Early Empiric Antibiotic Use in Patients Hospitalized With COVID-19: A Retrospective Cohort Study

Abstract

Objective: To investigate temporal trends and outcomes associated with early antibiotic prescribing in patients hospitalized with COVID-19.

Design: Retrospective propensity-matched cohort study using the National COVID Cohort Collaborative (N3C) database.

Setting: Sixty-six health systems throughout the United States that were contributing to the N3C database. Centers that had fewer than 500 admissions in their dataset were excluded.

Patients: Patients hospitalized with COVID-19 were included. Patients were defined to have early antibiotic use if they received at least 3 calendar days of intravenous antibiotics within the first 5 days of admission.

Interventions: None.

Measurements and main results: Of 322,867 qualifying first hospitalizations, 43,089 patients received early empiric antibiotics. Antibiotic use declined across all centers in the data collection period, from March 2020 (23%) to June 2022 (9.6%). Average rates of early empiric antibiotic use (EEAU) also varied significantly between centers (deviance explained 7.33% vs 20.0%, p < 0.001). Antibiotic use decreased slightly by day 2 of hospitalization and was significantly reduced by day 5. Mechanical ventilation before day 2 (odds ratio [OR] 3.57; 95% CI, 3.42-3.72), extracorporeal membrane oxygenation before day 2 (OR 2.14; 95% CI, 1.75-2.61), and early vasopressor use (OR 1.85; 95% CI, 1.78-1.93) but not region of residence was associated with EEAU. After propensity matching, EEAU was associated with an increased risk for in-hospital mortality (OR 1.27; 95% CI, 1.23-1.33), prolonged mechanical ventilation (OR 1.65; 95% CI, 1.50-1.82), late broad-spectrum antibiotic exposure (OR 3.24; 95% CI, 2.99-3.52), and late Clostridium difficile infection (OR 1.60; 95% CI, 1.37-1.87).

Conclusions: Although treatment of COVID-19 patients with empiric antibiotics has declined during the pandemic, the frequency of use remains high. There is significant inter-center variation in antibiotic prescribing practices and evidence of potential harm. Our findings are hypothesis-generating and future work should prospectively compare outcomes and adverse events.

Figure 1.

A, Absolute rates of early antibiotic usage by month and center. Each circle represents the rate for a center during a given month and the size of the circle is proportional to the number of COVID cases at that center that month. The red line represents the average rate of early antibiotic usage across all centers. B, Monthly rates of early antibiotic usage by center. Each row represents a single center throughout the entire study period. Centers are arranged by overall EEAU rate rank with the highest overall rate centers at the top of the figure. The color represents how that center compared with all other centers during that same month with higher percentiles representing more antibiotic usage (i.e., 75th percentile centers had a higher rate than 75% of all other centers that month). Cells are empty when that center reported no data for that month. EEAU = early empiric antibiotic use.

Figure 2.

Number of antibiotic orders by hospital day. Each order represents a specific drug administered to a single patient during that day. Some centers report concurrent administration of beta-lactam/beta-lactamase inhibitors as two separate medications so beta-lactamase inhibitors are excluded here. A patient on combination antimicrobial therapy would be represented as multiple orders.

Figure 3.

Percentage of total admissions with early usage of ECMO, early usage of IMV, early major surgery, traumatic admission diagnoses, and early usage of vasopressors. ECMO = extracorporeal membrane oxygenation, IMV = invasive mechanical ventilation.

Figure 4.

Rates of admissions with EEAU over time by early usage of ECMO, early usage of IMV, early major surgery, traumatic admission diagnoses, early usage of vasopressors. and procalcitonin status. EEAU = early empiric antibiotic use, ECMO = extracorporeal membrane oxygenation, IMV = invasive mechanical ventilation.