Model-Informed Dosing Optimization of Colistin Sulfate in Critically Ill Patients With and Without Continuous Renal Replacement Therapy

OBJECTIVES: This multicentre study aimed to evaluate the influence of continuous renal replacement therapy (CRRT) on the pharmacokinetics of colistin sulfate (CS) in critically ill patients and to propose optimized dosing regimens. METHODS: Serial blood samples were obtained from critically ill patients receiving CS. Total CS concentrations were measured using a validated LC-MS/MS assay. The NONMEM software was utilized to develop the population pharmacokinetic (PopPK) model of CS and identify covariates influencing its pharmacokinetics. Monte Carlo simulations were conducted to optimize dosing regimens based on the probability of target attainment. Clinical efficacy, microbiological eradication, and adverse events of colisitn sulfate were also assessed. Logistic regression was conducted to identify clinical success predictors. RESULTS: A total of 123 critically ill patients with 370 plasma concentration measurements were included. 29 patients (23.6%) received CRRT during CS treatment. The final PopPK model was best characterized by a two-compartment structure, with creatinine clearance and CRRT significantly affecting CS clearance. Monte Carlo simulations indicated that patients undergoing CRRT required higher doses, and the use of a loading dose facilitated rapid target attainment. Overall, 68.3% of patients achieved clinical success, and bacterial eradication was 65.0%. Clinical efficacy was positively associated with longer treatment duration and negatively associated with vasoactive agent use. Notably, acute kidney injury occurred in 21.9% of patients during CS therapy. CONCLUSION: This study highlights the impact of CRRT on the pharmacokinetics of CS in critically ill patients, necessitating higher doses, and the use of a loading dose is recommended for rapid target attainment.