Population pharmacokinetic analysis of colistin methanesulfonate and colistin after intravenous administration in critically ill patients with infections caused by gram-negative bacteria

Abstract

Colistin is used to treat infections caused by multidrug-resistant gram-negative bacteria (MDR-GNB). It is administered intravenously in the form of colistin methanesulfonate (CMS), which is hydrolyzed in vivo to the active drug. However, pharmacokinetic data are limited. The aim of the present study was to characterize the pharmacokinetics of CMS and colistin in a population of critically ill patients. Patients receiving colistin for the treatment of infections caused by MDR-GNB were enrolled in the study; however, patients receiving a renal replacement therapy were excluded. CMS was administered at a dose of 3 million units (240 mg) every 8 h. Venous blood was collected immediately before and at multiple occasions after the first and the fourth infusions. Plasma CMS and colistin concentrations were determined by a novel liquid chromatography-tandem mass spectrometry method after a rapid precipitation step that avoids the significant degradation of CMS and colistin. Population pharmacokinetic analysis was performed with the NONMEM program. Eighteen patients (6 females; mean age, 63.6 years; mean creatinine clearance, 82.3 ml/min) were included in the study. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.046 h and 2.3 h, respectively. The clearance of CMS was 13.7 liters/h. For colistin, a one-compartment model was sufficient to describe the data, and the estimated half-life was 14.4 h. The predicted maximum concentrations of drug in plasma were 0.60 mg/liter and 2.3 mg/liter for the first dose and at steady state, respectively. Colistin displayed a half-life that was significantly long in relation to the dosing interval. The implications of these findings are that the plasma colistin concentrations are insufficient before steady state and raise the question of whether the administration of a loading dose would benefit critically ill patients.

FIG. 1.

Observed individual concentrations of CMS (A) and colistin (B) in plasma after the administration of the first dose of CMS. Data for patients 14, 15, 17, and 18 (Table 1) were not available after the first dose.

FIG. 2.

Observed individual concentrations of CMS (A) and colistin (B) in plasma after the administration of the fourth dose of CMS. Data for patients 4, 14, 15, 16, 17, and 18 (Table 1) were not available after the fourth dose.

FIG. 3.

Visual predictive check of the model following the first dose (top row) and fourth dose (bottom row) for CMS (left) and colistin (right). The dark gray solid lines are the medians of the simulated data, with their 95% confidence interval (uncertainty) being indicated with areas shaded gray. The black dashed lines are the medians of the observed data (⋄) and should be within the 95% confidence intervals for a perfect model.

FIG. 4.

Model-predicted CMS (A) and colistin (B) concentrations in a typical patient following the use of the current dosing regimen (3 MU as a 15-min infusion of CMS every 8 h [q8h]) and alternative dosing regimens with loading doses of 9 or 12 MU CMS as infusions of 15 min or 2 h and a maintenance dose of 4.5 MU CMS every 12 h (q12h).