SHOCK, Vol. 47, Supplement 1, pp.

2629, 2017

Review Article
ARE EARLY ANTIBIOTICS IMPORTANT FOR EVERYONE?

Yeh-Li Ho, Vivian Vieira Tenorio Sales, and Daniel Joelsons

Intensive Care Unit of Infectious Diseases Department, Hospital das Clnicas da Faculdade de Medicina
da Universidade de Sao Paulo, Sao Paulo, Brazil

Received 9 Nov 2015; first review completed 22 Jan 2016; accepted in final form 12 Apr 2016

ABSTRACTSince the first edition of Surviving Sepsis Campaign Guidelines, the administration of intravenous antibiotics
in the first hours of sepsis is recommend. However, in the last ten years, several studies around importance of early
antibiotics in emergency room or in intensive care unit produced disparate results. Therefore, is early administration
of antibiotics a life-salver? In this article, we explore studies around this theme and some questions about what does
early antibiotics mean are addressed.
KEYWORDSAntibiotics, sepsis, time

INTRODUCTION
Twenty-three years after the publication of Definition for
Sepsis and Organ Failure and Guidelines for the Use of
Innovative Therapies in Sepsis by the American College of
Chest Physicians/ Society of Critical Care Medicine, despite
progressive reduction on mortality rate of sepsis, it remains
unacceptably high.
In 2002, an international group of critical care and infectious
disease experts came together to develop recommendations to
improve the outcome in severe sepsis and septic shock, and the
first Surviving Sepsis Campaign (SCC) guidelines for man-
agement of severe sepsis and septic shock was published in
2004 (1). The Campaign activities include predominantly
the development of sepsis bundles, mostly based on Rivers
findings (2) and data from other clinical trials (38). There-
after, reviews were performed and new recommendations were
introduced (911).
Data from the SSC database between January 2005 and
March 2008 in 165 hospitals showed that compliance with
the initial 6 h bundle targets increased linearly from 10.9%
of subjects to 31% by the end of 2 years in the campaign and
the unadjusted hospital mortality decreased from 37% to
30.8% (12).
Prescribing early antibiotics is globally widespread in life-
threatening bacterial infection situations and it is strongly
biologically plausible. Since the first edition of Surviving
Sepsis Campaign Guidelines, the administration of intravenous
antibiotics in the first hours of sepsis is recommend; however,
only in 2006, this recommendation gained evidence after the
publication of Kumar et al. (13). Kumar et al. (13) observed
survival of 82.7% if effective antimicrobials were administered
within 30 min of initial evidence of hypotension, 77.2% in the
Address reprint requests to Yeh-Li Ho, MD, PhD, Av. Dr. Eneas de Carvalho
Aguiar, 255-4o. andar-Infectologia, Sao Paulo, SP, CEP-05403-000, Brazil.
E-mail: ho.yeh@hc.fm.usp.br; hoyehli@yahoo.com.br
The authors report no conflicts of interest.
DOI: 10.1097/SHK.0000000000000696
Copyright 2016 by the Shock Society
26
Copyright 2016 by the Shock Society. Unauthorized reproduction of this article is prohibited.
second half hour, and 42% in the sixth hour and each hourly
delay increase 7.6% in mortality after onset of shock.
However, in the last 10 years, several studies around import-
ance of early antibiotics in emergency room or in intensive care
unit produced disparate results. Therefore, is early adminis-
tration of antibiotics a life-saver? Is this recommendation valid
for everyone? In the last few years, several evidences have
discovered that sometimes late antibiotics may not be the
bad guy.
STUDIES WITH EVIDENCE
Barie et al. (14) observed that the delay of antibiotics
administration (30-min intervals) was an independent predictor
of mortality (OR 1.021, 95% CI 1.0031.038) in critical
surgical illness patients. It is important to mention that 94%
of patients received appropriate antibiotics in this trial.
Gaieski et al. (15) evaluated the association between
mortality and time to antibiotics administered in patients with
severe sepsis or septic shock in whom early goal-directed
therapy was initiated in the emergency department. The authors
observed a significant association between time from screening
to appropriate antibiotics administration and mortality (19.5
[<1 h] vs. 33.2% [>1 h]; P 0.02); and between the time from
qualification for early goal directed therapy to appropriate
antibiotics administration (mortality 25.0 [<1 h] vs. 38.5%
[>1 h]; P 0.03).
In another similar trial, Puskarich et al. (16) evaluated the
association between time from initial antibiotics administration
and mortality in patients with septic shock treated based on
early resuscitation protocol. They also observed a significantly
increased mortality in patients who received initial antibiotics
