this article as: Seok H, Song J, Jeon JH, Choi HK, Choi WS, Moon S, Park DW, Timing of antibiotics in septic patients: a prospective cohort study, Clinical Microbiology and Infection, https:// doi.org/10.1016/j.cmi.2020.01.037. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases.
Figure 1. Flowchart of patients in this study.
Timing of antibiotics in septic patients: a prospective cohort study
Hyeri Seok1, Juhyun Song2, Ji Hoon Jeon1, Hee Kyoung Choi1, Won Suk Choi1, Sungwoo Moon2, Dae Won Park1
1
Division of Infectious Diseases, Department of Medicine, Korea University Ansan Hospital, Korea University
College of Medicine 2
Department of Emergency Medicine, Korea University Ansan Hospital, Korea University College of Medicine
Running title: Timing of antibiotics in sepsis Keywords: timing; antibiotics; appropriateness; sepsis; Sepsis-3 definition
Correspondence to: Dae Won Park, MD, PhD Division of Infectious Diseases, Department of Medicine, Korea University Ansan Hospital, Korea University Medicine, 123 Jeukgeum-ro, Danwon-gu, Ansan, 15355, Republic of Korea Tel: +82-31-412-4270, Fax: +82-31-412-5984 E-mail: [email protected]
Key points: The time to antibiotics may not affect the prognosis of patients with sepsis if a rapid and welltrained resuscitation is combined with appropriate antibiotic administration within a reasonable time.
ABSTRACT Objectives: We evaluated the effect of timing and appropriateness of antibiotics administration on mortality in patients diagnosed with sepsis according to the Sepsis-3 definition. Methods: This prospective cohort study was conducted in patients diagnosed with sepsis according to the Sepsis-3 definition at the emergency department (ED) of Korea University Ansan Hospital from January 2016 to January 2019. The time to antibiotics was defined as the time in hours from ED arrival to the first antibiotic administration. Cox proportional hazards regression analysis was used to estimate the association between time to antibiotics and 7, 14, and 28-day mortality. Results: Out of 482 patients enrolled in this study, 203/482 (42.1%) and 312/482 (64.7%) were diagnosed with septic shock and high-grade infection, respectively. The median time to antibiotics was 115 minutes. Antibiotics were administered within 3 and 6 hours in 340/482 (70.4%) and 450/482 (93.2%) patients, respectively. Initial appropriate empirical antibiotics were administered in 375/482 (77.8%) patients. The time to and appropriateness of the initial antibiotics were not associated with 7, 14, and 28-day mortality in multivariate analysis. The sequential organ failure assessment (SOFA) score (adjusted hazard ratio [aHR]: 1.229, 95% confidence interval [CI]: 1.093–1.381, P = 0.001) and initial lactate levels (aHR 1.128, 95% CI 1.034-1.230, P = 0.007), the Charlson comorbidity index (aHR 1.115, 95% CI 1.027-1.210, P = 0.014) and 2-hour lactate level (aHR 1.115, 95% CI 1.027-1.210, P = 0.009), and SOFA score (aHR 1.077, 95% CI 1.013-1.144, P = 0.018) affected 7, 14, and 28-day mortality, respectively. Subgroup analysis with septic shock, bacteremia, and highgrade infection did not affect the mortality rates. Conclusions: The time to antibiotics may not affect the prognosis of patients with sepsis if a rapid and welltrained resuscitation is combined with appropriate antibiotic administration within a reasonable time.
INTRODUCTION Despite high mortality and morbidity of sepsis [1,2], there are controversies regarding the ideal time for antibiotic administration in patients with sepsis. Some large retrospective studies have suggested that antibiotics should be administered as early as possible and preferably within an hour [3-8]. Subsequent studies have suggested overall compliance of sepsis bundle or focus on antibiotic stewardship may be more important than the time to antibiotics [4,9-13]. With the introduction of the Sepsis-3 definition, the sequential organ failure assessment (SOFA) score replaced the systemic inflammatory response syndrome (SIRS) definition of sepsis which was indicative of non-homeostatic host response [14,15]. Moreover, the new guideline emphasized the early recognition of sepsis and indicated that sepsis is not a specific illness but a dysfunctional host response syndrome [16,17]. The revised guideline recommended that antibiotics should be administered as soon as possible after the detection of sepsis or septic shock, preferably within an hour [15]. In practice, however, difficulties in diagnosing the site of infection and determining the appropriate empirical antibiotics may prevent the administration of antibiotics within 1 hour. This study was designed to evaluate the effect the early administration of antibiotics on mortality in patients diagnosed with Sepsis-3 definition and to identify the factors associated with the outcomes.
METHODS Study design, study population, and data collection A prospective cohort study was conducted to evaluate the effect of the timing of antibiotics administration on the outcomes of sepsis. The crude population was composed of the patients who visited the emergency department (ED) between January 2016 and January 2019 at the Korea University Ansan Hospital which is an 810-bed tertiary teaching hospital in Ansan, Republic of Korea. We enrolled adult patients who were older than 18 years and diagnosed with sepsis according to the 3rd International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3 definition) [14]. Initial antibiotics selection was determined by the first physician to diagnose sepsis and consulted with the infectious disease specialists if necessary. Patients with a history of antibiotic use within 24 hours before the ED visit were excluded from this study because the time of antibiotic administration was a significant variable. The demographic data, comorbidity status based on the Charlson comorbidity index, and laboratory data including initial and 2-hour follow-up lactate levels, C-reactive protein
(CRP), and procalcitonin were collected. The 7, 14, and 28-day mortality were the primary outcomes, and patients who were discharged prior to this time were checked for death by phone call. This study protocol was approved by the institutional review board of the Korea University Ansan Hospital (no. 2019AS0192). Written informed consent was obtained from each study participant, or legal representative if not available.
Definition According to the Sepsis-3 definition, sepsis was defined as patients with a SOFA score of 2 or more. Patients with sepsis who require vasopressors to maintain mean arterial pressure above 65 mmHg and those with serum lactate level >2 mmol/l was diagnosed with septic shock. The time to antibiotics administration was defined as the time from the arrival at the ED to the first antibiotic administration. The appropriateness of the antibiotic treatment was directly evaluated by the infectious disease specialist based on clinical response and sample culture results. If the clinical response and microbiological results differ in evaluating the appropriateness of antibiotics, the clinical response has been given priority over the microbiological findings. Based on a prior study, the grade of infection was classified according to the site of infection [18]. High-grade included pneumonia, skin and soft tissue infection, catheter-related bloodstream infection, and complicated intraabdominal infection whereas low-grade included urinary tract infection.
