Antibiotic Timing

OVERVIEW

The mantra for timing of antibiotics for serious infections is ‘hit hard, early and appropriately’

Despite the strong biological plausibility of a need for early antibiotics in patients with serious bacterial infections the importance of antibiotic timing is controversial

• no definitive causal link between early antibiotics and patient outcomes has been established in humans as conducting a randomized clinical trial to assess this would be unethical
• the outcomes of less severe infections are probably less time-sensitive with regard to antibiotics
• more severe infections probably are time-sensitive, however there may be a point beyond which antibiotic timing or any intervention will not impact outcome
• The issue is important at a systems level, as it impacts the prioritization of interventions and design of care processes in the ED and the ICU and may be tied to performance measures and funding

RATIONALE FOR EARLY ANTIBIOTICS

Early antibiotics may:

• prevent injury caused by microbial activity and toxin production
• prevent or ameliorate harmful host responses to infection

In severe sepsis syndromes:

• Mortality is not necessarily caused by the infection itself, but by the physiologic response to the infection and the multi-organ dysfunction syndrome (MODS) that ensues
• Administration of antibiotics, by killing the causative micro-organism, may halt or ameliorate physiologic progression to MODS
• microbial load increases as the infection progresses over time and the cytokine release that occurs when antibiotics are given may be more severe and increase the likelihood of progression to MODS
• Antibiotics should ideally be given before sepsis with hypotension occurs, as irreversible injury may result (supported by animal studies and some observational data)

SEVERE SEPSIS AND SEPTIC SHOCK

“For the greatest survival benefit, give antibiotics as early as possible and always within one hour of emergency department presentation or, for ward-based patients, recognition of severe sepsis or septic shock”
— Australian Therapeutic Guidelines (2014) recommendation

Overview

• Observational data has shown strong associations between early antibiotics and survival outcomes, however a recent (flawed) systematic review did not find a benefit for early antibiotics
• Many of the observational studies of antibiotic timing suffer from these important confounders:
  • failure to correct for severity of illness (e.g. sicker patients may be more likely to die and so receive antibiotics earlier as a result)
  • failure to determine if antibiotic choice was appropriate (e.g. microbiological confirmation of cause of sepsis and antibiotic sensitivity)

Surviving Sepsis Campaign Guidelines 2012 and 2015 update (see Surviving Sepsis Campaign Guidelines 2012)

• 2015 update: “broad spectrum antibiotics should be administered within 3 hours of the time of presentation”
• 2012 Guideline: “We recommend that empiric antimicrobials be administered within 1 hr of the identification of severe sepsis. Blood cultures should be obtained before administering antibiotics when possible, but this should not delay initiation of antibiotics. The empiric drug choice should be changed as epidemic and endemic ecologies dictate (eg, H1N1, methicillin-resistant S. aureus, chloroquine-resistant malaria, penicillin-resistant pneumococci, recent ICU stay, neutropenia) (grade 1D)”
• As of 2010, only 68% of patients in the SSC registry received antibiotics within 3 hours
• Recommendations are based on expert opinion and the retrospective study by Kumar et al, though it is supported by subsequent studies such as Ferrer et al, 2014

Kumar et al, 2006

• the classic retrospective cohort study of 2,731 septic shock ICU patients
• showed a strong correlation between delay in effective antibiotic therapy and in-hospital mortality after recurrent or persistent arterial hypotension (P <0.0001)
• decrease in survival by 7.6% for the delay of 1 hour of antibiotic therapy over the ensuing 6 hours
• only 50% of the patients received effective antibiotic therapy within the first 6 hours (i.e. appropriate in vitro activity for the isolated pathogenic microorganism or the underlying clinical syndrome)

Gaieski et al, 2010

• A single-center cohort study of 261 patients with severe sepsis undergoing early goal-directed therapy (EGDT)
• time from triage and qualification for EGDT to appropriate antibiotic therapy was significantly associated with reduced mortality at the <1 hour cutoff point (odds ratio = 0.3 and 0.5, each P <0.03)

