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The Golden Hour of Antibiotic Administration

in Severe Sepsis: Avoid a False Start Striving
for Gold*

Article in Critical Care Medicine · August 2014

DOI: 10.1097/CCM.0000000000000363 · Source: PubMed

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Editorials

The Golden Hour of Antibiotic Administration in

Severe Sepsis: Avoid a False Start Striving for Gold*
Arthur R. H. van Zanten, MD, PhD In addition, Kumar et al (5) in a retrospective study
Department of Intensive Care among 2,154 patients who received effective antibiotic ther-
Gelderse Vallei Hospital apy have observed that the survival rate was 80% in patients
Ede, The Netherlands given antibiotics within the first hour of persistent or recur-
rent hypotension. However, for each hour of delay during

S
epsis is defined as a systemic inflammatory response to the subsequent 6 hours, the chances of survival decreased
infection, and the annual prevalence is estimated at 19 by 7.6%. In multivariate analysis, the strongest predictor
million cases worldwide. Over the last 30 years, reported of outcome was time to effective antibiotic administration.
mortality rates in severe sepsis, defined as sepsis plus organ Only half the patients received effective antibiotics within
dysfunction, have dropped from over 80% to 20–30% due 6 hours of hypotension onset, and 30% had delays of more
to advances in training, better surveillance and monitoring, than 12 hours.
prompt initiation of therapy, and organ support (1). In this issue of Critical Care Medicine, Ferrer et al (6) report
Antibiotics are essential for effective treatment of infections a retrospective analysis of a large dataset of 28,150 patients
in critically ill patients. Therapy is founded on principles of with severe sepsis and septic shock collected prospectively for
appropriate drug selection based on (suspected) susceptibility the Surviving Sepsis Campaign in Europe, the United States,
patterns of the causative pathogen. The goal of antimicrobial and South America. They showed that delay in first antibiotic
administration is to achieve drug concentrations sufficiently administration was associated with increased in-hospital mor-
effective to exert maximum killing at the infection site and to tality. There was a linear increase in mortality risk for each hour
prevent the emergence of antimicrobial resistance (2). Selec- delay in antibiotic administration. Reducing time to first anti-
tion of empirical antibiotics should be based on the suspected biotic from more than 6 hours to less than 1 hour may induce
site of infection, setting such as community-acquired infection a mortality reduction of 9.5% (33.1% to 24.6%). Strengths of
or nosocomial infection, medical and culture history, and local this study are timing effects that were also observed in patients
microbial susceptibility results. with severe sepsis and without septic shock, extending exter-
The latest guidelines for the management of severe sepsis nal validity to severe sepsis. In addition, beneficial effects of
and septic shock provided by the Surviving Sepsis Campaign early antibiotic administration reported here are based on time
consortium recommend to timely commence appropriate IV from sepsis diagnosis and not related to onset of hypotension.
broad-spectrum antibiotics after forming a probable diagno- Limitations of the study are lack of information on antibiotic
sis and obtaining cultures (1B/1C grade recommendations to appropriateness and focus control.
administer antibiotics within 1 hr after diagnosis of either sep- These combined observations underline the importance
sis or septic shock) (3). of timely and appropriate initiation of antibiotics in septic
In general, “appropriate” treatment is defined as treatment patients. Antibiotic therapy shows to be lifesaving within the
matching the in vitro susceptibility of the pathogen. By per- “golden hour” after diagnosing severe sepsis or septic shock.
forming a systematic review and meta-analysis of available stud- However, there is possibly no other instance in medicine where
ies, Paul et al (4) have demonstrated that the pooled odds ratio therapy provided to a patient affects other patients and the
of appropriate antibiotic treatment during the first 48 hours for society by potentially reducing the armamentarium of effec-
all-cause mortality was 1.60 (95% CI, 1.37–1.86), corresponding tive antibiotics in future patients. Therefore, it is of paramount
to a number needed to treat of 10 (95% CI, 8–15). importance to administer antibiotics to only patients who
need antibiotics.
We have to be aware of a false start in patients with severe
*See also p. 1749. sepsis. This may be caused by underrecognition of sepsis
Key Words: antibiotics; appropriateness; mortality; sepsis; timing patients, causing undertreatment and consequently late ini-
Dr. van Zanten consulted for Nutricia/Danone, Baxter, and Fresenius Kabi tiation of antibiotics. Furthermore, inappropriate antibiotic
and lectured for Nutricia/Danone. His institution received grant support
from Nutricia/Danone and Asahi. selection may result in failing empirical treatment. Providing
Copyright © 2014 by the Society of Critical Care Medicine and Lippincott practical guidelines to emergency department physicians to
Williams & Wilkins select patients at risk for highly resistant bacteria in microbio-
DOI: 10.1097/CCM.0000000000000363 logically proven severe sepsis and septic shock has been shown

