We aimed to investigate the effect of timely antibiotic administration on outcomes in patients with severe sepsis and septic shock.
We analyzed data from a sepsis registry that included adult patients who initially presented to the emergency department (ED) and met criteria for severe sepsis or septic shock. Timely antibiotic use was defined as administration of a broad-spectrum antibiotic within three hours from the time of ED arrival. Multivariable logistic and linear regression analyses were performed to assess associations between timely administration of antibiotics and outcomes, including hospital mortality, 48-hour change in Sequential Organ Failure Assessment (SOFA) score (delta SOFA), and hospital length of stay (LOS).
A total of 591 patients were included in the study. In-hospital mortality was 16.9% for patients receiving timely antibiotics (n=377) and 22.9% for patients receiving delayed antibiotics (n=214; P=0.04). The adjusted odds ratio for in-hospital survival was 0.54 (95% confidence interval [CI], 0.34 to 0.87; P=0.01) in patients who received timely antibiotics. Timely antibiotic administration was also significantly associated with higher delta SOFA (2 vs. 1) and shorter hospital LOS among survivors (11 days vs. 15 days). Multivariable linear regression analyses showed that timely antibiotic administration was significantly associated with increased delta SOFA and decreased hospital LOS.
Antibiotic administration within three hours from the time of ED arrival was significantly associated with improved outcomes, including in-hospital survival, reversal of organ failure, and shorter hospital LOS, in patients with severe sepsis and septic shock.
Timely antibiotic administration is a particularly crucial element for survival in patients with severe sepsis and septic shock.
Timely administration of antibiotics was also associated with better reversal of organ failure and reduction of hospital length of stay.
Severe sepsis and septic shock are severe illnesses caused by infection that can lead to death through progression of systemic inflammatory response syndrome and multiple organ failure [
Proper treatment of the infection source is vital for effective and prompt treatment of patients with severe sepsis and septic shock. Early antibiotic treatment is a particularly crucial element [
This study explored the differences in prognosis based on early administration of antibiotics as recommended by the SSC guidelines in ED patients with severe sepsis and septic shock. We investigated the effect of early antibiotic administration on outcomes by assessing in-hospital mortality, hospital length of stay (LOS), and recovery from organ failure.
Using a retrospective cohort study design, we analyzed data from a sepsis registry comprised of patients who presented to the ED of Samsung Medical Center, an urban tertiary teaching hospital with 70,000 visits per year. The Institutional Review Board approved this study, and informed consent was waived because the study was retrospective and no intervention was required.
The subjects of this study were patients over 18 years of age with severe sepsis who had initial blood lactate concentrations of over 4 mmol/L and septic shock diagnosed at the time of ED arrival between August 2008 and March 2012. We excluded patients with terminal malignancies or a previously signed “Do Not Attempt Resuscitation (DNAR)” order, as well as patients who refused early goal-directed therapy.
