Colistin is an old antibiotic that has recently gained a considerable renewal of interest for the treatment of pulmonary infections due to multidrug-resistant Gram-negative bacteria. Nebulization seems to be a promising form of administration, but colistin is administered as an inactive prodrug, colistin methanesulfonate (CMS); however, differences between the intrapulmonary concentrations of the active moiety as a function of the route of administration in critically ill patients have not been precisely documented. In this study, CMS and colistin concentrations were measured on two separate occasions within the plasma and epithelial lining fluid (ELF) of critically ill patients (n ؍ 12) who had received 2 million international units (MIU) of CMS by aerosol delivery and then intravenous administration. The pharmacokinetic analysis was conducted using a population approach and completed by pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulations. The ELF colistin concentrations varied considerably (9.53 to 1,137 mg/liter), but they were much higher than those in plasma (0.15 to 0.73 mg/liter) after aerosol delivery but not after intravenous administration of CMS. Following CMS aerosol delivery, typically, 9% of the CMS dose reached the ELF, and only 1.4% was presystemically converted into colistin. PK-PD analysis concluded that there was much higher antimicrobial efficacy after CMS aerosol delivery than after intravenous administration. These new data seem to support the use of aerosol delivery of CMS for the treatment of pulmonary infections in critical care patients.
Colistin pharmacokinetics (PK) was investigated in young healthy volunteers after a 1-h infusion of 80 mg (1 million international units (MIU)) of the prodrug colistin methanesulfonate (CMS). Concentration levels of CMS and colistin were determined in plasma and urine using a new chromatographic assay and analyzed simultaneously with a population approach after correcting the urine-related data for postexcretion hydrolysis of CMS into colistin. CMS and colistin have low volumes of distribution (14.0 and 12.4 liters, respectively), consistent with distribution being restricted to extracellular fluid. CMS is mainly excreted unchanged in urine (70% on average), with a typical renal clearance estimated at 103 ml/min-close to the glomerular filtration rate. Colistin elimination is essentially extrarenal, given that its renal clearance is 1.9 ml/min, consistent with extensive reabsorption. Colistin elimination is not limited by the formation rate because its half-life (3 h) is longer than that of CMS. The values of these pharmacokinetic parameters will serve as reference points for future comparisons with patients' data.
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,...
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