Blood Culture Results Before and After Antimicrobial Administration in Patients With Severe Manifestations of Sepsis

Cheng M, Ann Intern Med. 2019;171:547-554: doi:10.7326/M19-1696

Clinical Question

• In patients with severe sepsis what is the sensitivity of blood cultures taken after the initiation of antimicrobial therapy?

Background

• Early empiric antibiotic therapy is one of the key management goals in septic shock. Delay in first antibiotic dose is associated with a linear increase in the risk of mortality for each hour delay in antibiotic administration
• Inappropriate antibiotic choice is also associated with an increase in mortality. The mortality increases from 18 to 34% in those who have had inappropriate antibiotic selection
• Knowing the microbiological diagnoses helps clinicians tailor antimicrobial therapy
• The surviving sepsis campaign recommends taking blood cultures before starting antimicrobial therapies. However, there is a concern that waiting for blood culture collection may delay antimicrobial therapy

Design

• Patient level, single-group diagnostic cohort study
• Prospective
• Observational
• Based on previous data, 335 patients were needed assuming that 35% of patients would be bacteremic on initial cultures and that a 10% maximum difference in sensitivity between pre- and postantimicrobial blood cultures would be deemed clinically acceptable. This number was revised to 328 patients based on the repeated measures design of the study. This gave the trial 90% power

Setting

• Seven urban emergency departments across Canada and the USA
• 330 participants presenting with severe sepsis to the ER between November 2013 and September 2018

Population

• Inclusion:
  • Patients 18 years of age or greater who presented to the emergency department with evidence of severe manifestations of sepsis
  • This included patients that had two of the four SIRS criteria, a suspected or confirmed infection AND either an initial serum lactate ≥4mmol/L or an initial systolic blood pressure < 90mmHg.
  • SIRS criteria includes
    • (1) temperature >38°C or <36°C
    • (2) heart rate > 90 beats per minute
    • (3) respiratory rate >20 breaths per minute or PaCO₂ <32 mm Hg
    • (4) white blood cell count >12,000/cu mm, <4,000/cu mm, or >10% immature (band) forms
  • Had 2 tests of blood cultures drawn before starting antibiotic therapy, and who were able to have additional sets drawn within 2 hours of empirical antibiotic administration

• Exclusion: Patients where excluded if they were known to have a  severe coagulopathy, a platelet count below 20 000 x 10⁹ cells/L, or an international normalized ratio above 6.0

Patient characteristics

• Mean age: 66
• Male: 63%
• Lactate >4: 62%
• BP <90: 57%
• Source of infection
  • Respiratory: 33%
  • Genitourinary: 18%
• Initial antimicrobial regimen
  • Piperacillin-tazobactem: 34%
  • Piperacillin-tazobactem + another antibiotics: 27%
  • 3rd generation cephalosporin +- another antibiotic: 23.4%
  • Carbapenem +- another antibiotic: 4.6%
• Repeat cultures obtained between:
  • 30-120 minutes from initiation of antimicrobial therapy, n = 264 (per-protocol analysis)
  • <30 minutes or >120 minutes from initiation of antimicrobial therapy, n= 61

Gold Standard Test

Test of Interest

• Blood cultures taken after antibiotic administration
  • Protocol stipulated that cultures were to be obtained between 30-120 minutes after treatment initiation
  • Protocol amended to include participants with repeated blood cultures up to 240 minutes after treatment initiation
    • The results were analysed as per the a priori decision for those participants who had results taken up to 120 minutes after antimicrobial therapy. A further analysis was added to include those patients who had the second lot of cultures taken 120-240 minutes after therapy
  • At 5 institutions 2 sets of cultures were taken after antibiotics and at 2 institutions 1 set of cultures were taken after antibiotics

Outcome

• Primary Outcome
  • Sensitivity of blood cultures obtained within 30-120 minutes after antimicrobial therapy
    • Per protocol population: 56.3% (95% C.I. 44.7% to 67.3%)
    • Entire study population (included patients with cultures obtained from 0-120 minutes): 52.9% (95% C.I. 42.8%-62.9%)
  • Rate of positive blood cultures in pre vs. post antimicrobial blood cultures
    • Per protocol population: 30.3% vs. 19.7%,  Absolute difference 10.6% (95% CI 3.3-17.9%)
    • Entire study population: 31.4% vs. 19.4%, Absolute difference 12% (95% C.I. 5.4-18.6%)
• Secondary Outcomes
  • If the patient had the first blood culture positive and received an antibiotic that the organism was susceptible to then the post-antimicrobial blood culture was only positive in 51.7% of cases
  • If the patient had the first blood culture positive and received an antibiotic that the organism was NOT susceptible to, then the postantimicrobial culture was positive in 66.7% of cases
  • If blood cultures were positive pre- and post- therapy the cultures became positive a median of 4 hours sooner after collection in the pre-therapy group

Authors’ Conclusions

• Drawing blood cultures after antimicrobial therapy in patients with severe sepsis significantly reduces the sensitivity of the blood culture

Strengths

• The trial used best practice when collecting blood culture samples pre-antimicrobial therapy, ie 2 separate sets, from 2 separate venepuncture sites. This reduced the chance of non-pathogenic contaminants
• The trial results adds weight to the recommendation that all efforts should be made to sample pre-therapy
• The contamination rate overall was 4.9% which is acceptable

Weaknesses

• The trial does not have a comparator control group, so time to antibiotic therapy is not measured and even if it was, there is no control group to determine whether taking blood cultures pre-antibiotics means there’s a delay in giving antibiotic therapy
• Only a proportion of patients screened were recruited. This limits the generalisability of these results as those that weren’t included may have had some fundamental differences from the study group
• Some variability between sites as to the method of taking the repeat blood cultures

The Bottom Line

• Positive blood cultures are far more likely to occur if cultures are drawn prior to antibiotic therapy. Logically, this is likely to help tailor antimicrobial therapy and allow de-escalation of treatment when results are obtained
• I will endeavour to take blood cultures in my patients in a timely fashion before antibiotics, providing there is no delay in giving antimicrobials

External Links

• [Abstract] Blood Culture Results Before and After Antimicrobial Administration in Patients with Severe Manifestation of Sepsis
• [further reading] Surviving Sepsis Guidelines
• [Further listening] David Sweet at Intensive Care Society, State of the Art Conference, 9-11th December 2019

Metadata

Summary author: Celia Bradford (with contribution from Hakeem Ha) @celiabradford
Summary date: February 10 2020
Peer-review editor: @davidslessor