Sepsis was defined as suspected or confirmed infection in the presence of two or more systemic inflammatory response syndrome criteria. The systemic inflammatory response syndrome is defined by two or more of the following conditions: (1) body temperature greater than 38°C or less than 36°C; (2) heart rate greater than 90 beats per minute; (3) respiratory rate greater than 20 breaths per minute or PaCO2 of less than 32 mmHg; and (4) white blood cell count greater than 12,000/mm3, less than 4,000/mm3, or the presence of more than 10% immature neutrophils (“bands”) [
Early antibiotic use was defined as administration of a broad-spectrum antibiotic within three hours from the time of ED arrival [
We analyzed the sepsis registry, which had been prospectively collected since August of 2008, for relevant patients presenting to the ED [
For intergroup comparisons, data included detailed patient characteristics, comorbidities, vital signs, sites of infection, hemodynamic indices, laboratory data, use of vasopressors, and use of mechanical ventilation. Data about achievements of early resuscitation targets were also recorded, including MAP ≥65 mmHg, central venous pressure (CVP) ≥8 mmHg, and central venous oxygen saturation (ScvO2) ≥70%. We assessed the achievement of resuscitation targets in six hours from the time zero, which was defined as when either hypotension or hyperlactatemia greater than 4 mmol/L was reported. If central line insertion followed by measurement of ScvO2 was not performed, the targets of CVP and ScvO2 were considered as not achieved. Acute Physiology and Chronic Health Evaluation (APACHE) II scores were examined for assessment of severity [
In-hospital mortality was the primary endpoint, and the secondary endpoints were 48-hour change in SOFA score, which reflected recovery from organ failure (delta SOFA=SOFA at ED recognition - SOFA after 48 hours); hospital LOS; intensive care unit (ICU)admission rate; and length of ICU stay [
Continuous variables were presented as the median and interquartile range (IQR), and the Wilcoxon rank sum test was used for comparisons. Categorical variables were compared using the chi-squared test. For analysis of the association with the in-hospital mortality rate, potential confounding variables were introduced in a backward stepwise logistic regression model (variable exit threshold set at P>0.05) including demographic factors (age, comorbidities, sites of infection), severity factors (APACHE II score, initial blood lactate concentration), and treatment factors (achievement of early resuscitation targets). The Hosmer-Lemeshow test was used to check the goodness of fit of the logistic regression. Correlation analyses were performed to evaluate the impacts of early antibiotic administration on delta SOFA and hospital LOS of survivors through multivariable linear regression analysis with backward stepwise procedures as above. Hospital LOS was analyzed after log transformation to achieve normality for linear regression analysis. A P-value less than 0.05 was considered significant. STATA ver. 11.0 (STATA Co., College Station, TX, USA) was used for statistical analysis.
Among a total of 738 patients with severe sepsis and septic shock, 591 patients were analyzed (
The in-hospital mortality rate was 16.2% for the early administration group and 22.9% for the delayed administration group, with a significant difference (P=0.04) (
In multivariable logistic regression analysis adjusted for confounding factors, early administration of antibiotics was independently associated with reduction of the in-hospital mortality rate (adjusted odds ratio [OR], 0.54; 95% confidence interval [CI], 0.34 to 0.87; P=0.01) (
In multivariable linear regression analysis on delta SOFA, early administration of antibiotics was significantly associated with an increase in the delta SOFA, which is evidence that early administration of antibiotics is related to recovery from organ failure (coefficient, 0.73; standard error, 0.36; P=0.04) (
This study analyzed the effect of timely administration of a broad-spectrum antibiotics to patients with severe sepsis and septic shock, as recommended by the 2012 SSC guidelines, on prognostic factors, including in-hospital mortality rate, level of recovery from organ failure, and the length of hospitalization. In this study, early administration of antibiotics was significantly associated with survival to hospital discharge and also had significant associations with reduction of 48-hour SOFA scores and reduced hospital LOS.
The correlation between timely administration of antibiotics and mortality rates among infected patients has been previously studied in community-dwelling patients with pneumonia, and McGarvey and Harper [
This study demonstrated that delayed administration of antibiotics for patients with severe sepsis and septic shock might worsen organ dysfunction or reduce the level of recovery of organs, which may consequently extend the length of treatment. Our results were adjusted for severity and achievement of early resuscitation targets, and demonstrated that early administration of antibiotics is an important qualitative index in the treatment of patients with severe sepsis and septic shock. In particular, it is noteworthy that although the group with early administration had a relatively high level of severity, the early administration group had a better prognosis. These results imply that delayed administration of antibiotics might not just increase the mortality rate but also raise the risk of complications during treatment, extend the length of hospitalization, and lead to increased medical costs.
