Individualized Treatment Effects of Cefepime vs Piperacillin-Tazobactam in Adults Hospitalized with Acute Infection

Abstract Rationale Among adults hospitalized with acute infection, a recent randomized trial observed no significant average treatment effect of cefepime versus piperacillin-tazobactam on acute kidney injury or death, but fewer days-alive-and-free-of delirium and coma with cefepime. Objectives To determine whether patients’ individual characteristics modify the effect of cefepime versus piperacillin-tazobactam on outcomes. Methods In this secondary analysis of the Antibiotic Choice On Renal Outcomes (ACORN) trial, an effect model was derived and validated to predict the effect of cefepime versus piperacillin-tazobactam for adults hospitalized with acute infection. The primary outcome was survival without acute kidney injury; the secondary outcome was survival without delirium or coma. Measurements and Main Results The individualized treatment effect predicted in the validation cohort significantly modified the effect of cefepime versus piperacillin-tazobactam on survival without acute kidney injury (Qini 1.68; 95% confidence interval [CI], 0.25-3.18; p-value = 0.01). Among 626 patients predicted to experience ≥5% benefit from cefepime, 81.2% of patients randomized to cefepime survived without acute kidney injury, versus 74.2% randomized to piperacillin-tazobactam (difference, 7.1%; 95%CI, 0.25 to 13.9%). Among 203 patients predicted to experience ≥5% benefit from piperacillin-tazobactam, 56.6% of patients randomized to cefepime survived without acute kidney injury, versus 63.0% randomized to piperacillin-tazobactam (difference, -6.3%; 95%CI, -20.7 to 8.2%). The effect of trial group on survival without delirium or coma was not modified by individual characteristics. Conclusions Patients’ individual characteristics modified the effect of cefepime versus piperacillin-tazobactam on survival without acute kidney injury but not on survival without delirium or coma.