New Colistin Population Pharmacokinetic Data in Critically Ill Patients Suggesting an Alternative Loading Dose Rationale

Abstract

Colistin is an old antibiotic that has recently gained a considerable renewal of interest as the last-line defense therapy against multidrug-resistant Gram-negative bacteria. It is administered as colistin methanesulfonate (CMS), an inactive prodrug, and it was shown that due to slow CMS conversion, colistin plasma concentrations increase very slowly after treatment initiation, which constitutes the rationale for a loading dose in critically ill patients. However, faster CMS conversion was observed in healthy volunteers but using a different CMS brand, which may also have a major impact on colistin pharmacokinetics. Seventythree critically ill patients not undergoing dialysis received multiple doses of CMS. The CMS concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and a pharmacokinetic analysis was conducted using a population approach. We confirmed that CMS renal clearance and colistin concentrations at steady state are mostly governed by creatinine clearance, but we predict a typical maximum concentration of drug in serum (C max ) of colistin close to 2 mg/liter, occurring 3 h after an initial dose of 2 million international units (MIU) of CMS. Accordingly, the estimated colistin half-life (t 1/2 ) was relatively short (3.1 h), with rapid attainment of steady state. Our results are only partially consistent with other recently published results. We confirm that the CMS maintenance dose should be adjusted according to renal function in critically ill patients. However, much higher than expected colistin concentrations were observed after the initial CMS dose, with rapid steady-state achievement. These discrepancies challenge the pharmacokinetic rationale for a loading dose, which may still be appropriate for rapid bacterial eradication and an improved clinical cure rate. Colistin is an antibiotic that has reemerged because of the increase of bacterial resistance among life-threatening Gramnegative pathogens (1). It is administered intravenously as a prodrug, colistin methanesulfonate (CMS), which is converted within the body into the active moiety. It was shown that colistin concentrations increase slowly after CMS administration in critically ill patients and that it takes 2 days to reach steady state, suggesting the benefits of treatment initiation with a loading dose (2). This front-loading strategy is now well accepted to increase efficacy and avoid the development of resistances (3-5). However, this slow appearance of colistin was not observed in healthy volunteers (6). The objective of this study was therefore to reassess colistin pharmacokinetics (PK) in critically ill patients using the same methodology, including CMS brand, as that for healthy volunteers. MATERIALS AND METHODSStudy design. The study was approved by the ethics committee of the principal investigator hospital. It was an open-label study conducted in 9 sites in France between May 2009 and December 2011. The eligible patients were hospitalized in the intensive care unit (ICU), were Ͼ18 years of age,...

Population Pharmacokinetics of Colistin Methanesulfonate and Colistin in Critically Ill Patients with Acute Renal Failure Requiring Intermittent Hemodialysis

“…CMS and colistin concentrations were measured as previously described (4,6,7,11) with a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay with a limit of quantification of 0.04 mg/liter for CMS and colistin.…”

“…CMS and colistin plasma concentrations were analyzed simultaneously using a nonlinear mixed-effect model, with Monolix version 4.3.2 (Lixoft). A previously reported PK model (6,12) was fitted to the data. CMS pharmacokinetics was described using a onecompartment model.…”

“…It has recently been shown that in intensive care unit (ICU) patients, colistin plasma concentrations at steady state are mostly governed by renal function and that creatinine clearance can be used for dosing regimen adaptation (5,6). Studies have also been conducted in critical care patients with acute renal failure requiring intermittent hemodialysis (HD) (5,(7)(8)(9).…”

“…However, focus was placed on CMS and colistin clearance during HD rather than between two consecutive HD sessions. CMS is produced by fermentation that results in a mixture of approximately 30 compounds, which may be partially converted into intermediates before administration and which explains that CMS and colistin pharmacokinetics (PK) may vary with the CMS brand (5,6,10). Therefore, the aim of this study was to characterize CMS and colistin PK in ICU patients with end-stage renal failure and to compare these results with those previously obtained from ICU patients with preserved renal function (6) and from healthy volunteers (4) receiving the same CMS brand.…”

Pharmacodynamic and pharmacokinetic considerations in the treatment of critically Ill patients infected with carbapenem-resistant Enterobacteriaceae

“…25,29 CMS itself is eliminated renally, which makes renal function a significant factor that determines the plasma concentrations of colistin. 24,25,27,28,30 Figure 1 diagrams the path from administration to elimination of the available polymyxin compounds. This conversion is highly variable between patients and makes prediction of colistin concentrations difficult.…”