Daptomycin is more efficacious than vancomycin against a methicillin-susceptible Staphylococcus aureus in experimental meningitis

Objectives: To test the efficacy of daptomycin, a cyclic lipopeptide antibiotic, against a methicillin-susceptible Staphylococcus aureus strain in experimental rabbit meningitis and to determine its penetration into non-inflamed and inflamed meninges Results: Over a treatment period of 8 h, daptomycin (15 mg/kg) was significantly superior to the comparator regimen vancomycin (−4.54 ± 1.12 log10/mL for daptomycin versus −3.43 ± 1.17 log10/mL for vancomycin). Daptomycin managed to sterilize 6 out of 10 CSFs compared with 4 out of 10 for vancomycin. The penetration of daptomycin into inflamed meninges was ∼5% and ∼2% into non-inflamed meninges. Conclusions: The superior bactericidal activity of daptomycin was confirmed in vivo and in time-killing assays in vitr

Efficacy of doripenem against Escherichia coli and Klebsiella pneumoniae in experimental meningitis

Objectives In this study the efficacy of doripenem, a new broad-spectrum carbapenem, was tested against an Escherichia coli strain and a Klebsiella pneumoniae strain in an experimental animal model. The comparator was cefepime monotherapy. Methods The rabbit meningitis model was used in this study and the penetration of doripenem through uninflamed and inflamed meninges was determined. Results Doripenem, injected three times (75 mg/kg), led to serum peak levels around 100 mg/L and trough levels around 5 mg/L, resulting in a penetration rate of 14% through inflamed meninges and 7% through uninflamed meninges. Against K. pneumoniae, doripenem was slightly but not significantly more efficacious than cefepime over 8 h (5.40 ± 1.37 log10 cfu/mL versus 3.59 ± 0.89 log10 cfu/mL for cefepime). Also against the E. coli strain doripenem was slightly superior to the comparator (5.55 ± 0.87 log10 cfu/mL versus 3.80 ± 1.10 log10 cfu/mL for cefepime), although the difference was not significant. Conclusions Doripenem is a potential monotherapy for the treatment of meningitis due to Gram-negative microorganism

Effects of EDP-420 on penicillin-resistant and quinolone- and penicillin-resistant pneumococci in the rabbit meningitis model

Objectives To test the efficacy of EDP-420, a new ketolide, in experimental pneumococcal meningitis and to determine its penetration into the CSF. Methods The experimental rabbit model was used in this study and EDP-420 was tested against a penicillin-resistant and a penicillin- and quinolone-resistant mutant. EDP-420 was also tested against both strains in time-killing assays over 8 h in vitro. Results In experimental meningitis, EDP-420 produced a bactericidal activity comparable to the standard regimen based on a combination of vancomycin with ceftriaxone against a penicillin-resistant Streptococcus pneumoniae and a penicillin- and quinolone-resistant S. pneumoniae isolate. The penetration of EDP-420 into inflamed meninges was 38% after an iv injection of 10 mg/kg. The bactericidal activity of EDP-420 was also confirmed in in vitro time-killing assays. Conclusions EDP-420 is an efficacious alternative treatment in pneumococcal meningitis, especially when resistant strains are suspecte

Identifying the concepts contained in outcome measures of clinical trials on four internal disorders using the international classification of functioning, disability and health as a reference

Objectives: To systematically identify and compare the concepts contained in outcome measures of clinical trials on chronic ischemic heart disease, diabetes mellitus, obesity and obstructive pulmonary disease, including asthma using the International Classification of Functioning, Disability and Health (ICF) as a reference. Methods: Randomized controlled trials between 1993 and 2003 were located in MEDLINE and selected according predefined criteria. The outcome measures were extracted and the concepts contained in the outcome measures were linked by so called “linking rules” to the ICF. Results: 166 trials on chronic ischemic heart disease, 227 trials on diabetes mellitus, 428 trials on obesity and 253 trials on obstructive pulmonary disease were included. 10 different health status questionnaires were extracted in chronic ischemic heart disease, 19 in diabetes mellitus, 47 in obesity, 39 in obstructive pulmonary disease. Across conditions at least 75% (range: 75-92%) of the extracted concepts could be linked to the ICF. In diabetes mellitus and obesity the most used ICF- categories were ‘general metabolic functions’ (b540), in obstructive pulmonary disease ‘respiratory functions’ (b440) and in chronic ischemic heart disease ‘heart functions’ (b410). Conclusions: In all four health conditions the majority of studies were drug trials focusing on clinically relevant parameters and not on functioning. The ICF provides a useful reference to identify and quantify the concepts contained in outcome measures used in clinical trials

Brain energy rescue:an emerging therapeutic concept for neurodegenerative disorders of ageing

The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner — a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes