Im 

et al. Critical Care (2022) 26:19

https://doi.org/10.1186/s13054-021-03883-0

RESEARCH Open Access

Time‑to‑antibiotics and clinical outcomes

in patients with sepsis and septic shock:
a prospective nationwide multicenter cohort
study
Yunjoo Im1†, Danbee Kang2†, Ryoung‑Eun Ko3, Yeon Joo Lee4, Sung Yoon Lim4, Sunghoon Park5, Soo Jin Na3,
Chi Ryang Chung3, Mi Hyeon Park6, Dong Kyu Oh6, Chae‑Man Lim6 and Gee Young Suh1,3,7* on behalf of the
Korean Sepsis Alliance (KSA) investigators 

Abstract 
Background:  Timely administration of antibiotics is one of the most important interventions in reducing mortality
in sepsis. However, administering antibiotics within a strict time threshold in all patients suspected with sepsis will
require huge amount of effort and resources and may increase the risk of unintentional exposure to broad-spectrum
antibiotics in patients without infection with its consequences. Thus, controversy still exists on whether clinicians
should target different time-to-antibiotics thresholds for patients with sepsis versus septic shock.
Methods:  This study analyzed prospectively collected data from an ongoing multicenter cohort of patients with
sepsis identified in the emergency department. Adjusted odds ratios (ORs) were compared for in-hospital mortality
of patients who had received antibiotics within 1 h to that of those who did not. Spline regression models were used
to assess the association of time-to-antibiotics as continuous variables and increasing risk of in-hospital mortality. The
differences in the association between time-to-antibiotics and in-hospital mortality were assessed according to the
presence of septic shock.
Results:  Overall, 3035 patients were included in the analysis. Among them, 601 (19.8%) presented with septic shock,
and 774 (25.5%) died. The adjusted OR for in-hospital mortality of patients whose time-to-antibiotics was within 1 h
was 0.78 (95% confidence interval [CI] 0.61–0.99; p = 0.046). The adjusted OR for in-hospital mortality was 0.66 (95% CI
0.44–0.99; p = 0.049) and statistically significant in patients with septic shock, whereas it was 0.85 (95% CI 0.64–1.15;
p = 0.300) in patients with sepsis but without shock. Among patients who received antibiotics within 3 h, those with
septic shock showed 35% (p = 0.042) increased risk of mortality for every 1-h delay in antibiotics, but no such trend
was observed in patients without shock.

*Correspondence: [email protected]
†
Yunjoo Im and Danbee Kang have contributed equally to this work.
1
Division of Pulmonary and Critical Care Medicine, Department
of Medicine, Samsung Medical Center, Sungkyunkwan University School
of Medicine, Seoul, Republic of Korea
Full list of author information is available at the end of the article
Monitored email for (KSA) investigators:  [email protected]

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Im et al. Critical Care (2022) 26:19 Page 2 of 10

Conclusion:  Timely administration of antibiotics improved outcomes in patients with septic shock; however, the
association between early antibiotic administration and outcome was not as clear in patients with sepsis without
shock.
Keywords:  Sepsis, Septic shock, Time-to-antibiotics, Hour-1 bundle, Mortality