Statistical analysis For comparison, Pearson χ² tests and Fisher’s exact tests were used for categorical variables, and Student’s t-test and Mann–Whitney U tests were used for continuous variables, as appropriate. Cox proportional hazards regression analysis was used to evaluate the association between the timing of antibiotic administration and 7, 14, and 28-day mortality. The report of multivariable regression model followed the guidance of Clinical Microbiology and Infection [19]. We included all variables associated with the dependent variable on bi-variable analysis (p < 0.1); and pre-defined variables such as the timing of antibiotics that made clinical sense. Variables adjusted in the cox regression model included age, sex, Charlson comorbidity index, onset of infection, grade of infection, SOFA score, septic shock, CRP levels, procalcitonin levels, initial and 2-hour lactate levels, bacteremia, and the timing of antibiotics. The variables related to the timing of antibiotics were analyzed by continuous variables based on hours and categorical variables over time, respectively. The final variables in the
model were determined by automated backward stepwise selection. The confidence interval (CI) was calculated by Wald statistics, and the overall evaluation was done with likelihood ratio and C-statistic. We conducted a sensitivity analysis in which all patients who died within 12 hours are excluded. All statistical analyses were performed using SPSS Statistics version 20.0 for Windows (IBM Corp., Armonk, NY, USA).
RESULTS Baseline characteristics of patients with sepsis During the study period, 482 and 203/482 (42.1%) patients were diagnosed with sepsis and septic shock, respectively (Figure 1). The all-cause 7, 14, and 28-day mortality of overall study population were 19.5% (94/482), 33.6% (162/482), and 49.4% (238/482), respectively. The median time to antibiotics was 115 minutes (interquartile range: 76–207; 160 to 138), and the appropriateness of initial antibiotics was 77.8% (375/482). The mean age of the patients was 72 years old, and 267/482 (55.4%) were male. The median Charlson comorbidity index was 4 (IQR: 3-6; 4 to 2). The most common mode of acquisition of infection was the longterm care facility followed by community and nosocomial infection. Respiratory and genitourinary infection accounted for more than 90% (435/482) of the cases, and 312/482 (64.7%) patients had a high-grade infection. The median SOFA score was 8 (IQR: 5-10, 8 to 3). The median initial and 2-hour follow-up lactate levels were 2.8 (IQR: 1.8-5.2, 4.1 to 3.7) and 2.1 (IQR: 1.4-3.4, 3.0 to 2.6) mmol/l, respectively. In initial blood culture, 154/482 (32.0%) patients had combined bacteremia. The other baseline characteristics are shown in Table 1.
Outcomes In this study, the risk factors for mortality in septic patients differed according to the days of death. The SOFA score (adjusted hazard ratio [aHR]: 1.229, 95% confidence interval [CI]: 1.093–1.381, P = 0.001) and initial lactate level (aHR: 1.128, 95% CI: 1.034–1.230, P = 0.007) had a significant association with increased 7-day mortality. The increased 14-day mortality was significantly associated with Charlson comorbidity index (aHR: 1.115, 95% CI: 1.027–1.210, P = 0.014) and 2-hour lactate level (aHR: 1.115, 95% CI: 1.027–1.210, P = 0.009). The SOFA score was significantly associated with increased 28-day mortality (aHR: 1.077, 95% CI: 1.013– 1.144, P = 0.018). The risk of 7, 14, and 28-day mortality for overall study population were as follows; 7-day
mortality, aHR: 1.000, 95% CI 0.997-1.003, P = 0.967; 14-day mortality, aHR 1.000, 95% CI 0.998-1.002, P = 0.935; 28-day mortality, aHR 1.000, 95% CI 0.998-1.002, P = 0.795. The appropriateness of empirical antibiotic selection had no effect on the mortality rate. The association between 7, 14, and 28-day mortality and other variables are shown in Table 2. After sensitivity analysis, the results remained unchanged and the data are presented in Supplementary Table 1.
Association between the time to the antibiotics and the outcomes Antibiotics were administered in 74/482 (15.4%), 340/482 (70.5%), and 450/482 (93.4%) patients within 1, 3, and 6 hours, respectively. The mortality rate among patients who received antibiotics within 3 hours, after 3 hours, within 6 hours, and after 6 hours was 52% (177/340), 43% (61/142), 49.3% (222/450), and 50% (16/32), respectively. The time to antibiotics administration did not affect the 7, 14, and 28-day mortality in the multivariate analysis. The 28-day mortality was unaffected when it was compared by dividing the antibiotic administration time by one hour (data not shown). In subgroup analyses, there was no significant association between 28-day mortality and the time to antibiotics in patients with septic shock, bacteremia, and high-grade infection. Detailed results are presented in Supplementary Table 2-4. In addition, the appropriateness of empirical antibiotic administration was not associated with 7, 14, and 28day mortality in multivariate analysis and in the subgroup analysis in patients with septic shock, bacteremia, and high-grade infection.
