Evaluation of a dosing regimen for continuous vancomycin infusion in critically ill patients: An observational study in intensive care unit patients

Purpose

We aimed to evaluate a dosing algorithm for continuous vancomycin administration in intensive care unit patients.

Materials and Methods

This observational study was conducted in a medical intensive care unit (German university hospital; June 2012-February 2013). Following a loading dose of 20 mg per kg actual body weight, vancomycin was administered continuously (20 or 30 mg of vancomycin per kg actual body weight over 24 hours depending on renal function). The vancomycin infusion rate was adjusted to achieve a target serum vancomycin concentration of 20-30 mg/L.

Results

Vancomycin was administered for a median (interquartile range) of 7 (5-9) days. The median vancomycin dose given as an initial bolus was 1750 (1400-2000) mg. The median daily vancomycin dose ranged from 480 (180–960) mg (day 6) to 3.120 (2596-3980) mg (day 1). Altogether, the achieved median serum vancomycin concentration was 29.0 (25.2-33.2) mg/L. On treatment days 1 to 7, we observed target serum vancomycin levels (20-30 mg/L) in 48%, 39%, 33%, 26%, 43%, 57%, and 69% of patients. Supra-therapeutic serum vancomycin concentrations (> 30 mg/L) were observed in 36%, 52%, 61%, 63%, 39%, 19%, and 15% of patients on treatment days 1 to 7.

Conclusions

The evaluated vancomycin dosing regimen for continuous infusion allowed rapid achievement of sufficient vancomycin serum levels. However, we frequently observed supra-therapeutic serum vancomycin concentrations in the first days of vancomycin treatment.     

Synthesis of C5-dicarboxylic acids from C2-units involving crotonyl-CoA carboxylase/reductase: the ethylmalonyl-CoA pathway

Fifty years ago, Kornberg and Krebs established the glyoxylate cycle as the pathway for the synthesis of cell constituents from C2-units. However, since then, many bacteria have been described that do not contain isocitrate lyase, the key enzyme of this pathway. Here, a pathway termed the ethylmalonyl-CoA pathway operating in such organisms is described. Isotopically labeled acetate and bicarbonate were transformed to ethylmalonyl-CoA by cell extracts of acetate-grown, isocitrate lyase-negative Rhodobacter sphaeroides as determined by NMR spectroscopy. Crotonyl-CoA carboxylase/reductase, catalyzing crotonyl-CoA + CO2 + NADPH --> ethylmalonyl-CoA- + NADP+ was identified as the key enzyme of the ethylmalonyl-CoA pathway. The reductive carboxylation of an enoyl-thioester is a unique biochemical reaction, unprecedented in biology. The enzyme from R. sphaeroides was heterologously produced in Escherichia coli and characterized. Crotonyl-CoA carboxylase/reductase (or its gene) can be used as a marker for the presence of the ethylmalonyl-CoA pathway, which functions not only in acetyl-CoA assimilation. In Streptomyces sp., it may also supply precursors (ethylmalonyl-CoA) for antibiotic biosynthesis. For methylotrophic bacteria such as Methylobacterium extorquens, extension of the serine cycle with reactions of the ethylmalonyl-CoA pathway leads to a simplified scheme for isocitrate lyase-independent C1 assimilation.     

Effect of an invasive strategy on in-hospital outcome in elderly patients with non-ST-elevation myocardial infarction

Aims: We sought to investigate the impact of an invasive treatmentin elderly patients presenting with non-ST elevation myocardialinfarction (NSTEMI) in clinical practice. Methods and results: We analysed data of consecutive elderly patients (75 years)with NSTEMI who were prospectively enrolled in the German AcuteCoronary Syndromes registry between July 2000 and November 2002.Overall 1936 patients were divided into two groups: 1005 (51.9%)underwent coronary angiography and/or revascularization, 931(48.1%) received conservative treatment. In the invasive group,percutaneous coronary intervention was performed in 37.5% within48 h and in 17.6% after 48 h, whereas 9.8% underwent coronaryartery bypass grafting within the hospital stay. In-hospitaldeath (12.5 vs. 6.0%, P < 0.0001) and death/myocardial infarction(17.3 vs. 9.6%, P < 0.0001) occurred significantly less oftenin patients with invasive strategy. After adjustment of theconfounding factors in the propensity score analysis the invasivestrategy remained superior for mortality (OR 0.55, 95% CI 0.35–0.86)and death and non-fatal myocardial infarction (OR 0.51, 95%CI 0.35–0.75) and 1 year mortality (OR 0.56, 95% CI 0.38–0.81).Major bleeding complications tended to be more frequent in theinvasive group (8.8 vs. 5.8%, P = 0.07). Conclusion: In clinical practice, in elderly patients with NSTEMI, an invasivestrategy is associated with an improved in-hospital and 1 yearoutcome but a trend towards more bleeding complications.     