Multiple steps, such as the initial examination, blood tests, diagnosis of sepsis, blood cultures, and prescription of antibiotics, are required before the actual administration of antibiotics, which makes timely administration difficult [
It is not only important that antibiotic administration be prompt, but that the antibiotics used in the early stages of sepsis are appropriate for the causative pathogens [
Our study was a retrospective observational study and had the following limitations. First, as a study of a single institution, the results of the study cannot be generalized to other institutions. Second, with a small study population, the administration time of antibiotics was not specifically analyzed, and we were unable to evaluate for a linear relationship between prognosis and time of antibiotic use, and we did not determine the ideal administration time for antibiotics. Third, although this study observed a relationship between appropriate timing of antibiotics and recovery from organ failure and length of hospitalization, we were unable to evaluate the mechanism by which early administration of antibiotics affects the recovery of organ failure and length of hospitalization. Additional studies are required to evaluate organ failure in detail. Lastly, although this study used a prospectively collected registry, additional data were collected through medical records. In conclusion, early administration of antibiotics within three hours from ED arrival for patients with severe sepsis or septic shock was significantly associated with reduced in-hospital mortality, recovery of organ dysfunction, and decreased hospital LOS.
No potential conflict of interest relevant to this article was reported.
Comparison of baseline patient characteristics
Variable | All patients (n=591) | Early group (n=377) | Delayed group (n=214) | P-value |
---|---|---|---|---|
Age (yr) | 66 (55-73) | 65 (55-73) | 67 (57-73) | 0.46 |
Gender (male) | 330 (55.8) | 214 (56.8) | 116 (54.2) | 0.55 |
Comorbidities | ||||
Hypertension | 193 (32.7) | 126 (33.4) | 67 (31.3) | 0.60 |
Diabetes | 132 (22.3) | 73 (19.4) | 59 (27.6) | 0.02 |
Cardiovascular disease | 65 (11.0) | 45 (11.9) | 20 (9.4) | 0.33 |
Chronic lung disease | 35 (5.9) | 25 (6.6) | 10 (4.7) | 0.33 |
Chronic renal disease | 27 (4.6) | 15 (4.0) | 12 (5.6) | 0.36 |
Chronic hepatic disease | 60 (10.2) | 35 (9.3) | 25 (11.7) | 0.35 |
Malignancy | 339 (57.4) | 221 (58.6) | 118 (55.1) | 0.41 |
Neutropenia | 100 (16.9) | 75 (19.9) | 25 (11.7) | 0.10 |
Suspected infection site | 0.54 | |||
Intra-abdominal infection | 229 (38.8) | 138 (36.6) | 91 (42.5) | 0.16 |
Pneumonia | 166 (28.1) | 108 (28.7) | 58 (27.1) | 0.69 |
Urinary tract infection | 94 (15.9) | 63 (16.7) | 31 (14.5) | 0.48 |
Others | 102 (17.3) | 68 (18.0) | 34 (15.9) | 0.51 |
Initial vital signs | ||||
MAP (mmHg) | 71 (60-84) | 71 (58-83) | 71 (62-86) | 0.19 |
Heart rate (/min) | 114 (97-132) | 114 (98-133) | 114 (95-130) | 0.37 |
Respiratory rate (/min ) | 20 (20-24) | 20 (20-24) | 20 (20-24) | 0.64 |
Body temperature (°C) | 38.0 (36.8-38.9) | 38.2 (37.0-39.0) | 37.2 (36.6-38.6) | <0.01 |
Positive blood culture | 233 (39.4) | 151 (40.1) | 82 (38.3) | 0.68 |
nitial presentation with hypotension | 247 (41.8) | 181 (48.0) | 66 (30.8) | < 0.01 |
nitial serum lactate (mmol/L) | 4.8 (4.1-6.4) | 4.8 (3.9-6.4) | 5.0 (4.2-6.2) | 0.27 |
APACHE II score | 15 (10-19) | 15 (11-20) | 14 (10-18) | 0.03 |
Jse of vasopressors within 24 hr | 364 (61.6) | 244 (64.7) | 120 (56.1) | 0.04 |
Mechanical ventilation | 78 (13.2) | 47 (12.5) | 31 (14.5) | 0.49 |
Targets of initial resuscitation | ||||
CVP≥8 mmHg achieved | 301 (50.9) | 206 (54.6) | 95 (44.4) | 0.02 |
MAP≥65 mmHg achieved | 582 (98.5) | 372 (98.7) | 210 (98.1) | 0.60 |
ScvO2≥70% achieved | 296 (50.1) | 206 (54.6) | 90 (42.1) | < 0.01 |
Values are presented as median (interquartile range) or number (%).
