Carbapenem use in extended-spectrum cephalosporin-resistant Enterobacterales infections in US hospitals and influence of IDSA guidance: a retrospective cohort study.

BACKGROUND: Disparate and rapidly changing practice recommendations from major professional infectious diseases societies for managing non-severe infections caused by extended-spectrum ß-lactamase-producing Enterobacterales might hamper carbapenem stewardship. We aimed to understand the real-world management of extended-spectrum cephalosporin-resistant (ECR) Enterobacterales infections in US hospitals and factors influencing preference for carbapenems over alternative treatments. METHODS: This retrospective cohort study included adults (aged ≥18 years) admitted to hospital with ECR Enterobacterales infections in the PINC AI database. Antibiotic regimens were assessed during empirical and targeted treatment periods and by infection severity and site. Likelihood of receiving targeted carbapenems over time and before or after initial release of the Infectious Diseases Society of America (IDSA) guidance on Sept 8, 2020, was established with generalised estimating equations controlling for patient, hospital, and temporal confounders. FINDINGS: Between Jan 1, 2018, and Dec 31, 2021, 30 041 inpatient encounters with ECR Enterobacterales infections were identified at 168 US hospitals, of which 16 006 (53·3%) encounters were in women and 14 035 (46·7%) were in men, with a mean age of 67·3 years (SD 15·1). Although few patients received carbapenems empirically (5324 [17·7%] of 30 041), many did so as targeted treatment (17 518 [58·3%] of 30 041), including subgroups of patients without septic shock (3031 [45·6%] of 6651) and patients with urinary tract infections without septic shock (1845 [46·8%] of 3943) in whom specific narrower-spectrum alternatives were active. Transitions from non-carbapenem to carbapenem antibiotics occurred most often on the day that the ECR phenotype was reported, regardless of illness severity. Carbapenems were the predominant choice to treat ECR Enterobacterales infections over time (adjusted odds ratio 1·00 [95% CI 1·00-1·00]), with no additional immediate change (1·07 [0·95-1·20]) or sustained change (0·99 [0·98-1·00]) after IDSA guidance release. INTERPRETATION: High carbapenem use in targeting non-severe ECR Enterobacterales infections in US hospitals predates 2020 IDSA guidance and has persisted thereafter. Efforts to increase awareness and implementation of recommendations among clinicians to use carbapenem-sparing alternatives in ECR Enterobacterales infections might decrease global carbapenem selective pressure. FUNDING: US National Institutes of Health Intramural Research Program, National Institute of Allergy and Infectious Diseases, and US Food and Drug Administration.

Validation of a Novel, Rapid Sepsis Diagnostic for Emergency Department Use.

OBJECTIVES: To assess the in vitro IntelliSep test, a microfluidic assay that quantifies the state of immune activation by evaluating the biophysical properties of leukocytes, as a rapid diagnostic for sepsis. DESIGN: Prospective cohort study. SETTING: Five emergency departments (EDs) in Louisiana, Missouri, North Carolina, and Washington. PATIENTS: Adult patients presenting to the ED with signs (two of four Systemic Inflammatory Response Syndrome criteria, where one must be temperature or WBC count) or suspicion (provider-ordered culture) of infection. INTERVENTIONS: All patients underwent testing with the IntelliSep using ethylene diamine tetraacetic acid-anticoagulated whole blood followed by retrospective adjudication for sepsis by sepsis-3 criteria by a blinded panel of physicians. MEASUREMENTS AND MAIN RESULTS: Of 599 patients enrolled, 572 patients were included in the final analysis. The result of the IntelliSep test is reported as the IntelliSep Index (ISI), ranging from 0.1 to 10.0, divided into three interpretation bands for the risk of sepsis: band 1 (low) to band 3 (high). The median turnaround time for ISI results was 7.2 minutes. The ISI resulted band 1 in 252 (44.1%), band 2 in 160 (28.0%), and band 3 in 160 (28.0%). Sepsis occurred in 26.6% (152 of 572 patients). Sepsis prevalence was 11.1% (95% CI, 7.5-15.7%) in band 1, 28.1% (95% CI, 21.3-35.8%) in band 2, and 49.4% (95% CI, 41.4-57.4%) in band 3. The Positive Percent Agreement of band 1 was 81.6% and the Negative Percent Agreement of band 3 was 80.7%, with an area under the receiver operating characteristic curve of 0.74. Compared with band 1, band 3 correlated with adverse clinical outcomes, including mortality, and resource utilization. CONCLUSIONS: Increasing ISI interpretation band is associated with increasing probability of sepsis in patients presenting to the ED with suspected infection.

Retrospective identification of infection in the emergency department: A significant challenge in sepsis clinical trials.