Take‑home message Methods

Timely administration of antibiotics improved outcomes Study design and population
in patients with septic shock. However, the association This prospective cohort study used data from an ongo-
between early antibiotic administration and outcome was ing nationwide cohort of the Korean Sepsis Alliance.
not as clear in patients with sepsis without shock. Patients were enrolled from 19 participating hospitals
between September 2019 and December 2020. The pro-
Introduction tocols for patient enrollment and data collection have
Sepsis is a life-threatening syndrome characterized by been described previously [18]. Patients were included
physiological, pathological, and biochemical abnormali- if they were  19  years old and diagnosed with sepsis or
ties that are induced by infection and associated with septic shock in the emergency department. The diagno-
multiorgan failure and high mortality [1]. Compelling ses of sepsis and septic shock were based on the third
evidence has shown that delay in the initiation of appro- International Consensus Definitions for Sepsis and Septic
priate antibiotic therapy is a risk factor for mortality; Shock (Sepsis-3) [1]. Patients were excluded if they were
therefore, administration of antibiotics is recognized as a not admitted to hospital wards or the intensive care unit
key component in the early treatment of sepsis [2–7]. In (ICU), not prescribed antibiotics, prescribed antibiotics
this regard, antibiotic administration has been included that was not in accordance with guidelines, prescribed
in the hour-1 bundle of the previous Surviving Sepsis antibiotics for which the cultured organism proved to be
Campaign guidelines, and the implementation of the resistant [8], or if their antibiotics were prescribed more
hour-1 bundle was highly recommended to reduce mor- than 12 h after time zero.
tality and morbidity [8, 9]. Indeed, several multinational The study was approved by the institutional review
studies reported that compliance to the Surviving Sep- boards of each participating hospital, and the require-
sis Campaign bundle was associated with mortality in ment for informed consent was waived because of the
patients with sepsis [10, 11]. noninterventional observational nature of the study.
Nevertheless, considerable controversy still exists
regarding the association between the time of antibiotic Clinical data collection
administration and clinical outcomes in patients with Data on demographic characteristics, coexisting con-
sepsis/septic shock, and whether the administration of ditions, severity of illness, treatment, and clinical
antibiotics within 1 h could improve outcomes in patients outcomes were collected. These variables included
with sepsis [12, 13]. The Infectious Diseases Society of demographic factors, such as age, sex, body mass index,
America recommends that the aggressive administra- comorbidities, Charlson comorbidity index score, his-
tion of antibiotics within 1  h might not be beneficial in tory of antibiotic administration or hospitalization for
sepsis [14] and may result in unintentional exposure to two or more days within the past 90  days before pre-
broad-spectrum antibiotics [15]. The American College senting to the emergency department, Clinical Frailty
of Emergency Physicians also noted a lack of evidence to Scale, admission source (e.g., other hospitals, skilled
recommend a strict time threshold for antibiotic admin- nursing facility, or home), measures of illness severity
istration in cases with sepsis [16]. In addition, organizing using the Sequential Organ Failure Assessment (SOFA)
timely administration of antibiotics requires considerable score [19], recognition of sepsis by physicians in the
effort and resources, and it may not be feasible to admin- emergency department, infection data including site of
ister antibiotics within 1 h of presentation in all patients infection (e.g., respiratory, abdominal, urinary, or skin/
with sepsis [17]. soft tissue), identification of pathogen, treatment data
Thus, this study aimed to evaluate the impact of time- including sepsis bundle compliance, appropriateness of
to-antibiotics on in-hospital mortality in patients with antibiotics, and time to administration of antibiotics,
sepsis. Furthermore, subgroup analysis was performed to and clinical outcomes, including length of in-hospital
assess whether the effect of time-to-antibiotics was sig- stay, in-hospital mortality, and admission/transfer to the
nificantly different between the sepsis and septic shock ICU.
groups.
 Im et al. Critical Care (2022) 26:19 Page 3 of 10

Time-to-antibiotics was calculated as the time inter- prescription or hospitalization for two or more days
val from time zero, defined as the time of triage in the within the past 90  days before presentation to the
emergency department to the time of antibiotic admin- emergency department, median initial SOFA score
istration. Physicians were considered to have recognized (< 6 vs. ≥ 6), recognition of sepsis by physicians in the
sepsis if the diagnosis of sepsis was included in the differ- emergency department, site of infection (respiratory or
ential diagnosis list in the medical records. abdominal), identification of pathogen, and admission/
transfer to the ICU. The interaction of time-to-antibiot-
Statistical analysis ics within 1 h with clinical characteristics was evaluated
Participants’ baseline characteristics were summarized using Wald tests for cross-product terms in regression
as numbers and proportions for categorical variables and models.
mean with standard deviation or median with interquar- All tests were two-sided, and a p-value < 0.05 was con-