APACHE, Acute Physiology and Chronic Health Evaluation; CVP, central venous pressure; MAP, mean arterial pressure; ScvO2, central venous oxygen saturation.
Comparison of outcomes including in-hospital mortality, delta SOFA, and length of hospital stay
Variable | All patients (n=591) | Early group (n=377) | Delayed group (n=214) | P-value |
---|---|---|---|---|
In-hospital mortality | 110 (18.6) | 61 (16.2) | 49 (22.9) | 0.04 |
SOFA score | ||||
Baseline | 7 (4-9) | 7 (4-10) | 6.5 (3-9) | 0.01 |
48 hours | 4 (2-7) | 4 (2-7) | 4 (1-8) | 0.61 |
Delta SOFA | 2 (0-4) | 2 (0-5) | 1 (-1 to 3) | < 0.01 |
In-hospital LOS (day) | ||||
All patients | 12 (7-22) | 11 (7-21) | 14.5 (8-24) | < 0.01 |
Survivors only | 12 (8-22) | 11 (8-22) | 15 (9-23) | < 0.01 |
ICU admission | 303 (51.3) | 190 (50.4) | 113 (52.8) | 0.57 |
LOS in ICU (day) | 3 (2-7) | 3 (2-6) | 3 (2-8) | 0.12 |
Values are presented as number (%) or median (interquartile range).
SOFA, Sequential Organ Failure Assessment; LOS, length of stay; ICU, intensive care unit.
Multivariable logistic regression analysis to identify independent predictors of in-hospital mortality
Variable | Adjusted OR | 95% CI | P-value |
---|---|---|---|
Timely antibiotic use | 0.54 | 0.34-0.87 | 0.01 |
APACHE II score | 1.06 | 1.03-1.10 | <0.01 |
Infection focus | |||
Abdomen | Reference | ||
Pneumonia | 2.31 | 1.34-3.94 | <0.01 |
Urinary tract infection | 0.19 | 0.52-0.66 | <0.01 |
Others | 1.76 | 0.93-3.33 | 0.08 |
Initial serum lactate (mmol/L) | 1.20 | 1.03-1.10 | <0.01 |
Hosmer-Lemeshow goodness-of-fit test, P=0.83.
OR, odds ratio; CI, confidence interval; APACHE, Acute Physiology and Chronic Health Evaluation.
Multivariable linear regression analysis for the delta SOFA and in-hospital length of stay
Variable | Regression coefficient | Standard error | P-value |
---|---|---|---|
Analysis for the delta SOFA | |||
Timely antibiotic use | 0.73 | 0.36 | 0.04 |
APACHE II score | 0.06 | 0.02 | <0.01 |
Initial serum lactate | -0.29 | 0.06 | <0.01 |
ScvO2 ≥ 70% achieved | 1.20 | 0.35 | <0.01 |
Analysis for in-hospital LOS |
|||
Timely antibiotic use | -0.28 | 0.08 | <0.01 |
APACHE II score | 0.01 | 0.01 | 0.06 |
Chronic renal disease | 0.36 | 0.18 | 0.05 |
Chronic hepatic disease | 0.39 | 0.13 | <0.01 |
Malignancy | 0.22 | 0.08 | 0.01 |
CVP≥8 mmHg achieved | 0.19 | 0.08 | 0.02 |
SOFA, Sequential Organ Failure Assessment; APACHE, Acute Physiology and Chronic Health Evaluation; ScvO2, central venous oxygen saturation; LOS, length of stay; CVP, central venous pressure.
The In-hospital LOS values were log transformed in order to obtain a normal distribution.