BACKGROUND: This study examined three methods for retrospectively identifying infection in emergency department (ED) patients: modified objective definitions of infection (MODI) from the CDC/NHSN, physician adjudication determination of infection, and ED treating physician behavior. METHODS: This study used a subset of data from a prospective sepsis trial. We used Fleiss's Kappa to compare agreement between two physicians retrospectively adjudicating infection based on the patient's medical record, modified infection definition from the CDC/NHSN, and ED treating physician behavior. RESULTS: Overall, there was similar agreement between physician adjudication of infection and MODI criteria (Kappa=0.59) compared to having two physicians independently identify infection through retrospective chart review (Kappa=0.58). ED treating physician behavior was a poorer proxy for infection when compared to the MODI criteria (0.41) and physician adjudication (Kappa = 0.50). CONCLUSIONS: Retrospective identification of infection poses a significant challenge in sepsis clinical trials. Using modified definitions of infection provides a standardized, less time consuming, and equally effective means of identifying infection compared to having multiple physicians adjudicate a patient's chart.

Assessment of a Cellular Host Response Test as a Sepsis Diagnostic for Those With Suspected Infection in the Emergency Department.

OBJECTIVES: Sepsis is a common cause of morbidity and mortality. A reliable, rapid, and early indicator can help improve efficiency of care and outcomes. To assess the IntelliSep test, a novel in vitro diagnostic that quantifies the state of immune activation by measuring the biophysical properties of leukocytes, as a rapid diagnostic for sepsis and a measure of severity of illness, as defined by Sequential Organ Failure Assessment and Acute Physiology and Chronic Health Evaluation-II scores and the need for hospitalization. DESIGN SETTING SUBJECTS: Adult patients presenting to two emergency departments in Baton Rouge, LA, with signs of infection (two of four systemic inflammatory response syndrome criteria, with at least one being aberration of temperature or WBC count) or suspicion of infection (a clinician order for culture of a body fluid), were prospectively enrolled. Sepsis status, per Sepsis-3 criteria, was determined through a 3-tiered retrospective and blinded adjudication process consisting of objective review, site-level clinician review, and final determination by independent physician adjudicators. MEASUREMENTS AND MAIN RESULTS: Of 266 patients in the final analysis, those with sepsis had higher IntelliSep Index (median = 6.9; interquartile range, 6.1-7.6) than those adjudicated as not septic (median = 4.7; interquartile range, 3.7-5.9; p < 0.001), with an area under the receiver operating characteristic curve of 0.89 and 0.83 when compared with unanimous and forced adjudication standards, respectively. Patients with higher IntelliSep Index had higher Sequential Organ Failure Assessment (3 [interquartile range, 1-5] vs 1 [interquartile range, 0-2]; p < 0.001) and Acute Physiology and Chronic Health Evaluation-II (7 [interquartile range, 3.5-11.5] vs 5 [interquartile range, 2-9]; p < 0.05) and were more likely to be admitted to the hospital (83.6% vs 48.3%; p < 0.001) compared with those with lower IntelliSep Index. CONCLUSIONS: In patients presenting to the emergency department with signs or suspicion of infection, the IntelliSep Index is a promising tool for the rapid diagnosis and risk stratification for sepsis.

Risk factors for mortality and progression to severe COVID-19 disease in the Southeast region in the United States: A report from the SEUS Study Group.

OBJECTIVE: Identify risk factors that could increase progression to severe disease and mortality in hospitalized SARS-CoV-2 patients in the Southeast region of the United States. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, retrospective cohort including 502 adults hospitalized with laboratory-confirmed COVID-19 between March 1, 2020, and May 8, 2020 within 1 of 15 participating hospitals in 5 health systems across 5 states in the Southeast United States. METHODS: The study objectives were to identify risk factors that could increase progression to hospital mortality and severe disease (defined as a composite of intensive care unit admission or requirement of mechanical ventilation) in hospitalized SARS-CoV-2 patients in the Southeast United States. RESULTS: In total, 502 patients were included, and 476 of 502 (95%) had clinically evaluable outcomes. The hospital mortality rate was 16% (76 of 476); 35% (177 of 502) required ICU admission and 18% (91 of 502) required mechanical ventilation. By both univariate and adjusted multivariate analyses, hospital mortality was independently associated with age (adjusted odds ratio [aOR], 2.03 for each decade increase; 95% confidence interval [CI], 1.56--2.69), male sex (aOR, 2.44; 95% CI, 1.34-4.59), and cardiovascular disease (aOR, 2.16; 95% CI, 1.15-4.09). As with mortality, risk of severe disease was independently associated with age (aOR, 1.17 for each decade increase; 95% CI, 1.00-1.37), male sex (aOR, 2.34; 95% CI, 1.54-3.60), and cardiovascular disease (aOR, 1.77; 95% CI, 1.09-2.85). CONCLUSIONS: In an adjusted multivariate analysis, advanced age, male sex, and cardiovascular disease increased risk of severe disease and mortality in patients with COVID-19 in the Southeast United States. In-hospital mortality risk doubled with each subsequent decade of life.