DISCUSSION This study showed that the time to antibiotic administration did not significantly affect the 7, 14, and 28-day mortality rates and the prognosis of septic patients after the application of the new Sepsis-3 definition. Notably, the outcome of patients with sepsis was approached from a physiologic point of view by analyzing mortality according to date. The 28-day mortality was relatively high (about 50%) because the study population was restricted to those whose follow-up and time for antibiotics administration were clearly identified. The SOFA score affected the 7 and 28-day mortality in overall sepsis patients. The SOFA score, which
reflects organ dysfunction, is a critical indicator for the evaluation of severity in sepsis, and it has become the most critical indicator since the introduction of Sepsis-3 definition. Although the concept of severe sepsis has been removed, we demonstrated that a high SOFA score may reflect the severity of sepsis by affecting the 7-day mortality which represents the severity of early sepsis [20]. Indeed, even in the subgroup analysis of patients with septic shock, bacteremia, and high-grade infection, the SOFA score affected the 7-day mortality. In addition, the SOFA score affected the 28-day mortality which was a critical factor in the diagnosis and prognosis of sepsis [21,22]. The initial lactate level affected the 7-day mortality in overall sepsis and all subgroup analyses patients. Meanwhile, the 2-hour lactate level affected the 14-day mortality of all sepsis, septic shock, and bactermic patients, and 28-day mortality of patients with septic shock. The lactate level of sepsis patients is a new concept introduced in the Sepsis-3 definition, and it is associated with early prognosis, especially in severe infection. Although controversial, some prior studies recommended normalization of lactate levels for the management of sepsis [15,23,24]. The 2-hour lactate level may be an indicator that determines the success of rapid resuscitation in sepsis patients suggesting that early resuscitation is critical for the management of sepsis and that the 2-hour lactate level must be checked [12, 19, 20]. Another factor related to the 14-day mortality is the Charlson comorbidity index, and this indicator may affect shock resilience which is critical for the success of resuscitation. Comorbidity has been reported to be associated with short- and long-term prognosis of sepsis in previous studies [25-27]. This study supports that comorbidity may affect the prognosis of sepsis, especially short-term prognosis. The time to antibiotics did not affect the 28-day mortality, and only the SOFA score was related to 28-day mortality. Previously, some large retrospective studies with high rates of septic shock suggested that the time to antibiotics affects mortality [4-8]. Subsequent studies, including several prospective studies that included patients with mild sepsis who were treated with qualified resuscitation following the sepsis bundle, suggested that the time to antibiotics did not affect mortality [9-13]. Therefore, we performed subgroup analysis in patients with septic shock, bacteremia, and high-grade infection; but the time to antibiotics was not associated with mortality. The time to antibiotics did not affect the outcome for the following reasons. First, in this study, the time to antibiotic was shorter than in other studies (median 112 minutes; 70.5% within 3 hours; 93.4% within 6 hours).
This is consistent with the study that showed no correlation between the time to antibiotics and 30-day mortality rate when adequate appropriate antibiotics, for which culture results were confirmed, were administered within 12 hours in patients with sepsis [29]. Second, in addition to the early administration of antibiotics, well-trained resuscitation may be a confounding variable.. In fact, another study by our research team reported that the rate of overall compliance with surviving sepsis campaign bundle was 83.3% [30]. Our observation that the time to antibiotics is not related to mortality does not imply that rapid antibiotics administration is not necessary. Rather, we want to emphasize that other critical goals should not be ignored for the sake of rapid antibiotic administration such as the efforts to find the cause of shock and site of infection, improvement of compliance of sepsis bundle, advances in antimicrobial stewardship, and the avoidance of broad-spectrum antibiotics to minimize antimicrobial resistance. We assumed that the appropriateness of the initial empirical antibiotics was relevant; however, it was not associated with the outcomes of patients with sepsis. The rate of the appropriateness of the empirical antibiotics in this study was 78% which was higher than 53% reported in previous studies [11,28,31], and this did not affect the prognosis of sepsis. However, a review article pointed out the methodological limitation of prior studies regarding the association between appropriate antibiotic therapy and mortality [32]. We also recognized the methodological limitations in defining and evaluating the appropriateness assessment. To overcome the limitation, we conducted a subgroup analysis on bacteremia patients and the outcomes remained unchanged. Further study is needed on the appropriateness of antibiotics for sepsis, which is validated on systematic methods. The advantages of this study are as follows. First, to our knowledge, this is the first prospective study to evaluate the relationship between the time to antibiotic and outcome of septic patients with Sepsis-3 definition. As the Sepsis-3 definition includes more actual sepsis patients than the previous Sepsis-2 definition, this increases the reliability of the results. Second, the study population was composed of a relatively homogenous group of patients who were admitted via the ED. In addition, we further refined the study population by excluding patients who had received antibiotics at the referred hospital or were lost to follow-up. The limitation of this study is that the study population was not large. We inevitably extended the study period to 3 years to increase the statistical significance. This included patients before the introduction of the Sepsis-3 definition, but the application of the Sepsis-3 definition was not a problem because the previous definition was more extensive. Additional follow-up study with Sepsis-3 definition would provide the detailed causal relationship between the
time to antibiotics administration and outcome in septic patients. In addition, we did not reflect the adequacy of resuscitation which may be a critical variable for the mortality of sepsis. In terms of defining and evaluating the appropriateness of antibiotics, this study has a methodological limitation in that it did not apply a validated and systematic method. In conclusion, the time to antibiotics administration did not affect 7, 14, and 28-day mortality in the treatment of patients with sepsis who visited the ED. Rather, the severity of sepsis was associated with 7-day mortality, and the success of resuscitation and comorbidity were significant factors affecting the 14-day mortality. The relatively adequate antibiotic administration within a reasonable time along with well-trained and rapid resuscitation may improve the prognosis of patients with sepsis.
Funding This work was supported by funding from the Korea University Medical Center [grant number K1722241] which was received by Dae Won Park.
Conflict of interest All authors certify that there are no potential conflicts of interest to declare.
Authors’ contribution Conceptualization: HS and DWP conceived the idea. JS and JHJ collected the data. HS, HKC, WSC, SM, and DWP analyzed the data. HS and DWP prepared the manuscript and made final edition of the document. All authors have read and approved the manuscript.