formed using SAS® Visual Analytics (SAS Institute Inc.,

tile range (IQR, 25th–75th percentiles) for continuous sidered statistically significant. All analyses were per-
variables. Preliminary analysis was performed to com-
pare the baseline characteristics and outcomes between USA) and STATA (version 14; StataCorp LP, College Sta-
patients who received antibiotics within 1  h and those tion, TX, USA).
after 1 h, using the Chi-square or Fisher’s exact tests for
categorical variables and the Mann–Whitney U test for Results
continuous variables. Study population
Odds ratios (ORs) with 95% confidence intervals (CIs) A total of 4251 patients were diagnosed with sepsis or
for in-hospital mortality were calculated using a condi- septic shock in the emergency department between Sep-
tional logistic regression model, considering between- tember 2019 and December 2020. Patients who were not
center differences as a stratification factor. To control for admitted to wards from the emergency room (n = 653),
other potential confounding factors, age, sex, Charlson had no available data for prescribed antibiotics (n = 78),
comorbidity index score, history of antibiotic prescrip- were prescribed antibiotics that was not in accordance
tion or hospitalization for two or more days within the with guidelines (n =  78), were prescribed antibiotics
past 90 days before presenting to the emergency depart- proved to be resistant to the cultured pathogen (n = 311),
ment, Clinical Frailty Scale, recognition of sepsis by phy- or had received antibiotics more than 12 h after time zero
sicians in the emergency department, initial SOFA score, (n = 96) were excluded. Consequently, 3035 patients were
diagnosis of sepsis or septic shock, site of infection, iden- included in the analyses (Fig. 1).
tification of pathogen, and admission/transfer to the ICU
were adjusted. Baseline characteristics of patients
Landmark analyses among patients who were alive The mean (standard deviation) age of study patients was
for more than 3  h after the diagnosis of sepsis or sep- 71.3 (13.5) years, 57.5% were men, and 601 (19.8%) were
tic shock were performed to avoid survivor treatment diagnosed with septic shock. The median time-to-antibi-
selection bias. In addition, time-to-antibiotics was mod- otics was 141  min (IQR, 80–230  min), and 512 (16.9%)
eled as a continuous variable using restricted cubic patients received antibiotics within 1 h.
splines with knots at the 5th, 35th, 65th, and 95th per- Compared to patients who did not receive antibiot-
centiles of the sample distribution to provide a flexible ics within 1 h, those who received antibiotics within 1 h
estimate of the dose–response relationship between were more likely to have a history of taking antibiotics
time-to-antibiotics and in-hospital mortality. In par- within the past 90  days (14.4% vs. 20.1%, p < 0.01), had
ticular, the association between in-hospital mortality a higher initial SOFA score (5 vs. 6, p < 0.01), and were
and time as a continuous variable was evaluated inde- diagnosed with septic shock (17.3% vs. 32.0%, p < 0.01)
pendently in patients receiving antibiotics within 3  h, (Table 1).
3  h  to 6  h, and after  6  h in patients with and without
septic shock. In‑hospital mortality
To assess the heterogeneity of associations between A total of 774 patients (25.5%) died during the study
administration of broad-spectrum antibiotics within period. No significant differences were found in unad-
an hour and in-hospital mortality, additional analyses justed in-hospital mortality between patients who
were performed by prespecified clinically relevant sub- received antibiotics within 1  h and those who did
groups defined by median age (< 75 vs. ≥ 75 years), sex, not receive antibiotics within 1  h (25.7% vs. 24.6%,
body mass index (< 25 vs. ≥ 25 kg/m2), Charlson comor- p = 0.61).
bidity index score (< 9 vs. ≥ 9) [20], history of antibiotic
Im et al. Critical Care (2022) 26:19 Page 4 of 10

Fig. 1  Flowchart of study participants

However, in the adjusted analysis, the OR for in- Subgroup analysis

hospital mortality of patients with time-to-antibiot- Subgroup analyses were performed to evaluate the influ-
ics within 1  h was 0.78 (95% CI 0.61–0.99; p = 0.046) ence of antibiotic administration within 1  h on in-hos-
compared to those with time-to-antibiotics not within pital mortality among the various subgroups (Fig.  4).
1 h. In subgroup analyses, the adjusted OR for in-hos- Administration of antibiotics within 1  h decreased
pital mortality in patients with sepsis without shock in-hospital mortality in patients with an initial SOFA
with time-to-antibiotics within 1  h was 0.85 (95% CI score > 6 (OR 0.65; 95% CI 0.48–0.87; p = 0.03) and those
0.64–1.15; p = 0.300). In patients with septic shock, who were recognized as having sepsis by physicians in
the adjusted OR for in-hospital mortality of patients the emergency department (OR 0.60; 95% CI 0.42–0.86;
with time-to-antibiotics within 1  h was 0.66 (95% CI p = 0.05). In addition, administration of antibiotics within
0.44–0.99; p = 0.049). The association between time- 1  h reduced in-hospital mortality in patients who were
to-antibiotics within 1  h and in-hospital mortality in younger than 75  years old (OR 0.63; 95% CI 0.44–0.91),
the landmark analysis, confined to patients who sur- did not have a history of antibiotic prescription within
vived more than 3 h, showed similar results to the pri- the past 90 days (OR 0.75; 95% CI 0.56–0.99), had non-
mary analysis (Table 2). pulmonary infection (OR 0.65; 95% CI 0.45–0.93), and
In spline regression models, the association between admitted to the ICU (OR 0.64; 95% CI 0.47–0.89).
time-to-antibiotics and in-hospital mortality was
nonlinear (p-value for nonlinear spline terms = 0.02,
Fig. 2), with a stronger association within 3 h of time- Discussion
to-antibiotics than that after 3  h (Fig.  3a). Within This multicenter prospective study assessed the impact of
3  h, patients with septic shock showed 35% (OR 1.35; time to administration of antibiotics on mortality in patients
95% CI 1.01–1.81; p = 0.042) increased risk of mor- with sepsis. For patients with septic shock, administration of
tality by every 1-h delay in antibiotic administration broad-spectrum antibiotics within 1 h of sepsis recognition
(Fig.  3b), but this trend was not observed in patients reduced in-hospital mortality. However, in patients with
without shock (OR 1.01; 95% CI 0.82–1.23; p = 0.94, sepsis without shock, the association between the antibiotic
Fig.  3c). Within the interval between 3 and 6  h and administration within 1 h and in-hospital mortality was not
after 6  h, no statistically significant increasing trends statistically significant. In spline regression models, limited
were observed in the association between time delay to patients who received antibiotics within 3 h, patients with
in antibiotic administration as a continuous variable septic shock showed an increased risk of mortality for every
and mortality in both patients with and without septic hour of delay in antibiotic administration, but no such trend
shock. was observed in those without shock.
 Im et al. Critical Care (2022) 26:19 Page 5 of 10

