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

The global burden of morbidity and mortality from sepsis is significant (1). Despite overall improvements in clinical outcomes, patients with sepsis and septic shock have short-term mortality rates approaching 20% (2). Although initial data for new treatments, such as activated protein C (3, 4), intensive insulin therapy (5), levosimendan (6), and -blockers (7), were promising, no novel host-directed therapies have consistently demonstrated a reduction in sepsis-associated mortality. The cornerstone of sepsis management continues to be early antimicrobial administration, source control, and supportive care (811). The Surviving Sepsis Campaign guidelines recommend that blood cultures be drawn before starting antimicrobial therapy, with 45-minute delays considered acceptable to achieve this goal (12). However, prompt initiation of effective antimicrobial therapy is a critical determinant of survival (13). Death has been associated with delayed antimicrobial therapy after the onset of septic shock (1417). Therefore, it is possible that administering antimicrobial agents before obtaining blood cultures could potentially decrease time to treatment and improve outcomes. Although specific microbiological diagnoses and antimicrobial susceptibility testing are important for determining the type and duration of treatment, the diagnostic sensitivity of blood cultures drawn shortly after antimicrobial administration in this population is not known. The purpose of this study was to determine whether the sensitivity of blood cultures decreased after administration of antimicrobial agents in patients with severe manifestations of sepsis. Methods Study Design We conducted the FABLED (eFfect of Antimicrobial administration on BLood culture positivity in patients with severe manifestations of sepsis in the Emergency Department) study, a patient-level, single-group, diagnostic study. The protocol was designed by the study management committee and reflects the standard of care in the participating institutions (Supplement). Seven urban emergency departments across Canada and the United States participated in the study. The research ethics boards at each recruiting center approved the protocol. The investigators remained unaware of the results throughout the enrollment period. The authors vouch for the data and analysis and for the fidelity of this report to the study protocol. Supplement. Supplementary Material. Participants We recruited adult patients (aged 18 years) who presented to the emergency department with severe manifestations of sepsis, who had 2 sets of blood cultures drawn before starting antibiotic therapy, and who were able to have additional sets drawn within 2 hours of empirical antimicrobial administration. The Supplement provides detailed inclusion and exclusion criteria. In brief, evidence of a systemic inflammatory response syndrome (18) as well as a presumed or confirmed source of infection in patients was required. Evidence of severity, including systolic blood pressure less than 90 mm Hg at prehospital assessment or in the emergency department or a serum lactate level of 4 mmol/L or greater (1921), was also required. These markers of severity were chosen because they are more likely to be present in patients with bloodstream infections and are associated with an increased risk for death independent of organ failure or shock (19, 20, 2224). Moreover, these variables are associated with a sicker patient population that is more likely to benefit from early empirical antimicrobial therapy. Patients were excluded if they had a clinically significant bleeding disorder, a platelet count less than 20000 109 cells/L, or an international normalized ratio greater than 6.0 because of the potential risk for harm from the additional venipuncture. Diagnostic Procedure Two sets of blood cultures were obtained from study participants before antimicrobial administration. Each set consisted of 1 aerobic and 1 anaerobic culture vial from a single venipuncture site; each set required a separate venipuncture. At 2 participating hospitals, the second set of blood cultures consisted of a single aerobic vial per institutional policy. After administration of the first antimicrobial agent, additional blood cultures were obtained. At 5 institutions, 2 additional sets of blood cultures were drawn with equal blood volumes before and after treatment initiation. At 2 institutions, 1 additional set of blood cultures was drawn after antimicrobial therapy was started because of institutional review board requirements to obtain the smallest acceptable blood culture volume per guideline recommendations (25) (Supplement). After treatment initiation, additional sets of blood cultures could be obtained from the same venipuncture to reduce the risk for harm from additional venipunctures. The protocol stipulated that repeated blood cultures were to be obtained between 30 and 120 minutes after treatment initiation. However, the