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Table 1. Baseline characteristics of the study population
Variables
Overall patients (n=482)
Septic shock (n=203)
Bacteremia (n=154)
High-grade infection (n=312)
Age, years
72 ± 15 (65–82)
71 ± 15 (61-81)
73 ± 14 (66-82)
71 ± 16 (64-82)
267 (55.4)
114 (56.2)
76 (49.4)
194 (62.2)
4 (3–6)
4 (3-6)
5 (3-6)
4 (3-6)
Community
182 (37.8)
77 (37.9)
54 (35.1)
111 (35.6)
Hospital
102 (21.2)
53 (26.1)
32 (20.8)
66 (21.2)
LTCF
198 (41.1)
73 (36.0)
68 (44.2)
135 (43.3)
High-grade
312 (64.7)
127 (62.6)
80 (51.9)
Low-grade
170 (35.3)
76 (37.4)
74 (48.1)
SOFA score
8 (5–10)
10 (8-12)
9 (7-11)
8 (5-10)
Septic shock
203 (42.1)
75 (48.7)
127 (40.7)
CRP (mg/dl)
10.33 (4.43–18.55)
11.42 (4.72-20.50)
14.18 (7.82-22.74)
10.07 (4.13-18.45)
Procalcitonin (ng/ml)
1.53 (0.34–12.79)
4.32 (0.87-27.10)
6.08 (1.15-27.33)
0.93 (0.28-6.74)
Initial lactate (mmol/l)
2.8 (1.8–5.2)
4.7 (2.9-7.8)
3.2 (1.9-6.1)
2.8 (1.8-5.1)
2-hour lactate (mmol/l)
2.1 (1.4–3.4)
3.2 (2.0-5.8)
2.2 (1.3-4.2)
2.3 (1.4-3.7)
154 (32.0)
75 (36.9)
115 (76–207)
106 (72-180)
113 (72-190)
118 (73-217)
74 (15.4)
31 (15.3)
28 (18.2)
49 (15.7)
Male Charlson comorbidity index Onset
Grade of infection
Bacteremia Time to antibiotics administration, minutes Antibiotics administration within 1 hour
80 (25.6)
Antibiotics administration within 3 hours
340 (70.5)
156 (76.8)
114 (74.0)
212 (67.9)
Antibiotics administration within 6 hours
450 (93.4)
192 (94.6)
146 (94.8)
287 (92.0)
Appropriateness of empirical antibiotics administration
375 (77.8)
156 (76.8)
107 (69.5)
244 (78.2)
All-cause 7-day mortality
94 (19.5)
59 (29.1)
36 (23.4)
57 (18.3)
All-cause 14-day mortality
162 (33.6)
89 (43.8)
59 (38.3)
103 (33.0)
All-cause 28-day mortality
238 (49.4)
132 (65.0)
80 (51.9)
161 (51.6)
NOTE. Data are expressed as number (%) of patients or median (interquartile range) unless otherwise indicated. LTCF, long-term care facility; CRP, C-reactive protein; SOFA, sequential organ failure assessment
Table 2. Risk factors for 7, 14, and 28-day mortality in overall sepsis patients
7-day mortality Variables
Univariate analysis
14-day mortality
Multivariate analysis
Univariate analysis
28-day mortality
Multivariate analysis
Univariate analysis
Multivariate analysis
HR (95% CI)* P-value HR (95% CI)* P-value HR (95% CI)* P-value HR (95% CI)* P-value HR (95% CI)* P-value HR (95% CI)* P-value Male
0.791 (0.528–1.186)
0.256
Age
1.013 (0.998–1.028)
0.098
CCI
1.185 <0.001 (1.078–1.303)
0.986 (0.959-1.015) 1.172 (0.997–1.378)
0.791 (0.581–1.076)
0.136
0.887 (0.687–1.144)
0.355
0.342
1.010 (0.999–1.022)
0.068
1.008 (0.999–1.017)
0.093
0.055
1.140 (1.058–1.229)
0.001
0.014
1.082 (1.015–1.153)
0.015
1.115 (1.027–1.210)
1.092 (0.995–1.198)
0.064
Onset Community 1.283
Hospital
1.085 (0.656–1.796)
0.751
0.968 (0.646–1.450)
0.874
0.964 (0.524-1.776)
0.908
1.037 (0.746–1.440)
0.830
LTCF
0.637 (0.396–1.025)
0.063
0.739 (0.521–1.049)
0.091
0.624 (0.357-1.092)
0.099
0.737 (0.551–0.986)
0.040
Grade of infection
0.826 (0.546–1.249)
0.365
0.934 (0.678–1.286)
0.676
1.138 (0.867–1.493)
0.352
SOFA
1.192 (1.124-1.263)
<0.001
1.229 (1.093-1.381)
0.001
1.133 (1.082-1.186)
<0.001
0.999 (0.916-1.091)
0.988
1.167 (1.123-1.213)
<0.001
1.077 (1.013-1.144)
0.018
Septic shock
2.564 (1.687-3.897)
<0.001
0.857 (0.316-2.321)
0.761
1.989 (1.459-2.712)
<0.001
1.175 (0.629-2.197)
0.613
2.124 (1.645-2.745)
<0.001
1.192 (0.728-1.951)
0.486
CRP
1.001 (0.982–1.021)
0.905
1.004 (0.989–1.018)
0.622
1.007 (0.995–1.019)
0.231
Procalcitonin
1.007 (1.001–1.014)
0.021
1.006 (1.001–1.011)
0.029
1.005 (1.000–1.009)
0.032
1.007 (0.998–1.016)
0.139
1.002 (0.994–1.010)
0.632
(0.797–2.066) 0.719 (0.460–1.124)
1.000 (0.994–1.007)
0.306 0.148
0.927
Lactate
1.099 <0.001 (1.061–1.139)
2-hour lactate
1.250 <0.001 (1.149–1.359)
Bacteremia
1.415 (0.933–2.145)
0.102
Timing of antibiotics
1.000 (0.999–1.002)
0.810
Antibiotics within 1 hour
0.716 (0.381–1.342)
Antibiotics within 3 hours Appropriateness of antibiotics
1.128
0.007
1.060 (1.025–1.096)
0.001
0.374
1.137 (1.056–1.224)
0.001
1.312 (0.952–1.806)
0.097
1.000 (0.999–1.001)
0.937
0.297
0.822 (0.524–1.288)
1.317 (0.823–2.108)
0.251
0.821 (0.516–1.305)
0.404
(1.034–1.230) 1.080 (0.912–1.278)
1.000 (0.997-1.003)
0.967
0.957 (0.841–1.088)
0.500
1.051 (1.021–1.081)
0.001
0.009
1.120 (1.050–1.195)
0.001
1.074 (0.642-1.794)
0.786
1.170 (0.894–1.531)
0.254
1.000 (0.998-1.002)
0.935
1.000 (0.999–1.001)
0.468
0.392
0.960 (0.676–1.363)
0.820
1.196 (0.844–1.695)
0.314
1.279 (0.956–1.711)
0.097
0.752 (0.531–1.066)
0.109
0.894 (0.662–1.209)
0.460
1.115 (1.027–1.210)
0.959 (0.862–1.066) 1.096 (0.976–1.230)
1.000 (0.998-1.002)
0.435 0.122
0.795
NOTE. *Values above 1 indicate increased risk, while lower levels indicate reduced risk. HR, hazard ratio; CI, confidence interval; CCI, Charlson comorbidity index; LTCF, long-term care facility; CRP, C-reactive protein; SOFA, sequential organ failure assessment
S1198-743X(20)30089-6
DOI:
https://doi.org/10.1016/j.cmi.2020.01.037
Reference:
CMI 1933
To appear in:
Clinical Microbiology and Infection
Received Date: 14 November 2019 Revised Date:
30 January 2020
Accepted Date: 31 January 2020
Please cite this article as: Seok H, Song J, Jeon JH, Choi HK, Choi WS, Moon S, Park DW, Timing of antibiotics in septic patients: a prospective cohort study, Clinical Microbiology and Infection, https:// doi.org/10.1016/j.cmi.2020.01.037. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases.