Variability in response to clopidogrel: where is the threshold for 'low response'?: reply

We appreciate to read Dr Komócsís comments toour article entitled ‘Low response to clopidogrel is associatedwith cardiovascular outcome after coronary stent implantation’. He critically remarked the mortality rate in our study. Indeed,we found an all-cause mortality of 5.2% within 3 months (cardiovascularmortality: 3.9%). However, it is worthy to note that we investigatedan unselected patient collective with moderate- to     

Fatty acids differentially influence phosphatidylinositol 3-kinase signal transduction in endothelial cells: impact on adhesion and apoptosis

In contrast to n-6 fatty acids like arachidonic acid (AA), the anti-inflammatory potential of n-3 fatty acids such as docosahexaenoic acid (DHA) has been demonstrated. We examined the phosphatidylinositol (PI)3-kinase dependent effects of AA versus DHA on monocyte rolling, adhesion and transmigration through inflammatory activated human umbilical venous endothelial cells (HUVEC) as well as on apoptosis, to investigate the impact on vascular inflammation. HUVEC were pre-incubated with AA, DHA or sham, and stimulated with VEGF, TNF-alpha or staurosporine. Rolling and adhesion were investigated by means of a parallel flow chamber; transmigration was performed in a static assay. Activation of PI3-kinase was measured as phosphorylation of protein kinase B (Akt). Apoptosis was determined by caspase-3 activity and annexin-V analysis. Pre-incubation of HUVEC with DHA markedly decreased TNF-alpha-induced monocyte rolling, adhesion, and transmigration, although expression of endothelial adhesion molecules was unchanged. In contrast, AA increased TNF-alpha-induced rolling. Both fatty acids did not alter TNF-alpha-mediated upregulation of the adhesion molecules ICAM-1, VCAM-1, and E-selectin. The divergent effects of AA and DHA were abrogated with PI3-kinase inhibitors. After pre-incubation with DHA, VEGF-, TNF-alpha- and staurosporine-induced phosphorylation of Akt was decreased when compared to AA. DHA pre-incubation significantly increased staurosporine-induced apoptosis. In addition, DHA in comparison to AA augmented staurosporine-mediated increase in caspase-3 activity. In conclusion, DHA-induced a reduction in rolling, adhesion and transmigration of monocytes through inflammatory activated HUVEC that is in part PI3-kinase dependent. PI3-kinase driven phosphorylation of Akt and apoptosis of HUVEC as contribution to the resolution of inflammation is differentially modulated by DHA versus AA.     

Chronic kidney disease impairs prognosis in electrical storm

Journal of Interventional Cardiac Electrophysiology - The study sought to assess the prognostic impact of chronic kidney disease (CKD) in patients with electrical storm (ES). ES represents a...     

Alzheimer's disease beta-amyloid peptides are released in association with exosomes

Although the exact etiology of Alzheimer's disease (AD) is a topic of debate, the consensus is that the accumulation of beta-amyloid (Abeta) peptides in the senile plaques is one of the hallmarks of the progression of the disease. The Abeta peptide is formed by the amyloidogenic cleavage of the amyloid precursor protein (APP) by beta- and gamma-secretases. The endocytic system has been implicated in the cleavages leading to the formation of Abeta. However, the identity of the intracellular compartment where the amyloidogenic secretases cleave and the mechanism by which the intracellularly generated Abeta is released into the extracellular milieu are not clear. Here, we show that beta-cleavage occurs in early endosomes followed by routing of Abeta to multivesicular bodies (MVBs) in HeLa and N2a cells. Subsequently, a minute fraction of Abeta peptides can be secreted from the cells in association with exosomes, intraluminal vesicles of MVBs that are released into the extracellular space as a result of fusion of MVBs with the plasma membrane. Exosomal proteins were found to accumulate in the plaques of AD patient brains, suggesting a role in the pathogenesis of AD.     

Body surface potential mapping investigating the ventricular activation patterns in the cardiac resynchronization of patients with left bundle-branch block and heart failure

Body surface potential mapping assessed mean cardiac electrical activation times displayed by isochronal maps in the right ventricle (RV; right ventricle mean activation time [mRV]), anterior septal area (anterior septal area mean activation time [mAS]), and left ventricle (left ventricle mean activation time [mLV]) of 28 patients (mean, 61.07 years; congestive heart failure class III-IV; ejection fraction, < or =40%; left bundle-branch block [LBBB] QRS, 180.17 milliseconds), before and after biventricular pacemaker implantation, comparing them, using reference values from a control group of healthy individuals with normal hearts (GNL), in (1) baseline native LBBB, where mRV and mAS values were similar (40.99 vs 43.62 milliseconds), with mLV delayed (80.99 milliseconds, P < .01) and dyssynchronous with RV/anterior septal area; (2) single-site RV pacing, where mRV was greater than in GNL (86.82 milliseconds, P < .001), with greater mAS/mLV difference (63.41 vs 102.7 milliseconds; P < .001); and (3) biventricular pacing (BIV-PM), where mLV and mRV were similar (71.99 vs 71.58 milliseconds), mRV was greater than in GNL and native LBBB (71.58 vs 35.1 and 40.99 milliseconds; P < .001), and mAS approached values in GNL and native LBBB (51.28 vs 50.14 and 43.62 milliseconds). Body surface potential mapping showed that similar RV/left ventricle activation times during biventricular pacing, nearing mAS, indicate synchronized ventricular activation pattern in patients with congestive heart failure/LBBB.     

Songbirds tune their vocal tract to the fundamental frequency of their song

In human speech, the sound generated by the larynx is modified by articulatory movements of the upper vocal tract, which acts as a variable resonant filter concentrating energy near particular frequencies, or formants, essential in speech recognition. Despite its potential importance in vocal communication, little is known about the presence of tunable vocal tract filters in other vertebrates. The tonal quality of much birdsong, in which upper harmonics have relatively little energy, depends on filtering of the vocal source, but the nature of this filter is controversial. Current hypotheses treat the songbird vocal tract as a rigid tube with a resonance that is modulated by the end-correction of a variable beak opening. Through x-ray cinematography of singing birds, we show that birdsong is accompanied by cyclical movements of the hyoid skeleton and changes in the diameter of the cranial end of the esophagus that maintain an inverse relationship between the volume of the oropharyngeal cavity and esophagus and the song's fundamental frequency. A computational acoustic model indicates that this song-related motor pattern tunes the major resonance of the oropharyngeal-esophageal cavity to actively track the song's fundamental frequency.