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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Background: In 2011/2012, the European Centre for Disease Prevention and Control

Infections due to carbapenem-resistant Klebsiella pneumoniae (CR-KP) have emerged as a public health problem worldwide given their spread dynamics and the limited therapeutic options. Our aim was to study the clinical outcome of patients with CR-KP infections in relation to antimicrobial treatment. CR-KP infections that occurred in a 10-month period (September 2009 to June 2010) in patients admitted to 19 intensive care units all over Greece were studied. A total of 127 CR-KP infections were reported. Central venous catheter bacteraemia was the most frequent infection, followed by ventilator-associated pneumonia (39 (30.7%) and 35 (27.6%) cases, respectively). Resistance to colistin, tigecycline, gentamicin and amikacin was detected in 20%, 33%, 21% and 64% of isolates, respectively. Regarding treatment, 107 cases received active treatment, including 1 or ≥2 active antibiotics in 65 (60.7%) and 42 (39.3%) cases, respectively. The most frequent combination was colistin plus aminoglycoside and tigecycline plus aminoglycoside (17 and 11 cases, respectively). Forty-eight (45.2%) of the cases that received active treatment were considered clinical failures, with 23.5% mortality at 14 days. Logistic regression analysis revealed that age ≤55 years, non-immunocompromised patients and patients who received colistin had higher successful response rates, while patients ≤55 years old had lower mortality rates at 14 days after the introduction of active treatment. CR-KP infections are associated with a significant clinical failure rate. Colistin remains a valuable antimicrobial agent for treating these infections, while the rise of resistance to the last available antibiotics further limits treatment options.

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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.

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