Figure 1. Flowchart of patients in this study.
Timing of antibiotics in septic patients: a prospective cohort study
Hyeri Seok1, Juhyun Song2, Ji Hoon Jeon1, Hee Kyoung Choi1, Won Suk Choi1, Sungwoo Moon2, Dae Won Park1
1
Division of Infectious Diseases, Department of Medicine, Korea University Ansan Hospital, Korea University
College of Medicine 2
Department of Emergency Medicine, Korea University Ansan Hospital, Korea University College of Medicine
Running title: Timing of antibiotics in sepsis Keywords: timing; antibiotics; appropriateness; sepsis; Sepsis-3 definition
Correspondence to: Dae Won Park, MD, PhD Division of Infectious Diseases, Department of Medicine, Korea University Ansan Hospital, Korea University Medicine, 123 Jeukgeum-ro, Danwon-gu, Ansan, 15355, Republic of Korea Tel: +82-31-412-4270, Fax: +82-31-412-5984 E-mail: [email protected]
Key points: The time to antibiotics may not affect the prognosis of patients with sepsis if a rapid and welltrained resuscitation is combined with appropriate antibiotic administration within a reasonable time.
ABSTRACT Objectives: We evaluated the effect of timing and appropriateness of antibiotics administration on mortality in patients diagnosed with sepsis according to the Sepsis-3 definition. Methods: This prospective cohort study was conducted in patients diagnosed with sepsis according to the Sepsis-3 definition at the emergency department (ED) of Korea University Ansan Hospital from January 2016 to January 2019. The time to antibiotics was defined as the time in hours from ED arrival to the first antibiotic administration. Cox proportional hazards regression analysis was used to estimate the association between time to antibiotics and 7, 14, and 28-day mortality. Results: Out of 482 patients enrolled in this study, 203/482 (42.1%) and 312/482 (64.7%) were diagnosed with septic shock and high-grade infection, respectively. The median time to antibiotics was 115 minutes. Antibiotics were administered within 3 and 6 hours in 340/482 (70.4%) and 450/482 (93.2%) patients, respectively. Initial appropriate empirical antibiotics were administered in 375/482 (77.8%) patients. The time to and appropriateness of the initial antibiotics were not associated with 7, 14, and 28-day mortality in multivariate analysis. The sequential organ failure assessment (SOFA) score (adjusted hazard ratio [aHR]: 1.229, 95% confidence interval [CI]: 1.093–1.381, P = 0.001) and initial lactate levels (aHR 1.128, 95% CI 1.034-1.230, P = 0.007), the Charlson comorbidity index (aHR 1.115, 95% CI 1.027-1.210, P = 0.014) and 2-hour lactate level (aHR 1.115, 95% CI 1.027-1.210, P = 0.009), and SOFA score (aHR 1.077, 95% CI 1.013-1.144, P = 0.018) affected 7, 14, and 28-day mortality, respectively. Subgroup analysis with septic shock, bacteremia, and highgrade infection did not affect the mortality rates. Conclusions: The time to antibiotics may not affect the prognosis of patients with sepsis if a rapid and welltrained resuscitation is combined with appropriate antibiotic administration within a reasonable time.
INTRODUCTION Despite high mortality and morbidity of sepsis [1,2], there are controversies regarding the ideal time for antibiotic administration in patients with sepsis. Some large retrospective studies have suggested that antibiotics should be administered as early as possible and preferably within an hour [3-8]. Subsequent studies have suggested overall compliance of sepsis bundle or focus on antibiotic stewardship may be more important than the time to antibiotics [4,9-13]. With the introduction of the Sepsis-3 definition, the sequential organ failure assessment (SOFA) score replaced the systemic inflammatory response syndrome (SIRS) definition of sepsis which was indicative of non-homeostatic host response [14,15]. Moreover, the new guideline emphasized the early recognition of sepsis and indicated that sepsis is not a specific illness but a dysfunctional host response syndrome [16,17]. The revised guideline recommended that antibiotics should be administered as soon as possible after the detection of sepsis or septic shock, preferably within an hour [15]. In practice, however, difficulties in diagnosing the site of infection and determining the appropriate empirical antibiotics may prevent the administration of antibiotics within 1 hour. This study was designed to evaluate the effect the early administration of antibiotics on mortality in patients diagnosed with Sepsis-3 definition and to identify the factors associated with the outcomes.
METHODS Study design, study population, and data collection A prospective cohort study was conducted to evaluate the effect of the timing of antibiotics administration on the outcomes of sepsis. The crude population was composed of the patients who visited the emergency department (ED) between January 2016 and January 2019 at the Korea University Ansan Hospital which is an 810-bed tertiary teaching hospital in Ansan, Republic of Korea. We enrolled adult patients who were older than 18 years and diagnosed with sepsis according to the 3rd International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3 definition) [14]. Initial antibiotics selection was determined by the first physician to diagnose sepsis and consulted with the infectious disease specialists if necessary. Patients with a history of antibiotic use within 24 hours before the ED visit were excluded from this study because the time of antibiotic administration was a significant variable. The demographic data, comorbidity status based on the Charlson comorbidity index, and laboratory data including initial and 2-hour follow-up lactate levels, C-reactive protein
(CRP), and procalcitonin were collected. The 7, 14, and 28-day mortality were the primary outcomes, and patients who were discharged prior to this time were checked for death by phone call. This study protocol was approved by the institutional review board of the Korea University Ansan Hospital (no. 2019AS0192). Written informed consent was obtained from each study participant, or legal representative if not available.
Definition According to the Sepsis-3 definition, sepsis was defined as patients with a SOFA score of 2 or more. Patients with sepsis who require vasopressors to maintain mean arterial pressure above 65 mmHg and those with serum lactate level >2 mmol/l was diagnosed with septic shock. The time to antibiotics administration was defined as the time from the arrival at the ED to the first antibiotic administration. The appropriateness of the antibiotic treatment was directly evaluated by the infectious disease specialist based on clinical response and sample culture results. If the clinical response and microbiological results differ in evaluating the appropriateness of antibiotics, the clinical response has been given priority over the microbiological findings. Based on a prior study, the grade of infection was classified according to the site of infection [18]. High-grade included pneumonia, skin and soft tissue infection, catheter-related bloodstream infection, and complicated intraabdominal infection whereas low-grade included urinary tract infection.