Puskarich et al, 2011

•  a preplanned analysis of a multicenter controlled trial (3 centers) in US EDs of 291 patients with septic shock (EMSHOCK NET)
•  found no change in mortality with hourly delayed antibiotic therapy up to 6 hours after triage or after recognition of shock
•  antibiotic administration before recognition of shock was associated with a lower mortality as compared with antibiotic administration after recognition of shock (odds ratio = 2.35, 95%CI 1.12 to 4.53)

Ferrer et al, 2014

• retrospective analysis of 17,990 patients with severe sepsis and septic shock from the multicenter, multinational Surviving Sepsis Campaign database (Europe, USA and South America)
• found an hourly increase in mortality with delay in antibiotic administration following recognition of severe sepsis, not just the onset of hypotension
• differences were statistically significant, as we  as clinically significant, beyond 2 hours

De Groot et al, 2015

• prospective multicenter study in three Dutch EDs
• 1,168 patients with sepsis (stratified into mild, moderate and severe;overall mortality of 10%)
• in those receiving antibiotics within 6 hours, a reduction in time to antibiotics was not found to be associated with an improvement in relevant clinical outcomes (28 mortality or LOS)

Sterling et al, 2015

• Systematic review of 11 studies that met inclusion criteria, comprising:
  • 16,178 patients with severe sepsis/ septic shock who who evaluable for antibiotic administration from emergency department triage, and
  • 11,017 patients who were evaluable for antibiotic administration from severe sepsis/septic shock recognition
• there was no significant mortality benefit of administering antibiotics within 3 hours of ED triage or within 1 hour of shock recognition in severe sepsis and septic shock
• The authors suggest that currently recommended timing metrics as measures of quality of care are not supported by the available evidence
• Problems: 7 studies were excluded because authors did not respond to requests for information (selection bias), unclear if antibiotic choice was appropriate in these studies and less than half of patients had confirmed bacteraemia (antibiotics would not be expected to benefit non-bacterial infections or infections with bacteria that are insensitive to the chosen antibiotic)

Garnacho-Montero et al, 2015

• A prospective obsertional study of 928 patients admitted to ICU with severe sepsis/ septic shock (68% with microbiological identification)
• Findings were:
  • Inadequate therapy prior to ICU admission was more common in nosocomial sepsis
  • Administration of appropriate empirical antimicrobial therapy early was associated with decreased mortality
  • Nearly all patients (98.3 %) received at least one dose of antibiotics before ICU admission, however they were inadequate in 31% of patients
  • Progression to septic shock  in patients with severe sepsis was associated with inadequate antimicrobial therapy prior to ICU admission

BACTERIAL MENINGITIS

Antimicrobial therapy (with adjunctive dexamethasone if indicated) should be initiated as quickly as possible if bacterial meningitis is suspected as it is a rapidly progressive condition

• immediately after performing a lumbar puncture (LP) no imaging needed
• immediately after obtaining blood cultures if a CT brain is indicated prior to performing a lumbar puncture

Evidence

• in addition to face validity, numerous observational studies show:
  • better outcomes with early antibiotics and worse outcomes with delay to antibiotics (Miner et al, 2001;Lepur and Barsić, 2005; Proulx et al, 2005; Auburtin et al, 2006)
  • worse outcomes with greater clinical severity (e.g. altered mental state, seizures, hypotension)  prior to antibiotic administration (Aronin et al, 1998; Lu et al, 2002; Lepur and Barsić, 2005)
• timing of antibiotics in patients that are lower-risk for bacterial meningitis but still need definitive testing to rule out the disease is less clear cut

PNEUMONIA

• The association between antibiotic timing and survival in pneumonia may be a function of the presentation (e.g. host response to infection) and not the antibiotic timing in itself
• Atypical presentations of pneumonia are associated with both delayed antibiotic administration and increased mortality (e.g. altered mental status, the absence of hypoxia, and the absence of fever) — when these factors that delay diagnosis are controlled for antibiotic timing is not related to mortality

