Steady‐state pharmacokinetic and pharmacodynamic profiling of colistin in critically ill patients with multi‐drug–resistant gram‐negative bacterial infections, along with differences in clinical, microbiological and safety outcome

Abstract

Limited data are present regarding the steady-state pharmacokinetics and pharmacodynamics of colistin in critically ill patients suffering from multi-drug-resistant gram-negative bacterial (MDR-GNB) infections. We aimed to profile the steady-state pharmacokinetics and pharmacodynamics of colistin in critically ill patients with MDR-GNB infections, along with determining the predictors that could influence the clinical, microbiological and safety outcome. We recruited 30 critically ill patients suffering from MDR-GNB infections in our prospective open-label study. Intravenous colistimethate sodium (CMS) 2 million IU was administered concurrently with inhalational CMS 1 million IU every 8 hours. Steady-state plasma colistin levels were measured. Logistic regression analysis was used to identify various predictors of clinical, microbiological and safety outcome. A large variability was observed in the steady-state colistin pharmacokinetic/pharmacodynamic parameters, along with the factors that influenced the clinical, microbiological and safety outcome. In conclusion, steady-state colistin pharmacokinetic and pharmacodynamic parameters observed in our study were largely consistent with those reported in previous studies. High acute physiology and chronic health evaluation II scores were associated with poor clinical outcome. Log-transformed colistin maximum concentration, area under the plasma concentration curve for 8 hours, apparent total body clearance and apparent volume of distribution were significantly associated with the safety outcome.

Population Pharmacokinetics of Colistin Methanesulfonate Sodium and Colistin in Critically Ill Patients: A Systematic Review

“…The V d value of colistin in critically ill patients in the Grégoire et al [11] study was consistent with the distribution in healthy volunteers [11,33], which did not represent the pathophysiological changes that occur in critically ill patients. Karaiskos et al [3] also observed a lower V d value (80.4 L) compared with earlier studies [4,6,10]. This was due to the volume of colistin being dependent on the available fraction of the A plus B form [3].…”

“…Colistin’s pharmacokinetics and clinical application have been studied extensively in the past. Unfortunately, studies have found inter- and intra-individual variability in the pharmacokinetics of colistin, resulting in extremely varied plasma concentrations following the same dosage schedule [ 2 , 3 , 4 , 5 ]. In vivo, CMS has complex pharmacokinetics and variable bioconversion, particularly in patients with varying degrees of renal function [ 2 , 6 ].…”

“…More investigations on the pharmacokinetics of CMS and colistin in critically ill patients, as well as their relationship to clinical efficacy and renal function, have recently been published [ 2 , 4 , 5 ]. Clinical failure has been linked to subtherapeutic colistin concentrations [ 5 ], although high colistin exposure has not been linked to longer survival [ 2 ].…”

“…Clinical failure has been linked to subtherapeutic colistin concentrations [ 5 ], although high colistin exposure has not been linked to longer survival [ 2 ]. Many studies have linked a high colistin concentration to acute renal damage [ 2 , 4 ]. Understanding how variables influenced CMS and colistin pharmacokinetic variability should help to improve therapy and avoid toxicity.…”

“…Understanding how variables influenced CMS and colistin pharmacokinetic variability should help to improve therapy and avoid toxicity. The safety outcome was substantially associated with pharmacokinetic measures, including maximum colistin concentration, the area under the plasma concentration curve for 8 h, apparent total body clearance, and apparent volume of distribution [ 4 ]. Many research used pharmacometrics methods to assess the effects of variable factors on CMS and colistin distribution [ 2 , 3 , 14 ].…”