Cefepime vs Piperacillin-Tazobactam in Adults Hospitalized With Acute Infection: The ACORN Randomized Clinical Trial.

Importance: Cefepime and piperacillin-tazobactam are commonly administered to hospitalized adults for empirical treatment of infection. Although piperacillin-tazobactam has been hypothesized to cause acute kidney injury and cefepime has been hypothesized to cause neurological dysfunction, their comparative safety has not been evaluated in a randomized clinical trial. Objective: To determine whether the choice between cefepime and piperacillin-tazobactam affects the risks of acute kidney injury or neurological dysfunction. Design, Setting, and Participants: The Antibiotic Choice on Renal Outcomes (ACORN) randomized clinical trial compared cefepime vs piperacillin-tazobactam in adults for whom a clinician initiated an order for antipseudomonal antibiotics within 12 hours of presentation to the hospital in the emergency department or medical intensive care unit at an academic medical center in the US between November 10, 2021, and October 7, 2022. The final date of follow-up was November 4, 2022. Interventions: Patients were randomized in a 1:1 ratio to cefepime or piperacillin-tazobactam. Main Outcomes and Measures: The primary outcome was the highest stage of acute kidney injury or death by day 14, measured on a 5-level ordinal scale ranging from no acute kidney injury to death. The 2 secondary outcomes were the incidence of major adverse kidney events at day 14 and the number of days alive and free of delirium and coma within 14 days. Results: There were 2511 patients included in the primary analysis (median age, 58 years [IQR, 43-69 years]; 42.7% were female; 16.3% were Non-Hispanic Black; 5.4% were Hispanic; 94.7% were enrolled in the emergency department; and 77.2% were receiving vancomycin at enrollment). The highest stage of acute kidney injury or death was not significantly different between the cefepime group and the piperacillin-tazobactam group; there were 85 patients (n = 1214; 7.0%) in the cefepime group with stage 3 acute kidney injury and 92 (7.6%) who died vs 97 patients (n = 1297; 7.5%) in the piperacillin-tazobactam group with stage 3 acute kidney injury and 78 (6.0%) who died (odds ratio, 0.95 [95% CI, 0.80 to 1.13], P = .56). The incidence of major adverse kidney events at day 14 did not differ between groups (124 patients [10.2%] in the cefepime group vs 114 patients [8.8%] in the piperacillin-tazobactam group; absolute difference, 1.4% [95% CI, -1.0% to 3.8%]). Patients in the cefepime group experienced fewer days alive and free of delirium and coma within 14 days (mean [SD], 11.9 [4.6] days vs 12.2 [4.3] days in the piperacillin-tazobactam group; odds ratio, 0.79 [95% CI, 0.65 to 0.95]). Conclusions and Relevance: Among hospitalized adults in this randomized clinical trial, treatment with piperacillin-tazobactam did not increase the incidence of acute kidney injury or death. Treatment with cefepime resulted in more neurological dysfunction. Trial Registration: ClinicalTrials.gov Identifier: NCT05094154.

Serial Thromboelastography and the Development of Venous Thromboembolism in Critically Ill Patients With COVID-19.

To test the hypothesis that relatively lower clot strength on thromboelastography maximum amplitude (MA) is associated with development of venous thromboembolism (VTE) in critically ill patients with COVID-19. DESIGN: Prospective, observational cohort study. SETTING: Tertiary care, academic medical center in Nashville, TN. PATIENTS: Patients with acute respiratory failure from COVID-19 pneumonia admitted to the adult medical ICU without known VTE at enrollment. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Ninety-eight consecutive critically ill adults with laboratory-confirmed COVID-19 were enrolled. Thromboelastography parameters and conventional coagulation parameters were measured on days 0 (within 48 hr of ICU admission), 3, 5, and 7 after enrollment. The primary outcome was diagnosis of VTE with confirmed deep venous thrombosis and/or pulmonary embolism by clinical imaging or autopsy. Twenty-six patients developed a VTE. Multivariable regression controlling for antiplatelet exposure and anticoagulation dose with death as a competing risk found that lower MA was associated with increased risk of VTE. Each 1 mm increase in enrollment and peak MA was associated with an 8% and 14% decrease in the risk of VTE, respectively (enrollment MA: subdistribution hazard ratio [SHR], 0.92; 95% CI, 0.87-0.97; p = 0.003 and peak MA: SHR, 0.86; 95% CI, 0.81-0.91; p < 0.001). Lower enrollment platelet counts and fibrinogen levels were also associated with increased risk of VTE (p = 0.002 and p = 0.01, respectively). Platelet count and fibrinogen level were positively associated with MA (multivariable model: adjusted R 2 = 0.51; p < 0.001). CONCLUSIONS: When controlling for the competing risk of death, lower enrollment and peak MA were associated with increased risk of VTE. Lower platelet counts and fibrinogen levels at enrollment were associated with increased risk of VTE. The association of diminished MA, platelet counts, and fibrinogen with VTE may suggest a relative consumptive coagulopathy in critically ill patients with COVID-19.

