Machine Learning for Pre-Culture ESBL Risk Stratification to Guide Empiric Antibiotic Selection: A 12-Hospital Study of Enterobacteriaceae Cultures

Empiric antibiotic therapy for suspected ESBL-producing Enterobacteriaceae must be selected 48-72 hours before culture results, forcing clinicians to choose between undertreating resistant infections and overusing carbapenems that drive further resistance. We developed a cost-sensitive XGBoost model predicting an ESBL phenotype (resistance to ceftriaxone, ceftazidime, cefepime or piperacillin-tazobactam) at culture ordering using 45 pre-culture EHR features across 132,955 cultures from 72,217 patients at 12 hospitals (14.41% with the ESBL phenotype). Cultures were partitioned at the patient level. At 90% sensitivity, the model achieved 95.8% NPV, reducing post-test ESBL probability to 4.2%, a threshold that may support safe carbapenem-sparing in non-ICU settings, while sparing 307 of every 1,000 cultures an unnecessary broad-spectrum course at the cost of 14 missed ESBL cases per 1,000. SHAP analysis identified prior ESBL colonization as the dominant predictor, ahead of prior organism burden and neighborhood deprivation; removing deprivation features caused minimal performance loss (DeltaAUROC = -0.020), enabling equitable bedside deployment. Discrimination was unchanged under a strict IDSA ESBL-E definition (AUROC 0.766), with specimen type added as a predictor (0.764) and without any class-imbalance correction (0.762), and ranged from 0.71 to 0.78 across organism strata.