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Imberti R.,Direzione Scientifica | Cusato M.,Laboratory of Clinical Pharmacokinetics | Villani P.,Laboratory of Clinical Pharmacokinetics | Carnevale L.,Fondazione IRCCS | And 4 more authors.
Chest | Year: 2010

Background: Infections caused by multidrug-resistant gram-negative bacteria have caused a resurgence of interest in colistin. To date, information about pharmacokinetics of colistin is very limited in critically ill patients, and no attempts have been made to evaluate its concentration in BAL. Methods: In this prospective, open-label study, 13 adult patients with ventilator-associated pneumonia caused by gram-negative bacteria were treated with colistin methanesulfonate (CMS) IV, 2 million International Units (174 mg) q8h, a usually recommended dose, for at least 2 days. Blood samples were collected from each patient at time intervals after the end of infusion. BAL was performed at 2 h. Colistin was measured by a selective, sensitive high-performance liquid chromatography-based method. Pharmacokinetic parameters were determined by noncompartmental analysis. Results: Patients received 2.19 ± 0.38 mg/kg (range, 1.58-3.16) of CMS per dose. At steady state, mean ± SD plasma colistin maximum (Cmax) and trough (Ctrough) concentrations were 2.21 ± 1.08 and 1.03 ± 0.69 μg/mL, respectively. Mean ± SD area under the plasma concentration-time curve from 0 to 8 h (AUC 0-8), apparent elimination half-life, and apparent volume of distribution were 11.5 ± 6.2 μg×h/mL, 5.9 ± 2.6 h, and 1.5 ± 1.1 L/kg, respectively. Cmax/minimum inhibitory concentration (MIC) ratio and AUC 0-24/MIC ratio (MIC = 2 μg/mL) were 1.1 ± 0.5 and 17.3 ± 9.3, respectively. Colistin was undetectable in BAL. Nephrotoxicity was not observed. Conclusions: Although the pharmacodynamic parameters that better predict the efficacy of colistin are not known in humans, in critically ill adult patients the IV administration of CMS 2 million International Units (174 mg) q8h results in apparently suboptimal plasma concentrations of colistin, which is undetectable in BAL. A better understanding of the pharmacokinetic- pharmacodynamic relationship of colistin is urgently needed to determine the optimal dosing regimen. © 2010 American College of Chest Physicians.

Saleri N.,Ministry of Health | Saleri N.,University of Brescia | Dembele S.M.,Ministry of Health | Villani P.,Laboratory of Clinical Pharmacokinetics | And 8 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2012

Objectives: Low plasma concentrations of rifampicin, an essential antituberculosis drug, have been reported particularly among HIV co-infected persons. In a prospective, longitudinal study we measured rifampicin systemic exposure at different timepoints during highly active antiretroviral therapy (HAART). Patients and methods: From May 2006 to April 2007, 16 tuberculosis (TB)/HIV co-infected patients were enrolled in Ouagadougou, Burkina Faso. All patients received fixed dose combinations of rifampicin, isoniazid, pyrazinamide and ethambutol under direct observation and HAART, consisting of a fixed dose combination of stavudine, lamivudine and nevirapine. Rifampicin concentrations during the dosing interval were determined by HPLC at three different timepoints: (i) after 2 weeks of TB therapy and before starting HIV therapy (T0); (ii) after 4 weeks of combined therapy (T1); and (iii) after 10 weeks of combined therapy (T2). Results: The median values of the area under the curve (AUC 0-24) of rifampicin increased by 39% at T1 (15.69 μg.h/mL; P=0.01) and by 83% at T2 (20.65 μg.h/mL; P=0.001) compared with T0 (11.28 μg.h/mL). Similar variations were observed for the median C max at T0 (2.24 μg/mL) compared with T2 (2.83 μg/mL; P = 0.003). However, none of the subjects had C max levels >8 μg/mL at either T0 or T2. Conclusions: Rifampicin systemic exposure increased during combined TB and HIV therapy, possibly due to increased drug absorption or decreased oral clearance, but remained invariably low in this population. Studies to define the C max rifampicin concentrations, which are associated with a significantly increased risk of treatment failure, are urgently warranted. © The Author 2011. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

Cusato M.,Laboratory of Clinical Pharmacokinetics | Niebel T.,Anesthesia Intensive Care and Pain Therapy Service | Bettinelli S.,Anesthesia Intensive Care and Pain Therapy Service | Regazzi M.,Laboratory of Clinical Pharmacokinetics
European Journal of Pain Supplements | Year: 2011

Local anesthetics (LA) are used for the prevention and relief of both acute and chronic pain. The local anesthetic molecule consists of three components; each of these contributes distinct properties to the molecule. The onset of action is determined by tissue pH, the pKa of the particular agent used, and the amount of nonionized drug available in the tissue. The duration of action depends on the length of time that the drug binds to the membrane. Most local anesthetics were produced as enantiomeric mixtures known as racemates, although it is recognized that each enantiomer possesses quite different pharmacological properties. All amide-type local anesthetics, except for lidocaine, contain a chiral center, meaning that two enantiomers exist. Enantiomers have the same physicochemical properties and differ only in the way that they rotate plane-polarized light. However, their biological behavior, in terms of pharmacokinetic and pharmacodynamic characteristics, can be very different. The clinical response to a particular local anesthetic or its toxicity may vary substantially from patient to patient; dosing often requires careful titration. Interindividual variability is caused by several factors including the pharmacokinetics features of the drug, pharmacodynamic properties or patient's characteristics. © 2011 European Federation of International Association for the Study of Pain Chapters.

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