The Surviving Sepsis campaign is one of the most important tools to treat sepsis and decrease mortality. Hemoculture, lactate level, and adequate fluid resuscitation are critical in sepsis treatment, as well as the use of antibiotics [13]. The latest 3-h bundle to 1-h bundle sepsis protocol recommends that earlier antibiotics administration predict better outcomes in patients with sepsis [7, 13]. Three areas of focus in current research in patients with sepsis have indicated that patients should receive the appropriate drug at the right time and dose. Previous studies showed better outcomes focusing only on the right time when they got antibiotics earlier than 1 h [21].
The Surviving Sepsis campaign 2021 recommend administering antimicrobials immediately, ideally within 1 h for adults with definite sepsis or probable and shock patient with possible sepsis. In possible sepsis patients without shock, they suggested an immediate investigation if concern for infection persists and antibiotics administration within 3 h [22]. The sepsis treatment bundle was a challenge for the physicians. If we administer too late antibiotics in probable sepsis, that will affect mortality. On the other hand, if we administer early antibiotics in non-shock possible sepsis, we may overuse antibiotics in those who did not finally diagnose sepsis.
In the primary outcome, the data showed that appropriate antibiotics (appropriate timing within 1 h, spectrum, and dose) did not affect 28-day mortality (adjusted OR, 0.57; 95% CI, 0.22–1.144) or in-hospital mortality. For mortality and secondary outcome, the adjusted covariates included respiratory rate SpO2 and qSOFA; we did not use fluid received in the 1-h bundle due to intravenous fluid received (80–100 ml).
Our research was the earlier study of the effect of antibiotics composing not only time to administration but also spectrum and dose in patients with sepsis that used the 1-h bundle for treatment in the ED.
Appropriate rational use must be composite of good quality in the right drug, dose, and time. In subgroup analysis, the appropriate only time to antibiotics (within 60 min) was not associated with 28-day mortality (adjusted OR, 1.23; 95% CI, 0.32–4.75; P=0.76) after adjusting for appropriate spectrum, RR, SpO2, and qSOFA.
Berrevoets et al. [2] reported the appropriateness of antibiotics using seven quality indicators (in terms of the intravenous route in sepsis, antibiotics within 3 h, prior hemoculture and specimen culture, antibiotics plan, prescribed according to guidelines, and adjusted dose) in the ED. Those authors found that appropriate antibiotic use in seven indicators was associated with reduced in-hospital mortality. They did not only focus on time, prescribed according to guidelines, dose, route, and plan. Our study used within 60 min to indicate appropriate timing, following the Surviving Sepsis Campaign in 2018 [7], focusing the right spectrum followed Stanford Antimicrobial Safety and Sustainability Program [19] and Ramathibodi Antibiotic Guide for Sepsis and Septic Shock, the right dose followed Stanford Health Care Antimicrobial Dosing Reference Guide [20].
Fibin et al. [23] reported no difference for in-hospital mortality before and after quality improvement in sepsis care, including administration of antibiotics within the first hour after triage. That result implies that the appropriate time to administer antibiotics in our population who were less severe with sepsis or the possible sepsis patients can be between “as soon as possible” to within 3 h. That may be compatible with recent data from The Surviving Sepsis campaign 2021 in the timing of antibiotics. Our study population has less severe sepsis due to screening from patients who present clinically possible sepsis in the ED and mostly community acquire. If we cut point inappropriate time more than 3 h in the less severe group, it may show a different outcome; however, the appropriate spectrum is important in 28-day mortality.
In the subgroup who had SOFA score ≥ 2 (Table 4), the appropriate antibiotics (appropriate timing within 1 h, spectrum, and dose) did not affect 28-day mortality or in-hospital mortality. However, we need more sample size to analyze mortality outcomes in severe or septic shock groups.
Only the appropriate spectrum of antibiotics subgroup was associated with decreased 28-day mortality (adjusted OR, 0.38; 95% CI, 0.15–0.99; P=0.047) and decrease in-hospital mortality (adjusted OR, 0.28; 95% CI, 0.13–0.61; P=0.001) (Table 3). Subgroup analysis for appropriate antibiotics dose was limited due to the small sample size for non-appropriate doses. From our data, that seems to be the right spectrum was more affected to 28-day mortality than the timing within 60 min.
We analyzed spectrum appropriateness according to two criteria. First, the source of infection developed sepsis and positive cultures received antibiotics which is proper antibiotics. In the source, there are suspected negative cultures, appropriate antibiotic-related source, and underlying disease, prior antibiotics, risk of hospital-acquired infection, and prior hospital admission. The appropriate spectrum of antibiotics seems to affect mortality, so updating the local antibiogram and following the antibiotic guideline protocol may improve the appropriate prescribing and decrease mortality.
The other secondary outcome, appropriate antibiotics (timing within 1 h, appropriate spectrum and dose), was not associated with an increased mean difference in 28-day ventilator-free and 28-day hospital-free days. In the subgroup, the appropriate spectrum of antibiotics seems to be associated with a 28-day ventilator and hospital-free day. In terms of clinical outcomes, this seems to be a small effect. However, in situations with overcrowding in the ED and a lack of available inpatient beds, appropriate antibiotics could affect the flow of treatment and the resuscitation process in the ED.
Based on our study findings, we can conclude that appropriate antibiotics timing within 1 h. The spectrum and dose do not affect 28-day mortality. It may be the inconclusive timing of antibiotics, and our data were in supra-tertiary care in urban areas. However, this result may support the recommendation of surviving sepsis campaign guideline; we advocated that the timing of administering antimicrobials must be categorized by probability and severity of sepsis. If the patients were high probability or high severity of sepsis, they should receive antimicrobials within 1 h. If the patients were low probability and low severity of sepsis, they should receive antimicrobials within 3 h; moreover, we recommend providing antibiotics with the appropriate spectrum as local antibiogram, following international or local guidelines, the appropriate dose in patients with sepsis in the ED.