Blood C&S before ABx

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Cheng. "Blood Culture Results Before and After Antimicrobial Administration in Patients With Severe Manifestations of Sepsis". Annals of Internal Medicine. 2019. epub ahead of print:.
PubMedFull textClinicalTrials.gov

Clinical Question

In patients that present to the emergency department with a bacteremia, does blood culturing become less accurate after antimicrobials are given compared to drawing cultures before antimicrobials given.

Bottom Line

Drawing cultures before antimicrbials are given will have better yield, however, some cultures may still grow after antimicrobials are given.

Major Points

The Surviving Sepsis Campaign guidelines [1] states as a best practice statement that cultures should be drawn prior to antimicrobials are administered. This trial was designed to test this statement. Following the work of the Rivers Trial and the work done by Kumar et al [2], rapid antimicrobial therapy following recognition of sepsis/shock has become the standard of care, with guidelines recommending administration within 1 hour.

The FABLED (eFfect of Antimicrobial administration on BLood culture positivity in patients with severe manifestations of sepsis in the Emergency Department) enrolled 325 septic patients presenting to 7 emergency departments in Canada and in the USA between 2013-2018. They included patients that presented in sepsis, using the SIRS criteria and signs of severe disease including blood pressure < 90 mmHg or lactate above 4 mmol/L. They excluded those at risk of bleeding as drawing additional blood cultures would have been at too high of a risk. They compared the sensitivity of blood cultures drawn before antimicrobials given to those drawn within 120 minutes of blood cultures given. Overall they found a loss of sensitivity of 12% (NNT = 9) when cultures were drawn after antimicrobials administered.

There are several potential issues with this trail, including that it was initiated before the publication of the new definition of sepsis (Sepsis-3)[3] which may have altered their findings with a different included sample population. To meet their sample size they had to extend the time interval to 240 minutes for the follow-up cultures. Finally, 2 institutions only allowed 1 set of follow-up cultures which may have led to false negatives. Overall, this was a well done and pragmatic trials that validates a long held belief and the best practice statement as part of the Surviving Sepsis Campaign.

Guidelines

Surviving Sepsis Campaign severe sepsis and septic shock (2016, adapted)[1]

  • Begin treatment and resuscitation immediately (best practice statement [BPS] are ungraded, strong recommendations)
  • For sepsis-induced hypoperfusion, give ≥30 mL/kg IV crystalloid fluid in the first 3 hours (strong recommendation, low quality evidence)
  • After initial resuscitation, given additional fluids guided by frequent reassessment of status of hemodynamics like HR, BP, PaO2, RR, temp, UOP, noninvasive, and/or invasive monitoring (BPS)
  • Target MAP of 65 mm Hg in patients requiring vasopressors (strong recommendation, moderate quality of evidence
    • Norepinephrine as first line vasopressor (strong recommendation, moderate quality of evidence)
      • Add vasopressin up to 0.03 U/min (weak recommendation, moderate quality of evidence) or epinephrine (weak recommendation, low quality of evidence) to raise MAP to target
      • Can add vasopressin up to 0.03 U/min to decrease norepinephrine dose (weak recommendation, moderate quality of evidence)
  • Suggested guiding resuscitation to normalize lactate in those with lactate elevations (weak recommendation, low quality of evidence)
  • Recommend cultures be drawn before antimicrobials given if this leads to no substantial delay in therapy (BPS)
  • Recommend administration of IV antimicrobials as soon as possible, preferably within 1 hour of recognition (strong recommendation, moderate quality of evidence)

Design

  • Multicenter, patient-level, single-group, diagnostic study
  • N=325
  • Setting: 7 emergency departments in Canada and America
  • Enrollment: November 2013 to September 2018
  • Analysis: Intention-to-treat
  • Primary Outcome: sensitivity of blood cultures drawn within 120 minutes (amended to 240 minutes) after antibiotic administration

Population

Inclusion Criteria

  • Adults (aged ≥18 years)
  • evidence of a systemic inflammatory response syndrome (SIRS)
    • systolic blood pressure < 90 mmHg at prehospital in the emergency department, or
    • serum lactate ≥ 4 mmol/L

Exclusion Criteria

  • clinically significant bleeding disorder
  • platelet count < 20 000 × 109 cells/L
  • international normalized ratio > 6.0

Baseline Characteristics

  • Demographics: mean age 65.6 years
  • Physiologic parameters: mean Charlson Comorbidity Index 1, Heart Rate >90 bpm 82%, requiring vasopressors 15%, respiratory failure 12%
  • SIRS criteria: respiratory >20 bpm 60%, Temperature >38 or <36 degC 51%, WBC >12 or <4 79%, Serum Lactate ≥4 mol/L 62%, systolic blood pressure <90 mmHg 57%
  • Comorbidities: Hypertension 34%, diabetes 27%, Cancer 23%, COPD 13%, Atrial Fibrillation 11%, Congestive heart failure 11%, Hepatitis C infection 10%, Intravenous drug use 8%, Cerebral Vascular disease 8%, coronary artery disease 8%, chronic kidney disease 8%, HIV infection 5%
  • Site of infection: 33% Respiratory, 18% genitourinary, 17% gastrointestinal, 13% skin and soft tissue, 5% other, 15% unknown
  • median time to repeat blood culture 70 minutes

Interventions

  • Blood cultures draw before antimicrobial therapy initiated
  • Blood cultures draw within 120 minutes after antimicrobials given

Outcomes

Comparisons are Prior to Antimicrobials vs. After Antimicrobials.

Primary Outcomes

Proportion of Positive Blood Cultures Before and After Initiation of Antimicrobial Therapy
31.4% vs. 19.4% (ARR 12.0, 95% CI 5.4-18.6; P < 0.001) NNT = 9

Secondary Outcomes

Sensitivity analysis with addition of culturing from differing sites (n=102)
52.9% increased to 67.7% (Absolute increase 14.7)

Subgroup Analysis

Per-protocol = Patients with blood cultures drawn within 30-120 minutes (n=264)

Per-protocol Proportion of Positive Blood Cultures Before and After Initiation of Antimicrobial Therapy
19.7% vs. 10.6% (ARR 10.6, 95% CI 3.3-17.9; P < 0.001) NNT = 10

Adverse Events

None reported

Criticisms

  • at 2 institutions only 1 blood culture after initiation of antimicrobials was allowed by their Research Ethics Board, this may have led to a false negative culture being observed
  • This trial was initiated prior to Sepsis-3[3] being published, using the new definitions of sepsis may have altered the results
  • Proportion of bacteremic patients that presented with sepsis was lower than expected or seen in other trials
  • Accepted time for follow-up cultures had to be extended to 240 minutes to meet their sample size

Funding

  • Vancouver Coastal Health
  • St. Paul's Hospital Foundation Emergency Department Support Fund
  • the Fonds de recherche Santé-Québec
  • Maricopa Medical Foundation.

Further Reading

  1. 1.0 1.1 Rhodes A, et al. "Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016." Critical Care Medicine. 2017;45(3)1-67.
  2. 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. 34:1589-96.
  3. 3.0 3.1 Singer M et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016. 315:801-10.