Statistical analysis For comparison, Pearson χ² tests and Fisher’s exact tests were used for categorical variables, and Student’s t-test and Mann–Whitney U tests were used for continuous variables, as appropriate. Cox proportional hazards regression analysis was used to evaluate the association between the timing of antibiotic administration and 7, 14, and 28-day mortality. The report of multivariable regression model followed the guidance of Clinical Microbiology and Infection [19]. We included all variables associated with the dependent variable on bi-variable analysis (p < 0.1); and pre-defined variables such as the timing of antibiotics that made clinical sense. Variables adjusted in the cox regression model included age, sex, Charlson comorbidity index, onset of infection, grade of infection, SOFA score, septic shock, CRP levels, procalcitonin levels, initial and 2-hour lactate levels, bacteremia, and the timing of antibiotics. The variables related to the timing of antibiotics were analyzed by continuous variables based on hours and categorical variables over time, respectively. The final variables in the
model were determined by automated backward stepwise selection. The confidence interval (CI) was calculated by Wald statistics, and the overall evaluation was done with likelihood ratio and C-statistic. We conducted a sensitivity analysis in which all patients who died within 12 hours are excluded. All statistical analyses were performed using SPSS Statistics version 20.0 for Windows (IBM Corp., Armonk, NY, USA).
RESULTS Baseline characteristics of patients with sepsis During the study period, 482 and 203/482 (42.1%) patients were diagnosed with sepsis and septic shock, respectively (Figure 1). The all-cause 7, 14, and 28-day mortality of overall study population were 19.5% (94/482), 33.6% (162/482), and 49.4% (238/482), respectively. The median time to antibiotics was 115 minutes (interquartile range: 76–207; 160 to 138), and the appropriateness of initial antibiotics was 77.8% (375/482). The mean age of the patients was 72 years old, and 267/482 (55.4%) were male. The median Charlson comorbidity index was 4 (IQR: 3-6; 4 to 2). The most common mode of acquisition of infection was the longterm care facility followed by community and nosocomial infection. Respiratory and genitourinary infection accounted for more than 90% (435/482) of the cases, and 312/482 (64.7%) patients had a high-grade infection. The median SOFA score was 8 (IQR: 5-10, 8 to 3). The median initial and 2-hour follow-up lactate levels were 2.8 (IQR: 1.8-5.2, 4.1 to 3.7) and 2.1 (IQR: 1.4-3.4, 3.0 to 2.6) mmol/l, respectively. In initial blood culture, 154/482 (32.0%) patients had combined bacteremia. The other baseline characteristics are shown in Table 1.
Outcomes In this study, the risk factors for mortality in septic patients differed according to the days of death. The SOFA score (adjusted hazard ratio [aHR]: 1.229, 95% confidence interval [CI]: 1.093–1.381, P = 0.001) and initial lactate level (aHR: 1.128, 95% CI: 1.034–1.230, P = 0.007) had a significant association with increased 7-day mortality. The increased 14-day mortality was significantly associated with Charlson comorbidity index (aHR: 1.115, 95% CI: 1.027–1.210, P = 0.014) and 2-hour lactate level (aHR: 1.115, 95% CI: 1.027–1.210, P = 0.009). The SOFA score was significantly associated with increased 28-day mortality (aHR: 1.077, 95% CI: 1.013– 1.144, P = 0.018). The risk of 7, 14, and 28-day mortality for overall study population were as follows; 7-day
mortality, aHR: 1.000, 95% CI 0.997-1.003, P = 0.967; 14-day mortality, aHR 1.000, 95% CI 0.998-1.002, P = 0.935; 28-day mortality, aHR 1.000, 95% CI 0.998-1.002, P = 0.795. The appropriateness of empirical antibiotic selection had no effect on the mortality rate. The association between 7, 14, and 28-day mortality and other variables are shown in Table 2. After sensitivity analysis, the results remained unchanged and the data are presented in Supplementary Table 1.
Association between the time to the antibiotics and the outcomes Antibiotics were administered in 74/482 (15.4%), 340/482 (70.5%), and 450/482 (93.4%) patients within 1, 3, and 6 hours, respectively. The mortality rate among patients who received antibiotics within 3 hours, after 3 hours, within 6 hours, and after 6 hours was 52% (177/340), 43% (61/142), 49.3% (222/450), and 50% (16/32), respectively. The time to antibiotics administration did not affect the 7, 14, and 28-day mortality in the multivariate analysis. The 28-day mortality was unaffected when it was compared by dividing the antibiotic administration time by one hour (data not shown). In subgroup analyses, there was no significant association between 28-day mortality and the time to antibiotics in patients with septic shock, bacteremia, and high-grade infection. Detailed results are presented in Supplementary Table 2-4. In addition, the appropriateness of empirical antibiotic administration was not associated with 7, 14, and 28day mortality in multivariate analysis and in the subgroup analysis in patients with septic shock, bacteremia, and high-grade infection.
