Multiplicity of cerebrospinal fluid functions: New challenges in health and disease

This review integrates eight aspects of cerebrospinal fluid (CSF) circulatory dynamics: formation rate, pressure, flow, volume, turnover rate, composition, recycling and reabsorption. Novel ways to modulate CSF formation emanate from recent analyses of choroid plexus transcription factors (E2F5), ion transporters (NaHCO3 cotransport), transport enzymes (isoforms of carbonic anhydrase), aquaporin 1 regulation, and plasticity of receptors for fluid-regulating neuropeptides. A greater appreciation of CSF pressure (CSFP) is being generated by fresh insights on peptidergic regulatory servomechanisms, the role of dysfunctional ependyma and circumventricular organs in causing congenital hydrocephalus, and the clinical use of algorithms to delineate CSFP waveforms for diagnostic and prognostic utility. Increasing attention focuses on CSF flow: how it impacts cerebral metabolism and hemodynamics, neural stem cell progression in the subventricular zone, and catabolite/peptide clearance from the CNS. The pathophysiological significance of changes in CSF volume is assessed from the respective viewpoints of hemodynamics (choroid plexus blood flow and pulsatility), hydrodynamics (choroidal hypo- and hypersecretion) and neuroendocrine factors (i.e., coordinated regulation by atrial natriuretic peptide, arginine vasopressin and basic fibroblast growth factor). In aging, normal pressure hydrocephalus and Alzheimer's disease, the expanding CSF space reduces the CSF turnover rate, thus compromising the CSF sink action to clear harmful metabolites (e.g., amyloid) from the CNS. Dwindling CSF dynamics greatly harms the interstitial environment of neurons. Accordingly the altered CSF composition in neurodegenerative diseases and senescence, because of adverse effects on neural processes and cognition, needs more effective clinical management. CSF recycling between subarachnoid space, brain and ventricles promotes interstitial fluid (ISF) convection with both trophic and excretory benefits. Finally, CSF reabsorption via multiple pathways (olfactory and spinal arachnoidal bulk flow) is likely complemented by fluid clearance across capillary walls (aquaporin 4) and arachnoid villi when CSFP and fluid retention are markedly elevated. A model is presented that links CSF and ISF homeostasis to coordinated fluxes of water and solutes at both the blood-CSF and blood-brain transport interfaces

In Vitro Activity of Doripenem against Pseudomonas aeruginosa and Burkholderia cepacia Isolates from both Cystic Fibrosis and Non-Cystic Fibrosis Patients

The in vitro activities of doripenem, imipenem, levofloxacin, piperacillin, ceftazidime, aztreonam, tobramycin, and cefepime were determined for 160 isolates of Pseudomonas aeruginosa (82 from cystic fibrosis [CF] patients) and 34 isolates of Burkholderia cepacia. Doripenem MIC(90)s were lower than those of all other comparative agents against all isolates combined and against all P. aeruginosa isolates. Doripenem was as active as levofloxacin and 2- to 32-fold more active than the other comparative agents against B. cepacia

Caspofungin Disk Diffusion Breakpoints and Quality Control▿

Interpretive disk diffusion breakpoints for caspofungin are proposed by evaluating 762 isolates of Candida spp., representing 10 different species obtained as part of the caspofungin clinical trials. Standardized broth microdilution reference tests were compared to the zone diameters observed with 5-μg caspofungin disks produced by two different disk manufacturers. Disk diffusion breakpoints of ≥11 mm for susceptible are proposed. Compared to results from MIC testing, these zone diameters produced error rates that were ≤0.3% for all categories. In addition, an eight-laboratory disk diffusion quality control (QC) study was performed, and QC ranges are proposed for the four QC strains recommended by the CLSI

In Vitro Antimicrobial Activity of a New Cephalosporin, Ceftaroline, and Determination of Quality Control Ranges for MIC Testing▿

The spectrum of activity of ceftaroline was evaluated against 1,247 bacterial isolates representing 44 different species or phenotypic groups. For the majority of species, the activity of ceftaroline was comparable or superior to that of ceftriaxone. MIC and/or disk diffusion quality control ranges of ceftaroline were determined for five standard ATCC reference strains

Broth Microdilution Susceptibility Testing of Brucella Species: Quality Control Limits for Ten Antimicrobial Agents against Three Standard Quality Control Strains