Table 1  Baseline characteristics of study participants according to time-to-antibiotics < 1 h or > 1 h (n = 3035)

Variables Administration of broad-spectrum antibiotics in 1 h p-value

No (n = 2523) Yes (n = 512)

Age, years 74 (63–81) 75 (65–81) 0.12

Sex, male 1448 (57.4) 298 (58.2) 0.74
Body mass index, kg/m2 21.8 (4.2) 22.0 (4.1) 0.41
Comorbidity
  Diabetes mellitus 966 (38.2) 200 (39.0) 0.75
  History of myocardial infarction 259 (10.3) 51 (9.9) 0.83
  Congestive heart failure 190 (7.5) 30 (5.9) 0.18
  Chronic neurological disease 495 (19.6) 88 (17.2) 0.20
  Chronic liver disease 280 (11.1) 51 (9.9) 0.68
  Chronic kidney disease 419 (16.6) 73 (14.2) 0.19
  Connective tissue disease 63 (2.5) 13 (2.5) 0.96
  Solid malignant tumors 474 (18.8) 99 (19.3) 0.78
Charlson comorbidity index score 5 (4–7) 5 (4–7) 0.14
  ≥ 9 336 (13.2) 70 (13.7) 0.83
History of antibiotic prescription within the past 90 days  < 0.01
  No 2070 (82.1) 390 (76.2)
  Yes 364 (14.4) 103 (20.1)
  Unknown 89 (3.5) 19 (3.7)
Hospitalization for two or more days within the past 90 days 1043 (41.3) 208 (40.6) 0.77
Clinical Frailty Scale 0.11
  Very fit 99 (3.9) 27 (5.3)
  Well 186 (7.4) 36 (7)
  Managing well 379 (15) 54 (10.5)
  Vulnerable 393 (15.6) 79 (15.4)
  Mildly frail 264 (10.5) 50 (9.8)
  Moderately frail 328 (13) 60 (11.7)
  Severely frail 479 (19) 115 (22.5)
  Very severely frail 380 (15.1) 86 (16.8)
  Terminally ill 15 (0.6) 5 (1)
Initial SOFA score 5 (4–8) 6 (4–9)  < 0.01
Septic shock 437 (17.3) 164 (32.0)  < 0.01
Recognition of sepsis by physicians in the emergency department 943 (37.4) 234 (45.7)  < 0.01
Site of infection*
  Respiratory 1199 (47.5) 259 (50.6) 0.21
  Abdominal 660 (26.2) 143 (27.9) 0.41
  Urinary 131 (5.2) 31 (6.1) 0.43
  Skin/soft tissue 90 (3.6) 13 (2.5) 0.24
Type of infection 0.16
  Community 1673 (66.3) 324 (63.3)
  Nursing home-acquired 179 (7.1) 29 (5.7)
  Nursing hospital-acquired 331 (13.1) 75 (14.6)
  Hospital-acquired 340 (13.5) 84 (16.4)
Identification of pathogen 1380 (54.7) 308 (60.2) 0.02
ICU admission/transfer 1205 (47.8) 288 (56.3)  < 0.01
Length of hospital stay, days 12 (6–20) 11 (6–19.5) 0.35
Bold values indicate parameters that are statistically significant
Data are presented as mean (SD), median (interquartile range), or number (%)
ER, emergency room; ICU, intensive care unit; SOFA, Sequential Organ Failure Assessment
*
Mutually nonexclusive
Im et al. Critical Care (2022) 26:19 Page 6 of 10

