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.

The emergence of KPC-2-producing K. pneumoniae in Greek hospitals creates an important challenge for clinicians and hospital epidemiologists, because it is added to the already high burden of antimicrobial resistance.

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.

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Clarithromycin accelerated the resolution of VAP and weaning from mechanical ventilation in surviving patients and delayed death in those who died of sepsis. The mortality rate at day 28 was not altered. Results are encouraging and render new perspectives on the management of sepsis and VAP.

MBL-producing Enterobacteriaceae can cause severe, often fatal infection in severely ill patients, irrespective of the MIC of carbapenems. Colonization with an MBL-producer is a preceding event, highlighting the importance of surveillance. Both infection control practices and antibiotic policies should be intensified to contain the spread of these problematic bacteria.

In recent years there has been renewed interest in colistin for the treatment of infections by multidrug-resistant Gram-negative bacteria, causing concern that increasing use may be accompanied by the emergence of resistance. This is a retrospective cohort study of colonization and infection by colistin-resistant (CR) gram-negative bacteria in critically ill patients. Colonization data were based on surveillance culture results. Among 150 patients, 78 (52%) were colonized by CR Gram-negative bacteria. Among them, 30 (20%) were colonized by Klebsiella pneumoniae isolates and 51 (34%) were colonized by intrinsically resistant to colistin (CIR) enterobacteriaceae. Seven cases of infection were caused by CR K. pneumoniae and 12 cases by CIR strains. The main risk factor for colonization by CR pathogens was colistin treatment.

dThis report describes the pharmacokinetics of colistin methanesulfonate (CMS) and colistin in five intensive care unit patients receiving continuous venovenous hemodiafiltration. For CMS, the mean maximum concentration of drug in plasma (C max ) after the fourth dose was 6.92 mg/liter and total clearance (CL) 8.23 liters/h. For colistin, the mean concentration was 0.92 mg/ liter and CL/metabolized fraction (f m ) 18.91 liters/h. Colistin concentrations were below the current MIC breakpoints, and the area under the concentration-time curve for the free, unbound fraction of the drug over 24 h in the steady state divided by the MIC (fAUC/MIC) was lower than recommended, suggesting that a dosage regimen of 160 mg CMS every 8 h (q8h) is inadequate.T he use of colistin, an old antibiotic, has recently reemerged due to the increased prevalence of infections caused by multidrugresistant Gram-negative bacteria (MDR-GNB), especially in critically ill patients (1, 2). Such patients often suffer from acute renal impairment necessitating renal replacement therapy (3). However, there are only scarce data on the effect of renal replacement methods on the pharmacokinetics of colistin (4-7). The present study was undertaken to study the elimination of colistin methanesulfonate (CMS) and colistin in patients undergoing continuous venovenous hemodiafiltration (CVVHDF) to contribute to the knowledge regarding the pharmacokinetics of colistin in this population.Patients admitted to the Critical Care Unit of University General Hospital Attikon in Athens, Greece, were eligible for the study if they fulfilled the following inclusion criteria: (i) they were 18 years of age or older; (ii) they were receiving colistin treatment as part of their standard care due to probable or documented infection by MDR-GNB; and (iii) they were receiving CVVHDF treatment as renal replacement therapy. For each patient, the following were recorded: age, body weight, serum creatinine (s-Cr), creatine clearance (CrCL), serum albumin (s-Alb), hemoglobin (Hb), hematocrit (Hct), and Acute Physiology and Chronic Health Evaluation II (APACHE II) score on the first day of colistin administration.The study was approved by the Ethics Committee of the Hospital (registration no. 3/30-3-07). Informed consent was provided by the patients or nearest relatives.CMS (colistin methanesulfonate [Colistin/Norma]; Norma Hellas, Athens, Greece) was administered every 8 h (q8h) by intravenous infusion over 15 min according to local practice at a dose of 2 million units (MU), equivalent to 160 mg CMS, dissolved in 100 ml of normal saline solution.Vascular access was obtained by insertion of a double lumen dialysis catheter. Each patient was dialyzed using the Prisma system (Hospal-Gambro). Continuous venovenous hemodiafiltration (CVVHDF) was performed using an acrylonitrile and sodium methallyl sulfonate copolymer hollow-fiber high-flux hemofilter (AN69 HF) with a membrane surface area of 0.9 m 2 (M100 predilution filter set; Hospal). Hemosol B0 solution (Gambro) was infused as a...