Optimizing Colistin Sulfate Dosing in Severe Infections: A Population Pharmacokinetic Model-Guided Approach

Abstrcat: Background: Colistin sulfate is effective against carbapenem-resistant Gram-negative bacilli but has a narrow therapeutic window, large pharmacokinetic variability, and high resistance risk. Clinical data remain limited, and individualized dosing guidance is urgently needed. This study aims to establish a population pharmacokinetic (PPK) model to optimize and guide precise individualized dosing of colistin sulfate in critically ill patients. Methods: Critically ill patients with confirmed CRO infections receiving intravenous colistin sulfate at the Second Hospital of Hebei Medical University from June 2021 to June 2023 were enrolled. A PPK model was developed using NONMEM. Goodness-of-fit (GOF) diagnostics and visual predictive check (VPC) were used to evaluate the predictive performance of the model, while the bootstrap method (BS) was used to assess its stability. Clinical efficacy, microbiological efficacy, and adverse reactions were assessed. Monte Carlo simulation calculated the probability of target attainment (PTA) across different MICs and renal function strata to optimize the colistin sulfate dosing regimen. Results: Among 51 patients, clinical efficacy was 60.78% (31/51), bacterial clearance 52.94% (27/51), and nephrotoxicity 3.92% (2/51). The PPK model included 123 concentration points (range: 0.12– 4.40 mg/L).A one-compartment linear elimination model best described the PK profile. Typical values of clearance (CL) and volume of distribution (V) were 1.66 L/h and 10.10 L, respectively. Creatinine clearance (CrCL) was identified as a significant covariate affecting CL. Monte Carlo simulation showed that the recommended regimen achieved PTA ≥ 90% only when MIC ≤ 0.5 μg/mL with normal renal function. When MIC ≥ 1 μg/mL, there was a risk of insufficient exposure in patients with normal renal function. When MIC ≥ 2 μg/mL, no dosing regimen achieved PTA ≥ 90%. Conclusion: Renal function significantly impacts colistin sulfate clearance. Dose adjustment based on CrCL is necessary. The standard dosing regimen risks underexposure in patients with normal renal function and MIC ≥ 1 mg/L. Off-label high-dose regimens should be considered in such cases to ensure adequate drug exposure.