Table 2  Risk-adjusted odds ratios (95% confidence interval) for antibiotic administration [15, 16]. In addition, these data
in-hospital mortality associated with administration of broad- are compatible with the most recent guidelines from the
spectrum antibiotics in 1 h Surviving Sepsis Campaign, which recommends antibi-
In-hospital mortality Administration of broad- p-value otic administration within 1 h in patients with shock, but
spectrum antibiotics in 1 h prioritizes rapid assessment of the likelihood of infection
No Yes in patients with possible sepsis without shock [21].
OR (95% CI)* The evidence supporting previous recommendations
for administration of broad-spectrum antibiotics within
All participants (n = 3035)
1 h in all patients with sepsis was mainly from studies on
  Overall Reference 0.78 (0.61–0.99) 0.046
patients confined to septic shock or based on retrospec-
  Without septic shock Reference 0.85 (0.64–1.15) 0.300
tive studies [2–4, 22, 23]. Two recent multicenter stud-
  With septic shock Reference 0.66 (0.44–0.99) 0.049
ies with a large sample sizes also support the findings of
Landmark analysis (N = 3018)
our study. In a study that investigated the effect of time
  Overall Reference 0.78 (0.61–0.99) 0.046
to treatment on mortality of mandated emergency care
  Without septic shock Reference 0.86 (0.64–1.15) 0.310
for sepsis in 149 New York hospitals, the odds of in-hos-
  With septic shock Reference 0.65 (0.43–0.98) 0.042
pital mortality were increased by 7% for every hour of
Bold values indicate parameters that are statistically significant delay in antibiotic administration in patients with septic
*
To control for other potential confounding factors, age, sex, Charlson shock, but not in those without shock [24]. In a retro-
comorbidity index score (< 9 vs. ≥ 9), history of antibiotic prescription or
hospitalization for two or more days within the past 90 days before presenting spective analysis of 35,000 patients with sepsis admitted
to the emergency department, recognition of sepsis by physicians in the in the emergency department of 21 hospitals in North-
emergency department, Clinical Frailty Scale score, initial SOFA score,
diagnosis (sepsis or septic shock), site of infection (pulmonary vs. abdominal),
ern California, a delay in antibiotic administration was
identification of pathogen, admission/transfer to ICU were adjusted associated with increased odds of mortality, which was
greatest in patients with septic shock [25]. However, in
this study, an increased OR of mortality was observed in
all sepsis severity strata. Notably, in this study, the defi-
nition of sepsis was based on administrative codes, with
its inherent limitations. Another large multicenter study
conducted in US showed that early administration of
antibiotics was associated with reduced long-term mor-
tality in sepsis patients identified using Sepsis-3 crite-
ria [7]. But this study was designed retrospectively and
mostly included less severe patients; only 7.3% of patients
needed vasopressors within 24 h. In our study, sepsis was
diagnosed using the Sepsis-3 criteria, and to the best of
our knowledge, our study is the first to comprehensively
evaluate the association between the time-to-antibiotic
administration and mortality of patients with sepsis or
septic shock classified according to the new diagnostic
criteria in a large prospective multicenter cohort.
Fig. 2  Estimated odds ratios (ORs) for in-hospital mortality by
time-to-antibiotics with 95% confidence interval (CI)s. Solid line and Aggressive treatment with rapid initiation of broad-
long dashed lines represent OR and its 95% CIs spectrum antibiotics in all patients suspected of sepsis
entails unnecessary exposure to antibiotics of a signifi-
cant number of patients who do not need antibiotics
together with the associated risk of adverse effects of
One of our most notable findings was the different antibiotics, increased level of antimicrobial resistance,
impact of time-to-antibiotics on mortality in patients increased economic burden, and adverse outcomes
with sepsis with and without shock. This finding supports [14, 26, 27]. Moreover, most hospitals do not have the
the recent statements from the Infectious Diseases Soci- resources to administer antibiotics within 1  h to all
ety of America and American College of Emergency Phy- patients with suspected sepsis. In fact, in a previous
sicians that emphasize the insufficient evidence of a strict study that investigated the effect of time to treatment
time threshold in the administration of antibiotics in on mortality of mandated emergency care for sepsis in
patients with sepsis and suggests that patients with septic 149 New York hospitals, more than half of the patients
shock might derive the greatest benefit from immediate
 Im et al. Critical Care (2022) 26:19 Page 7 of 10

