EM Nerd-The Case of the Microscopic Imperative

In the management of sepsis, the acquisition of blood cultures prior to the administration of antibiotics has been a long-held dictum, even before it gained the regulatory support due to its place in the SEP-1 3-hour bundle. But how much is lost if we defer the acquisition of blood cultures until after the administration of antibiotics in the sickest subset of septic patients for whom a delay to antibiotic administration may prove to be harmful. A recent paper by Cheng et al published (1) in Annals of Internal Medicine suggests there is, at the very least, a microbiological cost to such a deferral.

The authors enrolled adult patients (aged ≥18 years), who presented to one of seven emergency departments with severe sepsis, who had two sets of blood cultures drawn before starting antibiotic therapy, and who were able to have additional sets drawn within two hours of empirical antimicrobial administration. Severe sepsis was defined by two SIRS criteria, with a suspected or confirmed infectious source, and either hypotension (SBP<90 mmHG), or a serum lactate> 4 mmol/L. There were some procedural differences at the varying institutions participating in this study but essentially, two sets of blood cultures (one aerobic and one anaerobic culture vial in each set) were obtained prior to antimicrobial administration from separate venipuncture sites. Patients were required to have repeat blood cultures drawn between 30-120 minutes after the initiation of antibiotic therapy. Due to difficulty at some centers meeting the 120-minute goal, the authors extended their window to allow repeat cultures to be obtained within 240 minutes.

Over a five-year period the authors enrolled 325 patients. 43.4% of the cohort presented with a serum lactate level of 4 mmol/L while 37.8% had hypotension. 18.8% had both an elevated serum lactate and hypotension at the time of enrollment. Of the entire cohort, 102 of 325 (31.4%) patients had pre-antibiotic positive cultures. Comparatively, only 63 of 325 (19.4%) of the patients had post-antibiotic blood cultures which were positive. This was an absolute difference in yield of 12.0% (95% CI, 5.4% to 18.6%; P < 0.001). When only the 264 patients who had repeat blood cultures drawn within 120 minutes were included in the analysis, the results were fairly similar. The authors reported a 10.6% absolute difference in yield. The authors noted that this led to a sensitivity of post-antibiotic administration blood cultures of only 52.9% (CI, 42.8% to 62.9%). When the addition of cultures from other anatomic sites such as urine and sputum was incorporated, the sensitivity was 67.6% (CI, 57.7% to 76.6%).

This is fairly compelling data, confirming what most suspected. The ability to culture bacterial perpetrators becomes less efficacious once therapy intended to eliminate said perpetrators is initiated. And while this is an excellent study with fairly robust methods there were a number of methodological factors that may have led to the underestimation of the post-antibiotic culture’s performance. For example, as per the protocol not all the centers used identical methods for obtaining blood cultures in their pre and post antibiotic sets. Only five of the seven centers obtained two sets of cultures, pre and post antibiotic administration, while the remained two centers only obtained a single set of cultures after antibiotic administration. In addition, if two sets were drawn, the centers were permitted to draw the post-antibiotic cultures from the same venipuncture site. Furthermore, in a number of cases multiple organisms were identified on the pre-antibiotic cultures, but the post-antibiotic cultures were only positive for some of these organisms. By design these were considered as false negatives. Would these discordances have changed management? Would they have led to an inappropriate de-escalation of antibiotics, or were they simply the result of laboratory dissonance which had little effect on clinical care? These considerations have the potential for decreasing the apparent performance of the post-antibiotic cultures (2, 3).

It is important to remember that this is a diagnostic study which reports microbiotic data only. We are not presented with the clinical course of these patients. All patients received both pre and post-antibiotic cultures, thus we are unable to divine the clinical consequences any of these false negative post-antibiotic cultures may have caused. This study is also unable to assess the potential harms of delayed antibiotic administration in an attempt to obtain pre-antibiotic cultures.

Cheng et al present us with a clinical puzzle. In general, the yield of blood cultures is quite low in all patients receiving inpatient antibiotics (4). It is only in patients with septic shock that we see such high rates of positive cultures as we did with this cohort. But these are the very same patients in which a time-dependent benefit to the administration of antibiotics may exist (5). And so, while this is great data, that supports a long-held belief, it should not change our current practice. In sick patients presenting in septic shock, valiant efforts should be made to obtain blood cultures upon obtaining initial vascular access. But if for whatever reason, there is going to be a delay to obtaining cultures, antibiotics should not be withheld.

Sources Cited:

Cheng MP, Stenstrom R, Paquette K, et al, for the FABLED Investigators. Blood Culture Results Before and After Antimicrobial Administration in Patients With Severe Manifestations of Sepsis: A Diagnostic Study. Ann Intern Med. [Epub ahead of print 17 September 2019]
Lee A, Mirrett S, Reller LB, Weinstein MP. Detection of bloodstream infections in adults: how many blood cultures are needed?. J Clin Microbiol. 2007;45(11):3546-8.
Elantamilan D, Lyngdoh VW, Khyriem AB, et al. Comparative evaluation of the role of single and multiple blood specimens in the outcome of blood cultures using BacT/ALERT 3D (automated) blood culture system in a tertiary care hospital. Indian J Crit Care Med. 2016;20(9):530-3.
Rand KH, Beal SG, Rivera K, Allen B, Payton T, Lipori GP. Hourly Effect of Pretreatment With IV Antibiotics on Blood Culture Positivity Rate in Emergency Department Patients. Open Forum Infect Dis. 2019;6(5)
Seymour CW, Gesten F, Prescott HC, et al. Time to Treatment and Mortality during Mandated Emergency Care for Sepsis. N Engl J Med. 2017;376(23):2235-2244.