title: 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.
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. ami.mohamed@farmbio.uu.se
authors.forename: Ami F
authors.initials: AF
authors.lastname: Mohamed
authors.forename: Ilias
authors.initials: I
authors.lastname: Karaiskos
authors.forename: Diamantis
authors.initials: D
authors.lastname: Plachouras
authors.forename: Matti
authors.initials: M
authors.lastname: Karvanen
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Pontikis
authors.forename: Britt
authors.initials: B
authors.lastname: Jansson
authors.forename: Evangelos
authors.initials: E
authors.lastname: Papadomichelakis
authors.forename: Anastasia
authors.initials: A
authors.lastname: Antoniadou
authors.forename: Helen
authors.initials: H
authors.lastname: Giamarellou
authors.forename: Apostolos
authors.initials: A
authors.lastname: Armaganidis
authors.forename: Otto
authors.initials: O
authors.lastname: Cars
authors.forename: Lena E
authors.initials: LE
authors.lastname: Friberg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003091:Colistin / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016638:Critical Illness; D004305:Dose-Response Relationship, Drug; D005260:Female; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D011446:Prospective Studies; D011485:Protein Binding; D011550:Pseudomonas aeruginosa / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D003091:Colistin