after shock recognition compared with group before shock
recognition (OR, 2.4; 1.14.5); however, among patients
who received antibiotics after shock recognition, mortality
did not change with hourly delays in antibiotics administration.
Jalili et al. (17) investigated the effect of door-to-antibiotics
time in different sepsis severity degrees. The general mean
door-to-antibiotic time was 104.4 min and a significant
SHOCK JANUARY 2017
relationship between door-to-antibiotic time and patient sur-
vival was identified (P 0.005). When analyzed according to
severity, the early antibiotics initiation was associated with
significant improvement in survival rate for group with higher
severity scores (APACHE score >20) (P 0.05), but not for
patients with APACHE scores of 11 to 20 (P 0.46).
Analysis of a large dataset collected prospectively for the
Surviving Sepsis Campaign from 28,150 patients with severe
sepsis and septic shock, Ferrer et al. showed a statistically
significant increase in the probability of death associated with
the number of hours of delay for the first antibiotics admin-
istration. Hospital mortality was 32% in the first hour of
antibiotics administration, 28.1% in the second hours, and then
steadily increased until a peak of 39.6% in those patients who
received antibiotics after 6 h (18).
STUDIES WITHOUT EVIDENCE
Prior to SSC Guideline, Pelletier et al. (19) studied 274 stable
surgical patients with fever and time to initiate antibiotics. The
patients were classified according to time from fever to anti-
biotics intervention (less than 12, 1224, and more than 24 h)
and they were divided into three groups according to severity of
illness based on APACHE II scores. No statistic difference was
observed between the outcome and time of administration of
antibiotics, but with a propensity of higher survival rate on
those who waited for the microbiologic date results.
In a recent trial on a surgical intensive care unit in Virginia,
Hranjec et al. (20) compared an aggressive protocol of pre-
scribing antibiotics for 1 year and a conservative protocol for
another year only on septic or severe sepsis patients. On the
aggressive period, they started antimicrobial treatment on the
suspicion of infection just after collecting blood culture, if it
resulted negative after 72 h, the antimicrobial was stopped. On
the conservative protocol, the antimicrobial was withheld until
microbiological evidence of infection. They found out that on
the aggressive group, when compared with the conservative,
there were: more deaths (40% vs. 21% and P <0.001), a lower
chance of receiving initial appropriate treatment and a longer
duration of antimicrobial treatment.
Castellanos-Ortega et al. (21) evaluated mortality after
implementation of the SSC guidelines compared with historical
group. It was observed an in-hospital mortality reduction from
57.3% in the historical group to 37.5% in the intervention group
(P 0.001). The intervention group also had lower length of
stay for survivors in the hospital (36.2  34.8 days vs.
41.0  26.3 days; P 0.043) and in the intensive care units
(8.4  9.8 days vs. 11.0  9.5 days; P 0.004). However, in
analysis of impact of each single intervention on reduction of
mortality, the early administration of antibiotics did not reach
significant impact. The only single intervention with impact on
mortality was the achievement of ScvO2 >70%.
Davies et al. explored the impact of inappropriate empiric
antimicrobial therapy for the treatment of infection among
surgical patients. The study was a retrospective analysis of a
prospectively maintained database of all surgical patients
admitted to a tertiary care center and treated for sepsis (22).
Mortality of the group inappropriately treated for infectious
Copyright 2016 by the Shock Society. Unauthorized reproduction of this article is prohibited.
ARE EARLY ANTIBIOTICS IMPORTANT FOR EVERYONE? 27
episodes was 15% compared with 14% of appropriately treated
group. After adjusting for statistically significant variables,
inappropriately treated episodes of infection were not found
to be associated with an increased risk of mortality compared
with appropriately treated episodes of infection (P 0.36).
De Groot et al. (23) assayed the association between time to
antibiotics and outcomes in hospitalized emergency department
patients with different severity of sepsis. The association of
delayed administration of antibiotics (>3 h) and surviving was
observed only in PIRO groups 1 to 7. No association was found
in other stages of sepsis.
Vilella et al. (24) evaluated the impact of the implementation
of computerized physician order entry in time to administration
of antibiotics in emergency department and the consequence in
hospital-mortality with a diagnosis of sepsis, severe sepsis, or