DISCUSSION This study showed that the time to antibiotic administration did not significantly affect the 7, 14, and 28-day mortality rates and the prognosis of septic patients after the application of the new Sepsis-3 definition. Notably, the outcome of patients with sepsis was approached from a physiologic point of view by analyzing mortality according to date. The 28-day mortality was relatively high (about 50%) because the study population was restricted to those whose follow-up and time for antibiotics administration were clearly identified. The SOFA score affected the 7 and 28-day mortality in overall sepsis patients. The SOFA score, which
reflects organ dysfunction, is a critical indicator for the evaluation of severity in sepsis, and it has become the most critical indicator since the introduction of Sepsis-3 definition. Although the concept of severe sepsis has been removed, we demonstrated that a high SOFA score may reflect the severity of sepsis by affecting the 7-day mortality which represents the severity of early sepsis [20]. Indeed, even in the subgroup analysis of patients with septic shock, bacteremia, and high-grade infection, the SOFA score affected the 7-day mortality. In addition, the SOFA score affected the 28-day mortality which was a critical factor in the diagnosis and prognosis of sepsis [21,22]. The initial lactate level affected the 7-day mortality in overall sepsis and all subgroup analyses patients. Meanwhile, the 2-hour lactate level affected the 14-day mortality of all sepsis, septic shock, and bactermic patients, and 28-day mortality of patients with septic shock. The lactate level of sepsis patients is a new concept introduced in the Sepsis-3 definition, and it is associated with early prognosis, especially in severe infection. Although controversial, some prior studies recommended normalization of lactate levels for the management of sepsis [15,23,24]. The 2-hour lactate level may be an indicator that determines the success of rapid resuscitation in sepsis patients suggesting that early resuscitation is critical for the management of sepsis and that the 2-hour lactate level must be checked [12, 19, 20]. Another factor related to the 14-day mortality is the Charlson comorbidity index, and this indicator may affect shock resilience which is critical for the success of resuscitation. Comorbidity has been reported to be associated with short- and long-term prognosis of sepsis in previous studies [25-27]. This study supports that comorbidity may affect the prognosis of sepsis, especially short-term prognosis. The time to antibiotics did not affect the 28-day mortality, and only the SOFA score was related to 28-day mortality. Previously, some large retrospective studies with high rates of septic shock suggested that the time to antibiotics affects mortality [4-8]. Subsequent studies, including several prospective studies that included patients with mild sepsis who were treated with qualified resuscitation following the sepsis bundle, suggested that the time to antibiotics did not affect mortality [9-13]. Therefore, we performed subgroup analysis in patients with septic shock, bacteremia, and high-grade infection; but the time to antibiotics was not associated with mortality. The time to antibiotics did not affect the outcome for the following reasons. First, in this study, the time to antibiotic was shorter than in other studies (median 112 minutes; 70.5% within 3 hours; 93.4% within 6 hours).
This is consistent with the study that showed no correlation between the time to antibiotics and 30-day mortality rate when adequate appropriate antibiotics, for which culture results were confirmed, were administered within 12 hours in patients with sepsis [29]. Second, in addition to the early administration of antibiotics, well-trained resuscitation may be a confounding variable.. In fact, another study by our research team reported that the rate of overall compliance with surviving sepsis campaign bundle was 83.3% [30]. Our observation that the time to antibiotics is not related to mortality does not imply that rapid antibiotics administration is not necessary. Rather, we want to emphasize that other critical goals should not be ignored for the sake of rapid antibiotic administration such as the efforts to find the cause of shock and site of infection, improvement of compliance of sepsis bundle, advances in antimicrobial stewardship, and the avoidance of broad-spectrum antibiotics to minimize antimicrobial resistance. We assumed that the appropriateness of the initial empirical antibiotics was relevant; however, it was not associated with the outcomes of patients with sepsis. The rate of the appropriateness of the empirical antibiotics in this study was 78% which was higher than 53% reported in previous studies [11,28,31], and this did not affect the prognosis of sepsis. However, a review article pointed out the methodological limitation of prior studies regarding the association between appropriate antibiotic therapy and mortality [32]. We also recognized the methodological limitations in defining and evaluating the appropriateness assessment. To overcome the limitation, we conducted a subgroup analysis on bacteremia patients and the outcomes remained unchanged. Further study is needed on the appropriateness of antibiotics for sepsis, which is validated on systematic methods. The advantages of this study are as follows. First, to our knowledge, this is the first prospective study to evaluate the relationship between the time to antibiotic and outcome of septic patients with Sepsis-3 definition. As the Sepsis-3 definition includes more actual sepsis patients than the previous Sepsis-2 definition, this increases the reliability of the results. Second, the study population was composed of a relatively homogenous group of patients who were admitted via the ED. In addition, we further refined the study population by excluding patients who had received antibiotics at the referred hospital or were lost to follow-up. The limitation of this study is that the study population was not large. We inevitably extended the study period to 3 years to increase the statistical significance. This included patients before the introduction of the Sepsis-3 definition, but the application of the Sepsis-3 definition was not a problem because the previous definition was more extensive. Additional follow-up study with Sepsis-3 definition would provide the detailed causal relationship between the
time to antibiotics administration and outcome in septic patients. In addition, we did not reflect the adequacy of resuscitation which may be a critical variable for the mortality of sepsis. In terms of defining and evaluating the appropriateness of antibiotics, this study has a methodological limitation in that it did not apply a validated and systematic method. In conclusion, the time to antibiotics administration did not affect 7, 14, and 28-day mortality in the treatment of patients with sepsis who visited the ED. Rather, the severity of sepsis was associated with 7-day mortality, and the success of resuscitation and comorbidity were significant factors affecting the 14-day mortality. The relatively adequate antibiotic administration within a reasonable time along with well-trained and rapid resuscitation may improve the prognosis of patients with sepsis.
Funding This work was supported by funding from the Korea University Medical Center [grant number K1722241] which was received by Dae Won Park.
Conflict of interest All authors certify that there are no potential conflicts of interest to declare.
Authors’ contribution Conceptualization: HS and DWP conceived the idea. JS and JHJ collected the data. HS, HKC, WSC, SM, and DWP analyzed the data. HS and DWP prepared the manuscript and made final edition of the document. All authors have read and approved the manuscript.
