Background: Vancomycin, a key antibiotic for severe Gram-positive infections in ICUs, poses a high nephrotoxicity risk. Early prediction of kidney injury in critically ill patients is challenging. This study aimed to develop a machine learning model to predict vancomycin-related creatinine elevation using routine ICU data. Methods: We analyzed 10,288 ICU patients (aged 18-80) from the MIMIC-IV database who received vancomycin. Kidney injury was defined by KDIGO criteria (creatinine rise >=0.3 mg/dL within 48h or >=50% within 7d). Features were selected via SelectKBest (top 30) and Random Forest ranking (final 15). Six algorithms were tested with 5-fold cross-validation. Interpretability was evaluated using SHAP, Accumulated Local Effects (ALE), and Bayesian posterior sampling. Results: Of 10,288 patients, 2,903 (28.2%) developed creatinine elevation. CatBoost performed best (AUROC 0.818 [95% CI: 0.801-0.834], sensitivity 0.800, specificity 0.681, negative predictive value 0.900). Key predictors were phosphate, total bilirubin, magnesium, Charlson index, and APSIII. SHAP confirmed phosphate as a major risk factor. ALE showed dose-response patterns. Bayesian analysis estimated mean risk 60.5% (95% credible interval: 16.8-89.4%) in high-risk cases. Conclusions: This machine learning model predicts vancomycin-associated creatinine elevation from routine ICU data with strong accuracy and interpretability, enabling early risk detection and supporting timely interventions in critical care.

When I first became a doctor, I cared for an older man whom I'll call Ted. He was so sick with pneumonia that he was struggling to breathe. His primary-care physician had prescribed one antibiotic after another, but his symptoms had only worsened; by the time I saw him in the hospital, he had a high fever and was coughing up blood. His lungs seemed to be infected with methicillin-resistant Staphylococcus aureus (MRSA), a bacterium so hardy that few drugs can kill it. I placed an oxygen tube in his nostrils, and one of my colleagues inserted an I.V. into his arm. We decided to give him vancomycin, a last line of defense against otherwise untreatable infections.

The current best practice approach for the retrospective diagnosis of adverse drug events (ADEs) in hospitalized patients relies on a full patient chart review and a formal causality assessment by multiple medical experts. This evaluation serves to qualitatively estimate the probability of causation (PC); the probability that a drug was a necessary cause of an adverse event. This practice is manual, resource intensive and prone to human biases, and may thus benefit from data-driven decision support. Here, we pioneer a causal modeling approach using observational data to estimate a lower bound of the PC (PC$_{low}$). This method includes two key causal inference components: (1) the target trial emulation framework and (2) estimation of individualized treatment effects using machine learning. We apply our method to the clinically relevant use-case of vancomycin-induced acute kidney injury in intensive care patients, and compare our causal model-based PC$_{low}$ estimates to qualitative estimates of the PC provided by a medical expert. Important limitations and potential improvements are discussed, and we conclude that future improved causal models could provide essential data-driven support for medication safety monitoring in hospitalized patients.

Bacterial infections are responsible for high mortality worldwide. Antimicrobial resistance underlying the infection, and multifaceted patient's clinical status can hamper the correct choice of antibiotic treatment. Randomized clinical trials provide average treatment effect estimates but are not ideal for risk stratification and optimization of therapeutic choice, i.e., individualized treatment effects (ITE). Here, we leverage large-scale electronic health record data, collected from Southern US academic clinics, to emulate a clinical trial, i.e., 'target trial', and develop a machine learning model of mortality prediction and ITE estimation for patients diagnosed with acute bacterial skin and skin structure infection (ABSSSI) due to methicillin-resistant Staphylococcus aureus (MRSA). ABSSSI-MRSA is a challenging condition with reduced treatment options - vancomycin is the preferred choice, but it has non-negligible side effects. First, we use propensity score matching to emulate the trial and create a treatment randomized (vancomycin vs. other antibiotics) dataset. Next, we use this data to train various machine learning methods (including boosted/LASSO logistic regression, support vector machines, and random forest) and choose the best model in terms of area under the receiver characteristic (AUC) through bootstrap validation. Lastly, we use the models to calculate ITE and identify possible averted deaths by therapy change. The out-of-bag tests indicate that SVM and RF are the most accurate, with AUC of 81% and 78%, respectively, but BLR/LASSO is not far behind (76%). By calculating the counterfactuals using the BLR/LASSO, vancomycin increases the risk of death, but it shows a large variation (odds ratio 1.2, 95% range 0.4-3.8) and the contribution to outcome probability is modest. Instead, the RF exhibits stronger changes in ITE, suggesting more complex treatment heterogeneity.