Recommendations

• IDSA and ATS: ‘for patients admitted through the ED, the first antibiotic dose should be administered while [the patient is] still in the ED’
• ACEP Policy 2009: ‘Administer antibiotics as soon as feasible once the diagnosis of CAP is established; there is insufficient evidence to establish a benefit in morbidity or mortality from antibiotics administered within any specific time course’

REASONS FOR ANTIBIOTIC DELAYS

Presentation-level factors

• atypical presentation leading to delayed diagnosis
  • evolution of clinical symptoms and symptoms
  • ability to recognise clinical features
  • requirement for further diagnostic testing

Patient-level factors

• age and comorbid conditions that predispose patients to having atypical presentations
• history of drug reactions
• difficult IV access

System-level factors

• ED crowding
• inadequate staffing
• delays in diagnostic testing
• patient transfer

HOW LONG DOES IT REALLY TAKE TO ADMINISTER ANTIBIOTICS?

Time to antibiotics (from arrival in ED) in major RCTs:

• ARISE: median of 70 min
• PROCESS: majority within 3 hours
• PROMISE: median of 2.5 hours

Venkatesh, et al (2013) argued that ‘time from presentation’ should not be used as a recommendation for administration of antibiotics, but that time from recognition of septic shock is a more useful recommendation

• cross-sectional study of 267 consecutive ED patients with septic shock
• median time to definition of septic shock was 88 minutes, with 82% occurring within 3 hours
• Of the 221 (83.4%) patients who received antibiotics < 3 hours of arrival, 17.2% did not receive antibiotics within 1 hour of definition
• Of 207 patients who received antibiotics <1 hour of definition, 11.6% did not receive antibiotics within 3 hours of arrival
• Thus the arrival measure did not accurately classify performance in administration of antibiotics in 23.4% of patients

Similarly, Villar, et al (2014) found that 10% of ED patients first met criteria for severe sepsis or septic shock greater than 3 hours from emergency department arrival

Quality assurance

• both the intended and unintended consequences of measuring antibiotic timing must be considered
• measurement of antibiotic timing is associated with antibiotic overuse and misuse
• a focus on improving timing of antibiotic administration, unless adequately resourced, may decrease performance in other areas

CONCLUSION

• Despite current controversies, give appropriate antibiotics as soon as possible for severe infections
• Australian Therapeutic Guidelines recommend antibiotics should be given within one hour of emergency department presentation or, for ward-based patients, recognition of severe sepsis or septic shock

References and Links

LITFL

• CCC — Antibiotic Guidelines in ICU
• CCC — Antimicrobial dosing and kill characteristics

FOAM and web resources

• INTENSIVE — Ferrer et al, 2014: Antibiotic timing in Severe Sepsis (2014)
• REBELEM — Time to Antibiotics in Sepsis: A Metric Not Supported by “High Quality” Evidence (2015)