Brucella broth without supplementation is the recommended medium for broth microdilution susceptibility tests of Brucella abortus, B. melitensis, and B. suis. Based on an eight-laboratory collaborative study using a pH-adjusted modification of this medium, we propose MIC quality control ranges for three control strains against 10 antimicrobials that are potentially efficacious for treating infections caused by these agents of bioterrorism

Comparative In Vitro Antimicrobial Activity of Tigecycline, a New Glycylcycline Compound, in Freshly Prepared Medium and Quality Control▿

The in vitro spectra of activity of tigecycline and tetracycline were determined for 2,490 bacterial isolates representing 50 different species or phenotypic groups. All isolates were tested simultaneously by broth microdilution using freshly prepared Mueller-Hinton broth and by disk diffusion. Portions of these data were submitted to the Food and Drug Administration (FDA) in support of the sponsor's application for new drug approval. In a separate study, MIC and disk diffusion quality control ranges were determined. The tigecycline MICs at which 50%/90% of bacteria were inhibited were (in μg/ml) as follows: for Streptococcus spp., 0.06/0.12; for Moraxella catarrhalis, 0.06/0.12; for Staphylococcus spp., 0.12/0.25; for Enterococcus spp., 0.12/0.25; for Listeria monocytogenes, 0.12/0.12; for Neisseria meningitidis, 0.12/0.25; for Haemophilus spp., 0.25/0.5; for Enterobacteriaceae, 0.05/2.0; for non-Enterobacteriaceae, 0.5/8.0. Tigecycline was consistently more potent than tetracycline against all species studied. The data from this study confirm the FDA-approved MIC and disk diffusion breakpoints for tigecycline for Streptococcus spp. other than Streptococcus pneumoniae, enterococci, and Enterobacteriaceae. Provisional breakpoints for Haemophilus spp. and S. pneumoniae are proposed based on the data from this study. The following MIC and/or disk diffusion quality control ranges are proposed: Staphylococcus aureus ATCC 29213, 0.03 to 0.25 μg/ml; S. aureus ATCC 25923, 20 to 25 mm; Escherichia coli ATCC 25922, 0.03 to 0.25 μg/ml and 20 to 27 mm; Pseudomonas aeruginosa ATCC 27853, 9 to 13 mm, Enterococcus faecalis ATCC 29212, 0.03 to 0.12 μg/ml; S. pneumoniae ATCC 49619, 0.015 to 0.12 μg/ml and 23 to 29 mm; Haemophilus influenzae ATCC 49247, 0.06 to 0.5 μg/ml and 23 to 31 mm; and Neisseria gonorrhoeae ATCC 49226, 30 to 40 mm

Comparative In Vitro Antimicrobial Activities of Torezolid (TR-700), the Active Moiety of a New Oxazolidinone, Torezolid Phosphate (TR-701), Determination of Tentative Disk Diffusion Interpretive Criteria, and Quality Control Ranges▿

This study assessed the spectrum of activity of torezolid (TR-700), the active moiety of torezolid phosphate (TR-701), and proposes tentative MIC and disk diffusion breakpoints as well as quality control ranges. The in vitro susceptibilities of 1,096 bacterial isolates, representing 23 different species or phenotypic groups, were determined for torezolid, linezolid, cefotaxime, and levofloxacin using Clinical and Laboratory Standards Institute (CLSI) broth microdilution MICs, minimum bactericidal concentrations (MBCs), agar dilution, and disk diffusion testing methods. Torezolid was very active against the majority of Gram-positive strains, including methicillin-susceptible and -resistant Staphylococcus aureus (MIC50 = 0.25 μg/ml, MIC90 ≤ 0.5 μg/ml), coagulase-negative staphylococci (CNS; MIC50 = 0.25 μg/ml, MIC90 ≤ 0.5 μg/ml), enterococci (MIC50 and MIC90 ≤ 0.5 μg/ml), and streptococci (MIC50 and MIC90 ≤ 0.25 μg/ml). Based upon MIC90s, torezolid was 4-fold more active than linezolid against S. aureus, coagulase-negative staphylococci, and the enterococci and 8-fold more active than linezolid against the streptococci. With the use of tentative MIC breakpoints of ≤2 μg/ml for susceptibility, torezolid disk diffusion zone diameter breakpoints are proposed using a 20-μg disk. In addition, MIC quality control ranges of torezolid were determined for three CLSI-recognized standard ATCC reference strains