Thromboelastography Parameters and Platelet Count on Admission to the ICU and the Development of Venous Thromboembolism in Patients With Coronavirus Disease 2019.

OBJECTIVES: Determine if thromboelastography parameters and platelet count on the day of ICU admission are associated with the development of venous thromboembolism in patients with coronavirus disease 2019. DESIGN: Prospective, observational cohort study. SETTING: Tertiary-care, academic medical center in Nashville, TN. PATIENTS: Patients with coronavirus disease 2019 pneumonia and acute respiratory failure admitted to the adult ICU without venous thromboembolism at the time of ICU admission. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was development of venous thromboembolism during the index hospitalization. Venous thromboembolism was defined by clinical imaging or autopsy, demonstrating deep vein thrombosis or pulmonary embolism. Forty consecutive critically ill adults with laboratory-confirmed coronavirus disease 2019 were enrolled; 37 (92.5%) were hypercoagulable by at least one thromboelastography parameter at the time of ICU admission and 12 (30%) met the primary outcome of venous thromboembolism during the index hospitalization. Patients who developed venous thromboembolism had decreased measures of clotting (maximum amplitude, alpha angle, shear elastic modulus parameter, and clotting index) on ICU admission thromboelastography compared with patients who did not develop venous thromboembolism (p < 0.05 for all measures). For each individual thromboelastography parameter used to dichotomize patients as hypercoagulable, the rate of venous thromboembolism was not higher in those identified as hypercoagulable; in fact, the venous thromboembolism rate was higher in patients who were not hypercoagulable by thromboelastography for maximum amplitude (p = 0.04) and alpha angle (p = 0.001). Platelet count was positively correlated with maximum amplitude, alpha angle, G parameter, and clotting index, and significantly lower in patients who developed venous thromboembolism than those who did not (median 186 vs 278 103/µL, p = 0.046). Venous thromboembolism was associated with inhospital mortality (odds ratio, 6.3; 95% CI, 1.4-29; p = 0.02). CONCLUSIONS: Our data do not support the use of thromboelastography to risk stratify critically ill adults with coronavirus disease 2019 for the development of venous thromboembolism or to guide decisions about anticoagulation. Lower platelet count on ICU admission, which may reflect platelet aggregation, was associated with venous thromboembolism.

C-Reactive Protein Predicts Risk of Venous Thromboembolism in Pediatric Musculoskeletal Infection.

BACKGROUND: The rate of venous thromboembolism in children with musculoskeletal infections (MSKIs) is markedly elevated compared with hospitalized children in general. Predictive biomarkers to identify high-risk patients are needed to prevent the significant morbidity and rare mortality associated with thrombotic complications. We hypothesize that overactivation of the acute phase response is associated with the development of pathologic thrombi and we aim to determine whether elevations in C-reactive protein (CRP) are associated with increased rates of thrombosis in pediatric patients with MSKI. METHODS: A retrospective cohort study measuring CRP in pediatric MSKI patients with or without thrombotic complications. RESULTS: The magnitude and duration of elevation in CRP values correlated with the severity of infection and the development of pathologic thrombosis. In multivariable logistic regression, every 20 mg/L increase in peak CRP was associated with a 29% increased risk of thrombosis (P<0.001). Peak and total CRP were strong predictors of thrombosis with area under the receiver-operator curves of 0.90 and 0.92, respectively. CONCLUSIONS: Future prospective studies are warranted to further define the discriminatory power of CRP in predicting infection-provoked thrombosis. Pharmacologic prophylaxis and increased surveillance should be strongly considered in patients with MSKI, particularly those with disseminated disease and marked elevation of CRP. LEVEL OF EVIDENCE: Level III.