We retrospectively studied the incidence of anaerobic bacteremia during 6 years (1991-1996) at Turku University Central Hospital (Turku, Finland). The clinical significance of a positive anaerobic blood culture, the effect of a positive culture on the choice of antimicrobial therapy, and the outcome for patients were evaluated. Cultures of blood from 81 patients yielded anaerobic bacteria (4% of all bacteremias). Anaerobic bacteremia was clinically significant in 57 patients (0.18 cases per 1,000 admissions). Only half (28) of these patients received appropriate and effective antimicrobial treatment before the results of blood cultures were reported; for 18 patients (32%), initially ineffective treatment was changed on the basis of the bacteriologic results, and for 11 patients (19%), the treatment was not changed. The mortality in these patient groups was 18%, 17%, and 55%, respectively. Empirical therapy may provide coverage for anaerobes in only half of the patients with anaerobic bacteremia, and failure to pay attention to the results of anaerobic blood cultures may have serious consequences for patients.

The activity on alpha-adrenoreceptors of medetomidine ((+/-)-4-(alpha,2,3-trimethylbenzyl)imidazole), an alpha-methyl derivative of detomidine, has been characterized in vivo and in vitro using detomidine, MPV 207, MPV 295, azepexole, clonidine and xylazine for reference purposes. Medetomidine (1-100 micrograms/kg i.v.) was a hypotensive and bradycardic compound in anaesthetized rats. Furthermore, it induced vasopressor (PD50 1.7 microgram/kg) and sympatho-inhibitory (ID50 1.6 microgram/kg) actions in pithed rats, the effects being antagonized by idazoxan (0.3 mg/kg i.v.) but not by prazosin (0.1 mg/kg i.v.). Medetomidine (30-300 micrograms/kg i.m.) had an alpha 2-adrenoreceptor mediated sedative effect on chicks. Medetomidine was, overall, more potent than detomidine, MPV 207, clonidine, xylazine, MPV 295 or azepexole in central (sedation in the chick) and peripheral (cardiac presynaptic in the pithed rat) actions on alpha 2-adrenoreceptors. Clonidine had, however, about an equal potency to medetomidine in the vascular smooth muscle of the pithed rat. Like detomidine and MPV 295, medetomidine had no agonistic activity in the rat aortic ring, but high concentrations antagonized methoxamine-induced contractions, giving a pA2 value of 5.68 for alpha 1-adrenoreceptor antagonism. The overall lipophilicity (log P') of medetomidine in the octanol/buffer (pH 7.4, 24-26 degrees C, HPLC technique) was 2.80. In summary, the experimental data suggest that medetomidine is a lipophilic compound with selective alpha 2-adrenoreceptor-stimulating properties and high potency. It may, therefore, prove to be a suitable pharmacologic tool for interventions in alpha 2-adrenoreceptor mediated effects in the autonomic nervous system.

A prospective, observational, multicentre study of invasive candidosis (IC) in surgical patients in intensive care units (ICUs) was conducted from 2006 to 2008 in 72 ICUs in 14 European countries. A total of 779 patients (62.5% males, median age 63 years) with IC were included. The median rate of candidaemia was 9 per 1000 admissions. In 10.8% the infection was already present at the time of admission to ICU. Candida albicans accounted for 54% of the isolates, followed by Candida parapsilosis 18.5%, Candida glabrata 13.8%, Candida tropicalis 6%, Candida krusei 2.5%, and other species 5.3%. Infections due to C. krusei (57.9%) and C. glabrata (43.6%) had the highest crude mortality rate. The most common preceding surgery was abdominal (51.5%), followed by thoracic (20%) and neurosurgery (8.2%). Candida glabrata was more often isolated after abdominal surgery in patients ≥60 years, and C. parapsilosis was more often isolated in neurosurgery and multiple trauma patients as well as children ≤1 year of age. The most common first-line treatment was fluconazole (60%), followed by caspofungin (18.7%), liposomal amphotericin B (13%), voriconazole (4.8%) and other drugs (3.5%). Mortality in surgical patients with IC in ICU was 38.8%. Multivariate analysis showed that factors independently associated with mortality were: patient age ≥60 years (hazard ratio (HR) 1.9, p 0.001), central venous catheter (HR 1.8, p 0.05), corticosteroids (HR 1.5, p 0.03), not receiving systemic antifungal treatment for IC (HR 2.8, p <0.0001), and not removing intravascular lines (HR 1.6, p 0.02).

ABSTRACT:Medetomidine is a chiral imidazole derivate whose dextroenantiomer is pharmacologically active.

This article is available online at http://dmd.aspetjournals.org ABSTRACT:Selegiline was used as a model compound in a project aimed at comparing, evaluating, and integrating different in vitro approaches for the prediction of cytochrome P450 (P450)-catalyzed hepatic drug metabolism in humans (EUROCYP). Metabolic predictions were generated using homology modeling, cDNA-expressed P450 enzymes, human liver microsomes, primary cultured human hepatocytes, and precision-cut human liver slices. All of the in vitro systems correctly indicated the formation of two dealkylated metabolites, desmethylselegiline and methamphetamine. The metabolic instability of selegiline was demonstrated by all of the in vitro systems studied. Estimates of clearance varied from 16 l/h to 223 l/h. With the exception of one approach, all systems underpredicted the in vivo clearance in humans (236 l/h). Despite this, all approaches successfully classified selegiline as a high clearance compound. Homology modeling suggested the participation of CYP2B6 in the demethylation of selegiline and of CYP2D6 in the depropargylation of the drug. Studies with recombinant expressed enzymes and with human hepatic microsomal fraction supported the involvement of CYP2B6 but not of CYP2D6. These techniques also suggested the involvement of CYP1A2, CYP2C8, and CYP2C19 in the biotransformation of selegiline. In vitro, CYP2B6 was the most active form of P450 involved in selegiline metabolism. Metabolism by several enzymes operating in parallel implies a low interaction potential for the drug. None of the techniques alone was able to predict all aspects of the metabolic and kinetic behavior of selegiline in vivo. However, when used as an integrated package, all significant characteristics were predictable.For more than a decade, in vitro techniques have had a well established role in the early phases of drug development in predicting the pharmacokinetic and metabolic behavior of new chemical entities. When properly used, predictions based on results from in vitro studies will save both development costs and time. In addition, they greatly reduce the number of experimental animals used by the industry in absorption, distribution, metabolism, and excretion studies. Support for the increased utilization of in vitro techniques in drug metabolism studies has come from regulatory authorities (CDER/FDA, 1997). Most of these techniques are easily applicable to high throughput screening, which has further promoted their use recently (Rodrigues, 1997).Several in vitro methods for metabolic predictions are in common use, and even commercially available, but little attention has been paid to the validation of the systems in terms of quality of the predictions obtained and their usefulness in the process of drug development. In particular, comparisons of the data produced by different systems have been scarce. The present study was part of the EUROCYP project within the Biomed2 (Framework IV) program of the European Union. The goals of the project were to evaluate, compare, a...