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Table 1. Baseline characteristics of the study population
Variables
Overall patients (n=482)
Septic shock (n=203)
Bacteremia (n=154)
High-grade infection (n=312)
Age, years
72 ± 15 (65–82)
71 ± 15 (61-81)
73 ± 14 (66-82)
71 ± 16 (64-82)
267 (55.4)
114 (56.2)
76 (49.4)
194 (62.2)
4 (3–6)
4 (3-6)
5 (3-6)
4 (3-6)
Community
182 (37.8)
77 (37.9)
54 (35.1)
111 (35.6)
Hospital
102 (21.2)
53 (26.1)
32 (20.8)
66 (21.2)
LTCF
198 (41.1)
73 (36.0)
68 (44.2)
135 (43.3)
High-grade
312 (64.7)
127 (62.6)
80 (51.9)
Low-grade
170 (35.3)
76 (37.4)
74 (48.1)
SOFA score
8 (5–10)
10 (8-12)
9 (7-11)
8 (5-10)
Septic shock
203 (42.1)
75 (48.7)
127 (40.7)
CRP (mg/dl)
10.33 (4.43–18.55)
11.42 (4.72-20.50)
14.18 (7.82-22.74)
10.07 (4.13-18.45)
Procalcitonin (ng/ml)
1.53 (0.34–12.79)
4.32 (0.87-27.10)
6.08 (1.15-27.33)
0.93 (0.28-6.74)
Initial lactate (mmol/l)
2.8 (1.8–5.2)
4.7 (2.9-7.8)
3.2 (1.9-6.1)
2.8 (1.8-5.1)
2-hour lactate (mmol/l)
2.1 (1.4–3.4)
3.2 (2.0-5.8)
2.2 (1.3-4.2)
2.3 (1.4-3.7)
154 (32.0)
75 (36.9)
115 (76–207)
106 (72-180)
113 (72-190)
118 (73-217)
74 (15.4)
31 (15.3)
28 (18.2)
49 (15.7)
Male Charlson comorbidity index Onset
Grade of infection
Bacteremia Time to antibiotics administration, minutes Antibiotics administration within 1 hour
80 (25.6)
Antibiotics administration within 3 hours
340 (70.5)
156 (76.8)
114 (74.0)
212 (67.9)
Antibiotics administration within 6 hours
450 (93.4)
192 (94.6)
146 (94.8)
287 (92.0)
Appropriateness of empirical antibiotics administration
375 (77.8)
156 (76.8)
107 (69.5)
244 (78.2)
All-cause 7-day mortality
94 (19.5)
59 (29.1)
36 (23.4)
57 (18.3)
All-cause 14-day mortality
162 (33.6)
89 (43.8)
59 (38.3)
103 (33.0)
All-cause 28-day mortality
238 (49.4)
132 (65.0)
80 (51.9)
161 (51.6)
NOTE. Data are expressed as number (%) of patients or median (interquartile range) unless otherwise indicated. LTCF, long-term care facility; CRP, C-reactive protein; SOFA, sequential organ failure assessment
Table 2. Risk factors for 7, 14, and 28-day mortality in overall sepsis patients
7-day mortality Variables
Univariate analysis
14-day mortality
Multivariate analysis
Univariate analysis
28-day mortality
Multivariate analysis
Univariate analysis
Multivariate analysis
HR (95% CI)* P-value HR (95% CI)* P-value HR (95% CI)* P-value HR (95% CI)* P-value HR (95% CI)* P-value HR (95% CI)* P-value Male
0.791 (0.528–1.186)
0.256
Age
1.013 (0.998–1.028)
0.098
CCI
1.185 <0.001 (1.078–1.303)
0.986 (0.959-1.015) 1.172 (0.997–1.378)
0.791 (0.581–1.076)
0.136
0.887 (0.687–1.144)
0.355
0.342
1.010 (0.999–1.022)
0.068
1.008 (0.999–1.017)
0.093
0.055
1.140 (1.058–1.229)
0.001
0.014
1.082 (1.015–1.153)
0.015
1.115 (1.027–1.210)
1.092 (0.995–1.198)
0.064
Onset Community 1.283
Hospital
1.085 (0.656–1.796)
0.751
0.968 (0.646–1.450)
0.874
0.964 (0.524-1.776)
0.908
1.037 (0.746–1.440)
0.830
LTCF
0.637 (0.396–1.025)
0.063
0.739 (0.521–1.049)
0.091
0.624 (0.357-1.092)
0.099
0.737 (0.551–0.986)
0.040
Grade of infection
0.826 (0.546–1.249)
0.365
0.934 (0.678–1.286)
0.676
1.138 (0.867–1.493)
0.352
SOFA
1.192 (1.124-1.263)
<0.001
1.229 (1.093-1.381)
0.001
1.133 (1.082-1.186)
<0.001
0.999 (0.916-1.091)
0.988
1.167 (1.123-1.213)
<0.001
1.077 (1.013-1.144)
0.018
Septic shock
2.564 (1.687-3.897)
<0.001
0.857 (0.316-2.321)
0.761
1.989 (1.459-2.712)
<0.001
1.175 (0.629-2.197)
0.613
2.124 (1.645-2.745)
<0.001
1.192 (0.728-1.951)
0.486
CRP
1.001 (0.982–1.021)
0.905
1.004 (0.989–1.018)
0.622
1.007 (0.995–1.019)
0.231
Procalcitonin
1.007 (1.001–1.014)
0.021
1.006 (1.001–1.011)
0.029
1.005 (1.000–1.009)
0.032
1.007 (0.998–1.016)
0.139
1.002 (0.994–1.010)
0.632
(0.797–2.066) 0.719 (0.460–1.124)
1.000 (0.994–1.007)
0.306 0.148
0.927
Lactate
1.099 <0.001 (1.061–1.139)
2-hour lactate
1.250 <0.001 (1.149–1.359)
Bacteremia
1.415 (0.933–2.145)
0.102
Timing of antibiotics
1.000 (0.999–1.002)
0.810
Antibiotics within 1 hour
0.716 (0.381–1.342)
Antibiotics within 3 hours Appropriateness of antibiotics
1.128
0.007
1.060 (1.025–1.096)
0.001
0.374
1.137 (1.056–1.224)
0.001
1.312 (0.952–1.806)
0.097
1.000 (0.999–1.001)
0.937
0.297
0.822 (0.524–1.288)
1.317 (0.823–2.108)
0.251
0.821 (0.516–1.305)
0.404
(1.034–1.230) 1.080 (0.912–1.278)
1.000 (0.997-1.003)
0.967
0.957 (0.841–1.088)
0.500
1.051 (1.021–1.081)
0.001
0.009
1.120 (1.050–1.195)
0.001
1.074 (0.642-1.794)
0.786
1.170 (0.894–1.531)
0.254
1.000 (0.998-1.002)
0.935
1.000 (0.999–1.001)
0.468
0.392
0.960 (0.676–1.363)
0.820
1.196 (0.844–1.695)
0.314
1.279 (0.956–1.711)
0.097
0.752 (0.531–1.066)
0.109
0.894 (0.662–1.209)
0.460
1.115 (1.027–1.210)
0.959 (0.862–1.066) 1.096 (0.976–1.230)
1.000 (0.998-1.002)
0.435 0.122
0.795
NOTE. *Values above 1 indicate increased risk, while lower levels indicate reduced risk. HR, hazard ratio; CI, confidence interval; CCI, Charlson comorbidity index; LTCF, long-term care facility; CRP, C-reactive protein; SOFA, sequential organ failure assessment