Application of a Loading Dose of Colistin Methanesulfonate in Critically Ill Patients: Population Pharmacokinetics, Protein Binding, and Prediction of Bacterial Kill

Abstract

A previous pharmacokinetic study on dosing of colistin methanesulfonate (CMS) at 240 mg (3 million units [MU]) every 8 h indicated that colistin has a long half-life, resulting in insufficient concentrations for the first 12 to 48 h after initiation of treatment. A loading dose would therefore be beneficial. The aim of this study was to evaluate CMS and colistin pharmacokinetics following a 480-mg (6-MU) loading dose in critically ill patients and to explore the bacterial kill following the use of different dosing regimens obtained by predictions from a pharmacokinetic-pharmacodynamic model developed from an in vitro study on Pseudomonas aeruginosa. The unbound fractions of colistin A and colistin B were determined using equilibrium dialysis and considered in the predictions. Ten critically ill patients (6 males; mean age, 54 years; mean creatinine clearance, 82 ml/min) with infections caused by multidrug-resistant Gram-negative bacteria were enrolled in the study. The pharmacokinetic data collected after the first and eighth doses were analyzed simultaneously with the data from the previous study (total, 28 patients) in the NONMEM program. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.026 and 2.2 h, respectively. For colistin, a one-compartment model was sufficient and the estimated half-life was 18.5 h. The unbound fractions of colistin in the patients were 26 to 41% at clinical concentrations. Colistin A, but not colistin B, had a concentration-dependent binding. The predictions suggested that the time to 3-log-unit bacterial kill for a 480-mg loading dose was reduced to half of that for the dose of 240 mg.

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016

“…A loading dose of 1 g of vancomycin will fail to achieve early therapeutic levels for a significant subset of patients. In fact, loading doses of antimicrobials with low volumes of distribution (teicoplanin, vancomycin, colistin) are warranted in critically ill patients to more rapidly achieve therapeutic drug levels due to their expanded extracellular volume related to volume expansion following fluid resuscitation [148][149][150][151][152].…”

Polymyxins: Antibacterial Activity, Susceptibility Testing, and Resistance Mechanisms Encoded by Plasmids or Chromosomes

“…A study analyzing product data characteristics of intravenous CMS revealed a lack of uniformity between manufacturers, with quite broad variations in term of indications, dose regimens (3 to 12 MU/day), and PK (36). Moreover, dosing regimens given by manufacturers are often discordant with the dosing regimens recommended by the recent literature (21,34,41).…”

Multidrug-Resistant Gram-Negative Pneumonia and Infection in Intensive Care Unit

“…In addition, drugs with a low volume of distribution such as vancomycin and colistin, a higher loading dose is suggested [63][64][65]. For the β-lactams, it is the time when the plasma concentration of the drug should be above the pathogen minimum inhibitory concentration (MIC) level.…”