Pharmacokinetics of linezolid in critically ill patients

Introduction: Linezolid is an oxazolidinone antibiotic active against Gram-positive bacteria, and is most commonly used to treat life-threatening infections in critically ill patients. The pharmacokinetics of linezolid are profoundly altered in critically ill patients, partly due to decreased function of vital organs, and partly because life-sustaining drugs and devices may change the extent of its excretion.

Areas covered: This article is summarizes key changes in the pharmacokinetics of linezolid in critically ill patients. The changes summarized are clinically relevant and may serve as rationale for dosing recommendations in this particular population.

Expert opinion: While absorption and penetration of linezolid to tissues are not significantly changed in critically ill patients, protein binding of linezolid is decreased, volume of distribution increased, and metabolism may be inhibited leading to non-linear kinetics of elimination; these changes are responsible for high inter-individual variability of linezolid plasma concentrations, which requires therapeutic plasma monitoring and choice of continuous venous infusion as the administration method. Acute renal or liver failure decrease clearance of linezolid, but renal replacement therapy is capable of restoring clearance back to normal, obviating the need for dosage adjustment. More population pharmacokinetic studies are necessary which will identify and quantify the influence of various factors on clearance and plasma concentrations of linezolid in critically ill patients.     

Efficacy of orally applied probiotic capsules for bacterial vaginosis and other vaginal infections: a double-blind,randomized, placebo-controlled study

Objective

To assess the efficacy of orally administered capsules containing the probiotics Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 (Lactogyn, JGL, Rijeka, Croatia) compared to placebo in otherwise healthy women diagnosed with bacterial vaginosis.

Study design

Randomized, double-blind, multicentric, placebo-controlled trial, including a total of 544 subjects. Included were women older than 18 years of age, diagnosed with vaginal infection. Subjects received either probiotic (395 subjects or 72.6%) or identical-looking placebo capsules (149 subjects or 27.4%,) per day over a period of 6 weeks. Six and 12 weeks after the beginning of the study, subjects underwent two additional gynecological examinations and their vaginal swabs were evaluated by a clinical cytologist.

Results

Mean follow-up period after the baseline visit was 44 days. After this period, restitution to balanced vaginal microbiota was reported in 40 subjects (26.9%) in the placebo group, compared to 243 subjects (61.5%) in the probiotic group. Differences between groups were statistically significant at p < 0.001. After the additional 6 weeks of follow up, normal vaginal microbiota were still present in more than half (51.1%) of subjects in the probiotic group, but only in around one-fifth (20.8%) of subjects who were taking placebo (p < 0.001).

Conclusion

Oral probiotics could be an alternative, side effect-free treatment for one of the most common indications in gynecology, combining the good aspects of both metronidazole and vaginal capsules.     

No effect of fluticasone propionate on linear growth in preschool children with asthma

Background: Eighty percent of asthmatic children develop asthma symptoms by the age of 5 years. Inhaled corticosteroids (ICS), depending on dosage, may cause linear growth reduction and adrenal gland suppression. There are few studies about linear growth of preschool children with asthma. The aim of the present study was to investigate whether there is any effect of fluticasone propionate (FP) on linear growth and adrenal gland function. Methods: Twenty‐eight children aged 18–52 months with persistent asthma receiving ICS FP 100–200 µg daily were studied for 1 year. Patients were divided into two groups according to clinical parameters: well (group 1) and poorly controlled (group 2). Height was measured every 3 months and expressed as height standard deviation score (SDS). Cumulative dose of FP expressed in mg was calculated for every patient. Early morning levels of serum adrenocorticotropic hormone (ACTH) and cortisol were assessed at the beginning and at the end of the study. Results: Patients took FP for an average of 11 months in group 1 and 16 months in group 2, which was not statistically significantly different. At the end of the study height SDS difference was ?0.0143 in group 1 and ?0.2000 in group 2, which was not statistically significantly different (t= 0.6072, P= 0.5489). There was also no statistically significant difference for average cortisol (P= 0.4381) or ACTH (P= 0.5845) concentration at the end of the study. Conclusion: FP 100–200 µg daily had no effect on linear growth or on the hypothalamic–pituitary–adrenal gland axis but further follow up is necessary.     

