The second day of bacteremia under antibiotic therapy represents the most meaningful clinical cutoff both to define Staphylococcus aureus persistent bacteremia and to consider the implementation of additional diagnostic and therapeutic measures to reduce the high mortality in S aureus bacteremia, according to study results published in The Lancet Infectious Diseases.

In this secondary analysis of a prospective, observational cohort study (ClinicalTrials.gov identifier NCT02098850) from 17 tertiary care hospitals in 3 European countries (9 in the United Kingdom, 6 in Spain, and 2 in Germany), researchers analyzed mortality according to duration of bacteremia and to derive a clinically relevant definition for S aureus persistent bacteremia.

Adult patients who were consecutively hospitalized with monomicrobial S aureus bacteremia were included. Patients were excluded if no follow-up blood culture was taken, if the first follow-up blood culture was after 7 days, or if active antibiotic therapy was started more than 3 days after first blood culture.

Two different criteria for calculating the duration of bacteremia were compared: starting from the day of collection of the first positive blood culture (non-adjusted duration of bacteremia), or starting from the first day of active antibiotic therapy after collection of the first positive blood culture (adjusted duration of bacteremia).


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The primary outcome was 90-day mortality. Secondary outcomes were 30-day mortality and in-hospital mortality as well as development of a new metastatic focus. Whenever possible, survival data were confirmed by national death registry data.

Of the 1588 patients enrolled in the cohort, 987 (63% men) were included in the analysis. The median age was 65 years (interquartile range [IQR], 51-75), and the median number of follow-up cultures was 2 (IQR, 1-4). Death occurred in 174 (18%) patients within 30 days and in 273 (28%) within 90 days.

For both the non-adjusted and the antibiotic-adjusted duration of bacteremia, researchers found an increased risk of 90-day mortality if bacteremia persisted after day 1. Because the antibiotic-adjusted definition showed a stronger association with 90-day mortality, and antibiotics are needed to clear an infection, researchers chose this criterion for further analysis. With this criterion, median duration of bacteremia was 3 days (IQR, 2-5) in the 315 patients with positive follow-up blood cultures. Patients with more than 1 day of bacteremia presented with a higher Charlson comorbidity index score, higher sequential organ failure assessment score, higher amounts of C-reactive protein, and a longer interval from start of symptoms until first blood culture.

Crude 90-day mortality increased from 22% (148 of 672) with 1 day of bacteremia, to 39% (85 of 218) with 2 to 4 days, 43% (30 of 69) with 5 to 7 days, and 36% (10 of 28) with more than 7 days of bacteremia. A new metastatic focus occurred significantly more often in patients with delayed clearance with the highest rate of 22% (15 of 69) in patients with 5 to 7 days of bacteremia.

Researchers found that the second day of bacteremia under antibiotic therapy represented the highest hazard ratio (HR) and earliest cutoff to differentiate between patients who survived and those who died (adjusted HR, 1.93; 95% CI, 1.51-2.46; P <.0001). In concordance with this finding, 90-day mortality increased from 22% (148 of 672) with 1 day of bacteremia to 40% (125 of 315) with more than 1 day of bacteremia.

One study limitation of note was the observational design. Additional limitations include insufficient data for antibiotic therapy or serum antibiotic concentrations to include in the analyses, as well as the researchers’ decision to not record the number of patients excluded a priori due to ineligibility or refusal of consent.

“Hence, taking the first follow-up cultures after 24 hours, earlier than the recommended 48–72 hour interval, could help to identify patients at increased risk of death and metastatic spread,” stated the researchers. “Further studies are required to confirm whether this new cutoff will affect patient management and improve the outcome of patients with S aureus bacteremia,” they concluded.

Reference

Kuehl R, Morata L, Boeing C, et al; on behalf of the International Staphylococcus aureus collaboration study group and the ESCMID Study Group for Bloodstream Infections, Endocarditis and Sepsis. Defining persistent Staphylococcus aureus bacteraemia: secondary analysis of a prospective cohort study [published online August 4, 2020]. Lancet Infect Dis. doi:10.1016/S1473-3099(20)30447-3