Unnecessary antibiotic use is a major driver of antimicrobial resistance, an urgent public health threat. There is an unmet need for improved diagnostics for identifying bacterial etiology in acute respiratory infection (ARI). Hospitalized adults with ARI underwent comprehensive microbiologic testing and those with definitive viral (n = 280), bacterial (n = 129), or mixed viral-bacterial infection (n = 95) had whole blood RNA sequencing. A hard-thresholded, mostly relaxed, LASSO-constrained logistic regression model was used to select a parsimonious gene set (