Population Pharmacokinetics of Colistin Sulfate in Critically Ill Patients: Exposure and Clinical Efficacy

Abstract

Background: Presently, colistin is commercially available in two different forms, namely, colistin sulfate and its sulphomethylated derivative, colistimethate sodium (CMS). However, in the currently reported studies, most of the clinical studies on colistin for parenteral use are referred to as CMS. Data on the pharmacokinetics (PK), clinical efficacy, and side effects of colistin sulfate in clinical use have not been reported.Methods: This retrospective study was performed on carbapenem-resistant organism (CRO)-infected patients treated with colistin sulfate for more than 72 h. The population pharmacokinetic model was developed using the NONMEM program. The clinical outcomes including clinical treatment efficacy, microbiological eradication, and nephrotoxicity were assessed. Monte Carlo simulation was utilized to calculate the probability of target attainment (PTA) in patients with normal or decreased renal function.Results: A total of 42 patients were enrolled, of which 25 (59.52%) patients were considered clinical treatment success and 29 (69.06%) patients had successful bacteria elimination at the end of treatment. Remarkably, no patient developed colistin sulfate-related nephrotoxicity. A total of 112 colistin concentrations with a range of 0.28–6.20 mg/L were included for PK modeling. The PK characteristic of colistin was well illustrated by a one-compartment model with linear elimination, and creatinine clearance (CrCL) was identified as a covariate on the clearance of colistin sulfate that significantly explained inter-individual variability. Monte Carlo simulations showed that the recommended dose regimen of colistin sulfate, according to the label sheet, of a daily dose of 1–1.5 million IU/day, given in 2–3 doses, could attain PTA > 90% for MICs ≤ 0.5 μg/mL, and that a daily dose of 1 million IU/day could pose a risk of subtherapeutic exposure for MIC ≥1 μg/ml in renal healthy patients.Conclusion: Renal function significantly affects the clearance of colistin sulfate. A dose of 750,000 U every 12 h was recommended for pathogens with MIC ≤1 μg/ml. The dosage recommended by the label inserts had a risk of subtherapeutic exposure for pathogens with MIC ≥2 μg/ml. Despite higher exposure to colistin in patients with acute renal insufficiency, dose reduction was not recommended.

Population pharmacokinetics of intravenous colistin sulfate and dosage optimization in critically ill patients

“…In the present study, the estimated typical value of CL was 1.50 L/h for colistin sulfate, which was lower than the CL of colistin converted from CMS (2.92 L/h) ( Couet et al, 2011 ), and similar to the CL of polymyxin B reported previously (range 1.59–2.86 L/h) ( Wang et al, 2021 ; Chen et al, 2022 ). CrCL was identified to have a significant effect on the CL of colistin sulfate, which was in agreement with a previous study ( Yu et al, 2022 ) and the disposition characteristic of polymyxin B ( Wang et al, 2020 ; Li et al, 2021b ; Yu et al, 2021 ). Monte Carlo simulations demonstrated that the colistin sulfate exposure showed significant negative correlation with renal function.…”

“…In the current study, we used f AUC/MIC ≥20 to evaluate the PTA ( Dudhani et al, 2010b ), which is widely used to optimize the regimen for polymyxin B ( Li et al, 2021b ; Yu et al, 2021 ). The regimen of a 1.0–1.5 million IU daily dose recommended by the current label of colistin sulfate reach PTA ≥90% only for MIC values ≤ 0.5 mg/L, which was in line with a previous study ( Yu et al, 2022 ). High-dose regimens should be considered for the patients infected by organisms with an MIC of ≥1 mg/L.…”

“…To date, there have been limited population pharmacokinetic studies of colistin sulfate in patients ( Yu et al, 2022 ). Our results showed that a two-compartment model with first-order elimination best fitted the PK of colistin sulfate in critically ill patients, which was inconsistent with a previous study in which a one-compartment model with linear-elimination was used to describe the pharmacokinetic characteristics of colistin sulfate ( Yu et al, 2022 ). This could be due to the intensive combined scattered sampling strategy used in the current study ( Chen et al, 2022 ).…”

“…Colistin sulfate, the active form of colistin, has been widely used in China since 2019 ( Yu et al, 2022 ; You-ning et al, 2021 ). To date, there are limited data on pharmacokinetic properties of colistin sulfate in humans.…”

“…CMS is the form of inactive prodrug which needs to be converted into the active moiety (colistin) to exert its bactericidal effect ( Al-Khayyat and Aronson, 1973 ; Sivanesan et al, 2016 ). The current understanding of colistin sulfate pharmacokinetics in patients is based on one study ( Yu et al, 2022 ), in which the PK parameters of colistin sulfate were reported to be similar to those of polymyxin B. In that study, plasma samples were used to describe the pharmacokinetic characteristics of colistin sulfate and creatinine clearance (CrCL) was identified as a covariate for the clearance of colistin sulfate.…”