protocol was amended to include participants with repeated blood cultures up to 240 minutes after antimicrobial therapy because of the difficulties in obtaining repeated blood cultures within 120 minutes of treatment initiation. Antimicrobial agents were administered as standard infusions per routine practice. Blood cultures were obtained and processed at each study site according to local standard operating procedures. All other aspects of clinical care were at the discretion of the treating emergency physician and were based on local institutional guidelines. There were no changes in sepsis protocols throughout the study period. Written informed consent was obtained from all patients or their surrogate decision maker before enrollment in the study. Given the low probability of harm to participants and the time-dependent nature of the diagnostic procedure, the institutional review boards for all participating institutions approved delayed consent in cases where patients lacked mental capacity and a surrogate decision maker could not be reached. In such cases, retrospective written consent was obtained from patients once they regained capacity or when a surrogate decision maker could be reached. Baseline demographic and clinical data were recorded for all patients. Outcomes The primary outcome was to determine the sensitivity of blood cultures obtained within 120 minutes after antimicrobial therapy was initiated in patients with severe manifestations of sepsis. We defined preantimicrobial blood cultures as the reference standard for bacteremia. A noncontaminant organism (25) growing in any of the preantimicrobial blood cultures, but absent from all postantimicrobial blood cultures, was defined as a discordant result. Postantimicrobial blood cultures that grew the same organisms as those obtained before antimicrobial therapy, regardless of the number of positive blood culture vials per set, was defined as a concordant result. In the setting of a polymicrobial bloodstream infection, all noncontaminant organisms recovered in the preantimicrobial blood cultures must have been present in the postantimicrobial blood cultures to have been considered concordant. Contaminant organisms were defined as low-virulence skin flora recovered from a single set of blood cultures when other sets were negative (25) (Supplement). All cases of potential contaminants were reviewed by 2 specialists (M.P.C. and C.P.Y.) in infectious diseases and medical microbiology. Appropriate antimicrobial therapy was defined according to Clinical and Laboratory Standards Institute interpretive criteria as administration of an antimicrobial agent to which the pathogen was susceptible (26). The main secondary outcome was to evaluate the sensitivity of postantimicrobial blood cultures interpreted in the context of microbiological culture results available from other anatomical sites. Sample Size On the basis of previously published data (10, 13) and local sepsis epidemiology, we estimated conservatively that 35% of patients with severe manifestations of sepsis would be bacteremic. On the basis of a matched design, preantimicrobial blood culture positivity proportion of 35%, desired power of 90%, 2-tailed error rate of 5%, and minimum clinically significant difference of 10% in sensitivity, 328 patients were required based on the repeated-measures design of the study. A 10% difference was chosen as the maximum difference in sensitivity between pre- and postantimicrobial blood cultures that would be deemed clinically acceptable through consultation with the infectious disease, emergency medicine, and critical care medicine specialists involved in development of the study protocol. Statistical Analysis Data from all hospital centers were consolidated, and the final data set was inspected for errors, outliers, and missing values. All study participants had complete data for the exposures and outcomes of interest. No patients were omitted because of missing data. The statistical unit of analysis was the blood culture pairing for each patient. The population for primary analysis was defined as any participant recruited to the study in whom both pre- and postantimicrobial (within 240 minutes after initiation of antimicrobial therapy) blood cultures were obtained. An a priori decision was made to analyze the results in the per protocol (PP) population, consisting of participants who had postantimicrobial blood cultures drawn between 30 and 120 minutes after initiation of antimicrobial treatment. Baseline patient characteristics are presented as proportions for categorical variables, means and SDs for age, and medians and interquartile ranges for nonnormally distributed data. The sample population was described per preantimicrobial blood culture results. Nonnormally distributed variables were compared using the Wilcoxon or the Wilcoxon signed-rank test for unpaired and paired data, respectively. Binary and categorical data were analyzed using the Fisher exact test or chi-sq