Critical Care Medicine www.ccmjournal.org 1931

Editorials

to reduce risk of initial inappropriate therapy (7). Finally, inap- antibiotic misuse. Critical care antibiotic stewardship is essen-
propriate antibiotic dosing, an often neglected but probably tial to preserve effective antibiotic therapy for future patients.
important factor, may cause therapy failure (8).
By contrast, a false start may also be relevant when antibiot- REFERENCES
ics are given to patients without sepsis. Tachycardia or an ele- 1. Angus DC, van der Poll T: Severe sepsis and septic shock. N Engl J
vated WBC count may reflect an inflammatory response due to Med 2013; 369:840–851
2. Pinder M, Bellomo R, Lipman J: Pharmacological principles of anti-
bacterial infection; however, this can also be seen in many non- biotic prescription in the critically ill. Anaesth Intensive Care 2002;
bacterial infections and more important many noninfectious 30:134–144
conditions (9). Trying hard to avoid late initiation of antibiot- 3. Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign
ics may lead to antibiotic administration to patients without Guidelines Committee including the Pediatric Subgroup: Surviving
sepsis campaign: International guidelines for management of severe
infections. Risks for individual patients from side effects and sepsis and septic shock: 2012. Crit Care Med 2013; 41:580–637
allergies related to unnecessary antibiotic exposure are limited. 4. Paul M, Shani V, Muchtar E, et al: Systematic review and meta-analy-
However, unnecessary antibiotic use may increase the number sis of the efficacy of appropriate empiric antibiotic therapy for sepsis.
Antimicrob Agents Chemother 2010; 54:4851–4863
of antibiotic exposure days, increasing the risk of resistance
5. Kumar A, Roberts D, Wood KE, et al: Duration of hypotension before
emergence in individuals as well as on a population scale. More initiation of effective antimicrobial therapy is the critical determinant of
importantly, when inflammatory signals are not due to an survival in human septic shock. Crit Care Med 2006; 34:1589–1596
infection, the process to proper diagnosis is hampered, delay- 6. Ferrer R, Martin-Loeches I, Phillips G, et al: Empiric Antibiotic Treatment
Reduces Mortality in Severe Sepsis and Septic Shock From the First
ing initiation of the optimal therapy for noninfectious condi- Hour: Results From a Guideline-Based Performance Improvement
tions, potentially reducing chances for a beneficial outcome. Program. Crit Care Med 2014; 42:1749–1755
When time to antibiotics in community-acquired pneumo- 7. Capp R, Chang Y, Brown DF: Effective antibiotic treatment pre-
nia (not pulmonary sepsis), as is common in some countries, is scribed by emergency physicians in patients admitted to the inten-
sive care unit with severe sepsis or septic shock: Where is the gap?
used as a quality indicator, use of such indicators and the desire J Emerg Med 2011; 41:573–580
to meet required targets may have unintended consequences 8. van Zanten AR, Polderman KH, van Geijlswijk IM, et al: Ciprofloxacin
(10). At least five studies have shown that overuse of antibiot- pharmacokinetics in critically ill patients: A prospective cohort study.
ics in the emergency department may be the consequence (11). J Crit Care 2008; 23:422–430
9. Levy MM, Fink MP, Marshall JC, et al; SCCM/ESICM/ACCP/ATS/
Therefore, clinicians should ensure that the infection diagnosis SIS: 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis
is robust to prevent unnecessary treatment with broad-spec- Definitions Conference. Crit Care Med 2003; 31:1250–1256
trum antibiotics. All antibiotic treatments should be subject 10. Carlet J, Pittet D: Access to antibiotics: A safety and equity challenge
to review after 2–3 days and when culture results become for the next decade. Antimicrob Resist Infect Control 2013; 2:1
11. Pines JM, Isserman JA, Hinfey PB: The measurement of time to first
available. After initial broad-spectrum antibiotic therapy, de- antibiotic dose for pneumonia in the emergency department: A white
escalation based on culture results has been shown to reduce paper and position statement prepared for the American Academy of
mortality in septic patients (12). Emergency Medicine. J Emerg Med 2009; 37:335–340
The “golden hour” for antibiotics in sepsis and septic 12. Garnacho-Montero J, Gutiérrez-Pizarraya A, Escoresca-Ortega A, et
al: De-escalation of empirical therapy is associated with lower mortal-
shock has been clearly demonstrated; however, when striv- ity in patients with severe sepsis and septic shock. Intensive Care
ing for gold, we have to avoid making a false start concerning Med 2014; 40:32–40

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