Fig. 3  a Estimated odds ratios (ORs) for in-hospital mortality by time-to-antibiotics with 95% confidence intervals (CI), confined to patients with
time-to-antibiotics within 3 h. b Estimated ORs for in-hospital mortality by time-to-antibiotics with 95% CIs, confined to patients without shock and
time-to-antibiotics within 3 h. c Estimated ORs for in-hospital mortality by time-to-antibiotics with 95% CIs, confined to patients with shock and
time-to-antibiotics within 3 h. Solid line and long dashed lines represent OR and its 95% CIs

with sepsis did not receive antibiotics within 3 h of sep- because the objective of the study was to examine the
sis onset despite the implementation of the severe sepsis impact of early administration of appropriate antibiotic
and septic shock management bundle [22]. Selecting a treatment on patient outcomes. In addition, the results
subpopulation of patients who could benefit most from were adjusted for all confounders thought to influence
this intervention could help in prioritizing areas of the outcome. Moreover, landmark analysis was per-
improvement in the management of sepsis/septic shock. formed as a sensitivity analysis to adjust for survivor
In addition to the presence of shock, our study indicates treatment selection bias.
that patients with several distinguishing characteristics Potential limitations should be acknowledged to fully
might benefit from early antibiotic treatment. A signifi- appreciate the results of our study. First, as this study was
cant reduction in in-hospital mortality was observed in conducted only in patients from 19 centers in the Repub-
patients who had higher SOFA scores or were admit- lic of Korea, the results might not be generalizable to
ted to the ICU due to early administration of antibiot- different regions. All participating centers were univer-
ics, suggesting that patients with clinically severe disease sity-affiliated with many tertiary referral centers. Second,
should receive antibiotics as soon as possible. Other fac- although this study included more than 3000 patients,
tors associated with improved survival were younger age, the generalizability of our findings was limited with a
non-pulmonary infection as the cause of sepsis, and no relatively small sample size. It might have underestimated
previous history of antibiotic treatment within 3 months. the effect of intravenous antibiotic administration in 1 h
Further studies are needed to confirm if patients with to reduce mortality in patients without shock, and might
these characteristics might benefit from the early admin- not have the enough power to decipher small but impor-
istration of antibiotics. One interesting factor associated tant difference in specific subgroups. Third, this study
with improved outcome was the recognition of sepsis by included only patients who were diagnosed with sepsis
the treating physician in the emergency room. This may at presentation to the emergency room. Thus, the results
also be a surrogate marker of patients’ disease severity may not be generalizable to patients with sepsis in the
because clinicians might be more inclined to give a diag- hospital.
nosis of sepsis to patients who are severely ill compared
to just labeling them according to the site of infection. Conclusion
It would be interesting to identify if better education of Timely administration of antibiotics improved outcomes
emergency physicians on the recognition and treatment in patients with septic shock; however, the association
of sepsis might lead to better outcomes in patients with between early antibiotic administration and outcome
sepsis [28]. was not as clear in those with sepsis without shock. Fur-
One of the strengths of our study is that biases associ- ther studies are warranted to investigate the relationship
ated with observational studies were reduced as much as between time-to-antibiotics and adverse outcomes in
possible. Patients who did not receive antibiotics or who patients with sepsis without shock.
did not receive appropriate antibiotics were excluded
Im et al. Critical Care (2022) 26:19 Page 8 of 10

Fig. 4  Risk-adjusted odds ratios (ORs) of in-hospital mortality by time-to-antibiotics in the prespecified subgroups for all study participants. Shown
are ORs, with 95% confidence intervals, for in-hospital death for each hour of time-to-antibiotics
 Im et al. Critical Care (2022) 26:19 Page 9 of 10

Abbreviations Received: 13 November 2021 Accepted: 23 December 2021

CI: Confidence intervals; ICU: Intensive care unit; IQR: Interquartile Range; OR:
Odds ratio; OS: Overall survival; SOFA: Sequential Organ Failure Assessment.

Acknowledgements
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