Journal articles

• Aronin SI, Peduzzi P, Quagliarello VJ. Community-acquired bacterial meningitis: risk stratification for adverse clinical outcome and effect of antibiotic timing. Annals of internal medicine. 129(11):862-9. 1998. [pubmed]
• Auburtin M, Wolff M, Charpentier J. Detrimental role of delayed antibiotic administration and penicillin-nonsusceptible strains in adult intensive care unit patients with pneumococcal meningitis: the PNEUMOREA prospective multicenter study. Critical care medicine. 34(11):2758-65. 2006. [pubmed]
• Gaieski DF, et al, 2010. Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department. Crit Care Med. 2010 Apr;38(4):1045-53. doi: 10.1097/CCM.0b013e3181cc4824. PubMed PMID: 20048677.
• Garnacho-Montero J, Gutiérrez-Pizarraya A, Escoresca-Ortega A, Fernández-Delgado E, López-Sánchez JM. Adequate antibiotic therapy prior to ICU admission in patients with severe sepsis and septic shock reduces hospital mortality. Critical care (London, England). 19:302. 2015. [pubmed] [free full text]
• Kumar A, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006 Jun;34(6):1589-96. PubMed PMID: 16625125.
• Lepur D, Barsić B. Community-acquired bacterial meningitis in adults: antibiotic timing in disease course and outcome. Infection. 35(4):225-31. 2007. [pubmed]
• Levy MM, Dellinger RP, Townsend SR, Linde-Zwirble WT, Marshall JC, Bion J, Schorr C, Artigas A, Ramsay G, Beale R, Parker MM, Gerlach H, Reinhart K, Silva E, Harvey M, Regan S, Angus DC. The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Intensive Care Med. 2010 Feb;36(2):222-31. doi: 10.1007/s00134-009-1738-3. PMC2826633.
• Lu CH, Huang CR, Chang WN. Community-acquired bacterial meningitis in adults: the epidemiology, timing of appropriate antimicrobial therapy, and prognostic factors. Clinical neurology and neurosurgery. 104(4):352-8. 2002. [pubmed]
• Miner JR, Heegaard W, Mapes A, Biros M. Presentation, time to antibiotics, and mortality of patients with bacterial meningitis at an urban county medical center. The Journal of emergency medicine. 21(4):387-92. 2001. [pubmed]
• Pines JM. Timing of antibiotics for acute, severe infections. Emerg Med Clin North Am. 2008 May;26(2):245-57, vii. doi: 10.1016/j.emc.2008.01.004. Review. PubMed PMID: 18406974.
• Pines JM, Isserman JA, Hinfey PB. The measurement of time to first antibiotic dose for pneumonia in the emergency department: a white paper and position statement prepared for the American Academy of Emergency Medicine. J Emerg Med. 2009 Oct;37(3):335-40. doi: 10.1016/j.jemermed.2009.06.127. Epub 2009 Aug 31. Review. PubMed PMID: 19717266.
• Proulx N, Fréchette D, Toye B, Chan J, Kravcik S. Delays in the administration of antibiotics are associated with mortality from adult acute bacterial meningitis. QJM : monthly journal of the Association of Physicians. 98(4):291-8. 2005. [pubmed]
• Nazarian DJ, Eddy OL, Lukens TW, Weingart SD, Decker WW. Clinical policy: critical issues in the management of adult patients presenting to the emergency department with community-acquired pneumonia. Ann Emerg Med. 2009 Nov;54(5):704-31. doi: 10.1016/j.annemergmed.2009.07.002. Review. PubMed PMID: 19853781.
• Puskarich MA, et al; Emergency Medicine Shock Research Network (EMSHOCKNET). Association between timing of antibiotic administration and mortality from septic shock in patients treated with a quantitative resuscitation protocol. Crit Care Med. 2011 Sep;39(9):2066-71. doi: 10.1097/CCM.0b013e31821e87ab. PubMed PMID: 21572327; PubMed Central PMCID: PMC3158284.
• Sterling SA, Miller WR, Pryor J, Puskarich MA, Jones AE. The Impact of Timing of Antibiotics on Outcomes in Severe Sepsis and Septic Shock: A Systematic Review and Meta-Analysis. Critical care medicine. 43(9):1907-15. 2015. [pubmed]
• van Zanten AR. The golden hour of antibiotic administration in severe sepsis: avoid a false start striving for gold*. Crit Care Med. 2014 Aug;42(8):1931-2. doi: 10.1097/CCM.0000000000000363. PubMed PMID: 25029127.
• Villar J, Clement JP, Stotts J. Many emergency department patients with severe sepsis and septic shock do not meet diagnostic criteria within 3 hours of arrival. Annals of emergency medicine. 64(1):48-54. 2014. [pubmed]
• Vilella AL, Seifert CF. Timing and appropriateness of initial antibiotic therapy in newly presenting septic patients. The American journal of emergency medicine. 32(1):7-13. 2014. [pubmed]