The polymyxin antibiotics colistin (polymyxin E) and polymyxin B became available in the 1950s and thus did not undergo contemporary drug development procedures. Their clinical use has recently resurged, assuming an important role as salvage therapy for otherwise untreatable gram‐negative infections. Since their reintroduction into the clinic, significant confusion remains due to the existence of several different conventions used to describe doses of the polymyxins, differences in their formulations, outdated product information, and uncertainties about susceptibility testing that has led to lack of clarity on how to optimally utilize and dose colistin and polymyxin B. We report consensus therapeutic guidelines for agent selection and dosing of the polymyxin antibiotics for optimal use in adult patients, as endorsed by the American College of Clinical Pharmacy (ACCP), Infectious Diseases Society of America (IDSA), International Society of Anti‐Infective Pharmacology (ISAP), Society for Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). The European Society for Clinical Microbiology and Infectious Diseases (ESCMID) endorses this document as a consensus statement. The overall conclusions in the document are endorsed by the European Committee on Antimicrobial Susceptibility Testing (EUCAST). We established a diverse international expert panel to make therapeutic recommendations regarding the pharmacokinetic and pharmacodynamic properties of the drugs and pharmacokinetic targets, polymyxin agent selection, dosing, dosage adjustment and monitoring of colistin and polymyxin B, use of polymyxin‐based combination therapy, intrathecal therapy, inhalation therapy, toxicity, and prevention of renal failure. The treatment guidelines provide the first ever consensus recommendations for colistin and polymyxin B therapy that are intended to guide optimal clinical use.

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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.

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