septic shock. The authors observed a dramatic decrease of
median time to administration of antibiotics, but this did not
alter the mortality. Appropriateness of empiric antibiotic regi-
mens was similar between surviving and non-surviving
patients.
Yahav et al. (25) reviewed results of observational studies to
examining the association between time to first antibiotic dose
and mortality in hospitalized community-acquired pneumonia.
Eighteen (11 prospective and 7 retrospective) were found.
Despite significant heterogeneity, no advantage in crude
mortality rates for early (<4 h) versus later antibiotic treatment
was observed.
In a meta-analysis to evaluate the use of delayed antibiotics
compared with immediate or no antibiotics strategy for acute
respiratory tract infections, Spurling et al. (26) reviewed 10
random controlled trials. No hospitalized studies were included
in the analysis. No difference was observed between delayed,
immediate, and no prescribed antibiotics for resolution of
clinical symptoms. In patients with acute otitis media and sore
throat, immediate antibiotics were more effective than delayed
for fever, pain, and malaise in some studies. Delayed antibiotics
resulted in a significant reduction in antibiotic use compared
with immediate antibiotics. A strategy of no antibiotics resulted
in least antibiotic use.
In a recent meta-analysis, Sterling et al. (27) evaluated 11
studies based on their inclusion criteria, totalizing 11,017
patients. No significant mortality benefit of administering
antibiotics within 3 h of emergency department screening or
within 1 h of shock recognition in severe sepsis and septic
shock was detected.
ARE EARLY ANTIBIOTICS IMPORTANT
FOR EVERY ONE?
Based on results of actual studies, there is not enough
evidence to support current recommendation of early admin-
istration of antibiotics. However, what is the correct time to
administer antibiotics? What does early antibiotics mean?
What is the harm of early administration of antibiotics?
Maybe, the question is not restricted to time of adminis-
tration of antibiotics, but our incapacity to differentiate an
inflammatory process to an infectious process. Currently, the
tools used to help the diagnosis of an infectious process have
28 SHOCK VOL. 47, SUPPLEMENT 1
sensibility and specify limitation. Several studies showed
infection biomarkers like C-reactive protein and procalcitonin
present safety and efficacy to discontinue antibiotics, but both
had great limitation to differentiate infection from inflam-
mation process and consequently, limitation to start antibiotics
treatment (28).
Klein Klouwenberg et al. (29) evaluated the likelihood of
infection in patients with presumed sepsis diagnosis at ICU
admission. In a prospective study, 2,579 patients treated for
sepsis were included. Thirteen percent had a post-hoc infection
likelihood of none, and an additional 30% of only
possible. In multivariable analysis, patients with an unlikely
infection had a higher mortality rate compared with patients
with a definite infection. The consequence of the risk of a
wrong diagnosis of sepsis is the lack of investigation to other
diagnosis and error in the treatment.
Second, we do not have a tool to determine which patient
with infection needs antibiotics to control and solve an infec-
tious process. This ignorance usually results in an excessive use
of antimicrobials. Simultaneously, the early use of antibiotics
can induce more risk of inappropriate prescription (19,20,23).
Additionally, the unnecessary use of antibiotics can contribute
to increase of bacterial resistance and drug toxicity.
However, it is important to remember the risk of delay of
adequately antibiotic in severe sepsis and septic shock patients.
Based on current model of sepsis, the early antibiotics and
prompt focus control remain important approaches to these
patients (30).
Finally, studies with evidence of benefit of early antibiotics
showed advantage of administration before, or at the moment of
recognition of sepsis status (1417). The question is around the
ability of a clinician to recognize a sepsis status, which is
usually late and the delayed recognition of sepsis is a main
determinant of death in sepsis (31).
CONCLUSION
Regardless of the questions around Are the early antibiotics
important for everyone, the appropriate prescription and
administration of antibiotics has to be part of bundle in assist-
ance to septic patient. Early prescription includes correct
choice of empirical antimicrobial and de-escalation of anti-
biotics once the culture result is available.
Subsequent evaluation to differential diagnosis has to be
done and daily assessment about suspension is necessary to
avoid overuse of antibiotics.
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