Discovery of a Lead Compound for Specific Inhibition of Type I Collagen Production in Fibrosis

Fibrosis is a major medical problem caused by excessive synthesis of the extracellular matrix, composed predominantly of type I collagen, in various tissues. There are no approved antifibrotic drugs, and the major obstacle in finding clinically relevant compounds is the lack of specificity of current experimental drugs for type I collagen. Here we describe the discovery of a lead compound that specifically inhibited secretion of type I collagen by fibroblasts in culture at IC₅₀ = 4.5 μM. The inhibition was specific for type I collagen, because secretion of fibronectin was not affected. In vitro, the compound inhibited binding of LARP6, the master regulator of translation of type I collagen mRNAs, to the 5′ stem-loop sequence element which regulates their translation. Because binding of LARP6 to collagen mRNAs is crucial for the development of fibrosis, this inhibitor represents a promising lead for optimization into specific antifibrotic drugs.     

How the Duration Period of Erythropoietin Treatment Influences the Oxidative Status of Hemodialysis Patients

Background: End-stage renal disease is a state of enhanced oxidative stress (OS) and hemodialysis (HD) and renal anemia further augment this disbalance. Anemia correction with erythropoietin (EPO) may improve oxidative status. However, there is no evidence of time dependent effects of EPO therapy on redox status of HD patients.Objective: The aim of this study was to evaluate whether the duration of EPO treatment may affect OS parameters in uremic patients.Patients and methods: 104 HD patients and 29 healthy volunteers were included. Patients were divided into 3 groups according to the duration of EPO treatment. Forth group consisted of HD patients without EPO treatment. Plasma and erythrocyte malondialdehyde (MDA, MDA_rbc), reactive carbonyl groups (RCG), plasma sulfhydryl (-SH) groups and total antioxidative capacity (TAC) levels were evaluated.Results: HD patients both with and without EPO treatment, showed a significant increase in all oxidative parameters without significance between EPO treated and -untreated group. The decrease in MDA and MDA_rbc levels coincided with the duration of EPO treatment. A negative correlation was observed between the duration of EPO treatment and serum MDA (r=˗0.309, p=0.003). Increasing periods of EPO treatment were associated with decrease in RCG, without significance between EPO groups. Increase in TAC accompanied increasing durations of EPO treatment, with EPO treatment for more than 24 months causing the most striking changes (p<0.05). There were no significant differences in ˗SH levels between EPO subgroups.Conclusion: Our results suggest that long term administration of EPO attenuated the lipid peroxidation process and restored the levels of antioxidants.     

Quantification of blood flow and volume in arterioles and venules of the rat cerebral cortex using functional micro-ultrasound

Relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF), and blood flow speed are key parameters that characterize cerebral hemodynamics. We used contrast-enhanced functional micro-ultrasound (fMUS) imaging employing a disruption-replenishment imaging sequence to quantify these hemodynamic parameters in the anesthetized rat brain. The method has a spatial resolution of about 100μm in-plane and around 600μm through-plane, which is comparable to fMRI, and it has a superior temporal resolution of 40ms per frame. We found no significant difference in rCBV of cortical and subcortical gray matter (0.89±0.08 and 0.61±0.09 times the brain-average value, respectively). The rCBV was significantly higher in the vascular regions on the pial surface (3.89±0.71) and in the area of major vessels in the subcortical gray matter (2.02±0.31). Parametric images of rCBV, rCBF, and blood flow speed demonstrate spatial heterogeneity of these parameters on the 100μm scale. Segmentation of the cortex in arteriolar and venular-dominated regions identified through color Doppler imaging showed that rCBV is higher and flow speed is lower in venules than in arterioles. Finally, we show that the dependence of rCBV on rCBF was significantly different in cortical versus subcortical gray matter: the exponent α in the power law relation rCBV=s·rCBF(α) was 0.37±0.13 in cortical and 0.75±0.16 in subcortical gray matter. This work demonstrates that functional micro-ultrasound imaging affords quantification of hemodynamic parameters in the anesthetized rodent brain. This modality is a promising tool for neuroscientists studying these parameters in rodent models of diseases with a cerebrovascular component, such as stroke, neurodegeneration, and venous collagenosis. It is of particular import for studying conditions that selectively affect arteriolar versus venular compartments.