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Population Pharmacokinetics and Model-Informed Precision Dosing of Colistin Sulfate in Critically Ill Patients with Carbapenem-Resistant Gram-Negative Infections: A Prospective Pharmacokinetic-Pharmacodynamic Study

Year: 2026

Type: article

Abstract: Background: Independently evaluated population pharmacokinetic models and clinically derived pharmacokinetic/pharmacodynamic targets for colistin sulfate remain limited. We aimed to develop and evaluate a model, explore an efficacy threshold, and construct a research model-informed precision dosing calculator. Methods: This prospective study included 55 critically ill patients with microbiologically confirmed infection caused by carbapenem-resistant Gram-negative bacteria (CR-GNB) for model development and 15 with suspected CR-GNB infection without microbiological confirmation for independent evaluation of concentration predictions. Plasma concentrations were measured by validated ultra-performance liquid chromatography-tandem mass spectrometry. Modeling used nonlinear mixed-effects modeling software (NONMEM). Logistic regression and receiver operating characteristic (ROC) analysis assessed efficacy predictors and the exploratory threshold. Monte Carlo simulations evaluated probability of target attainment (PTA). Results: A two-compartment model with creatinine clearance (CrCL) as a covariate on clearance (CL) best described the data (typical CL = 6.67 × (CrCL/76.9) 0.648 L/h). Independent evaluation yielded a relative root mean square error of 37.4%, with 53.7% of predictions within ± 30% of observations. Clinical efficacy was achieved in 24/55 patients. The ratio of 24-hour steady-state area under the concentration-time curve (AUC ss,24h ) to minimum inhibitory concentration (MIC) and the Acute Physiology and Chronic Health Evaluation II (APACHE II) score were independently associated with efficacy (odds ratios per one-unit increase, 1.04 and 0.81, respectively). The exploratory AUC ss,24h /MIC cut-off was 40.53 (area under the ROC curve, 0.712). At MIC ≥ 1 mg/L, no evaluated monotherapy regimen achieved PTA ≥ 90% in patients with normal or augmented renal function. Conclusion: This study provides a pharmacokinetic model with preliminary independent predictive evaluation, an exploratory exposure threshold, and an open-access research dosing calculator. Prospective multicenter validation is required before clinical implementation. Keywords: colistin sulfate, pharmacokinetic/pharmacodynamic, carbapenem-resistant Gram-negative bacteria, critically ill patients, model-informed precision dosing

Source: Drug Design Development and Therapy

DOI: 10.2147/dddt.s641015