Optimising carbapenem use through a national quality improvement programme

Background: Concern about increasing carbapenem and piperacillin/tazobactam use led the Scottish Antimicrobial Prescribing Group (SAPG) to develop national guidance on optimal use of these agents, and to implement a quality improvement programme to assess the impact of guidance on practice. Objectives: To evaluate how SAPG guidance had been implemented by health boards, assess how this translated into clinical practice, and investigate clinicians’ views and behaviours about prescribing carbapenems and alternative agents. Methods: Local implementation of SAPG guidance was assessed using an online survey. A bespoke Point Prevalence Survey was used to evaluate prescribing. Clinicians’ experience of using carbapenems and alternatives was examined through semi-structured interviews. National prescribing data were analysed to assess the impact of the programme. Results: There were greater local restrictions for carbapenems than for piperacillin/tazobactam. Laboratory result suppression was inconsistent between boards and carbapenem sparing antibiotics were not widely available. Compliance with local guidelines was good for meropenem but lower for piperacillin/tazobactam. Indication for use was well documented but review/stop dates were poorly documented for both antibiotics. Decisions to prescribe a carbapenem were influenced by local guidelines and specialist advice. Many clinicians lacked confidence to de-escalate treatment. Use of both antibiotics decreased during the course of the programme. Conclusions: A multi-faceted quality improvement programme was used to gather intelligence, promote behaviour change and focus interventions on use of carbapenems and piperacillin/tazobactam. Use of these antimicrobials decreased during the programme; a trend not seen in Europe outwith the UK. The programme could be generalised to other antimicrobials

Glutathione and glutamate in schizophrenia: a 7T MRS study

In schizophrenia, abnormal neural metabolite concentrations may arise from cortical damage following neuroinflammatory processes implicated in acute episodes. Inflammation is associated with increased glutamate, whereas the antioxidant glutathione may protect against inflammation-induced oxidative stress. We hypothesized that patients with stable schizophrenia would exhibit a reduction in glutathione, glutamate, and/or glutamine in the cerebral cortex, consistent with a post-inflammatory response, and that this reduction would be most marked in patients with “residual schizophrenia”, in whom an early stage with positive psychotic symptoms has progressed to a late stage characterized by long-term negative symptoms and impairments. We recruited 28 patients with stable schizophrenia and 45 healthy participants matched for age, gender, and parental socio-economic status. We measured glutathione, glutamate and glutamine concentrations in the anterior cingulate cortex (ACC), left insula, and visual cortex using 7T proton magnetic resonance spectroscopy (MRS). Glutathione and glutamate were significantly correlated in all three voxels. Glutamine concentrations across the three voxels were significantly correlated with each other. Principal components analysis (PCA) produced three clear components: an ACC glutathione–glutamate component; an insula-visual glutathione–glutamate component; and a glutamine component. Patients with stable schizophrenia had significantly lower scores on the ACC glutathione–glutamate component, an effect almost entirely leveraged by the sub-group of patients with residual schizophrenia. All three metabolite concentration values in the ACC were significantly reduced in this group. These findings are consistent with the hypothesis that excitotoxicity during the acute phase of illness leads to reduced glutathione and glutamate in the residual phase of the illness

Measuring temporal, spectral and spatial changes in electrophysiological brain network connectivity

The topic of functional connectivity in neuroimaging is expanding rapidly and many studies now focus on coupling between spatially separate brain regions. These studies show that a relatively small number of large scale networks exist within the brain, and that healthy function of these networks is disrupted in many clinical populations. To date, the vast majority of studies probing connectivity employ techniques that compute time averaged correlation over several minutes, and between specific pre-defined brain locations. However, increasing evidence suggests that functional connectivity is non-stationary in time. Further, electrophysiological measurements show that connectivity is dependent on the frequency band of neural oscillations. It is also conceivable that networks exhibit a degree of spatial inhomogeneity, i.e. the large scale networks that we observe may result from the time average of multiple transiently synchronised sub-networks, each with their own spatial signature. This means that the next generation of neuroimaging tools to compute functional connectivity must account for spatial inhomogeneity, spectral non-uniformity and temporal non-stationarity. Here, we present a means to achieve this via application of windowed canonical correlation analysis (CCA) to source space projected MEG data. We describe the generation of time–frequency connectivity plots, showing the temporal and spectral distribution of coupling between brain regions. Moreover, CCA over voxels provides a means to assess spatial non-uniformity within short time–frequency windows. The feasibility of this technique is demonstrated in simulation and in a resting state MEG experiment where we elucidate multiple distinct spatio-temporal-spectral modes of covariation between the left and right sensorimotor areas

Glutathione and glutamate in schizophrenia: a 7T MRS study

In schizophrenia, abnormal neural metabolite concentrations may arise from cortical damage following neuroinflammatory processes implicated in acute episodes. Inflammation is associated with increased glutamate, whereas the antioxidant glutathione may protect against inflammation-induced oxidative stress. We hypothesized that patients with stable schizophrenia would exhibit a reduction in glutathione, glutamate and/or glutamine in the cerebral cortex, consistent with a postinflammatory response, and that this reduction would be most marked in patients with residual schizophrenia an early stage with positive psychotic symptoms has progressed to a late stage characterised by long-term negative symptoms and impairments. We recruited 28 patients with stable schizophrenia and 45 healthy participants matched for age, gender and parental socio-economic status. We measured glutathione, glutamate and glutamine concentrations in the anterior cingulate cortex (ACC), left insula, and visual cortex using 7T proton Magnetic Resonance Spectroscopy (MRS). Glutathione and glutamate were significantly correlated in all three voxels. Glutamine concentrations across the three voxels were significantly correlated with each other. Principal Components Analysis (PCA) produced three clear components: an ACC glutathione-glutamate component; an insula-visual glutathione-glutamate component; and a glutamine component. Patients with stable schizophrenia had significantly lower scores on the ACC glutathione-glutamate component, an effect almost entirely leveraged by the sub-group of patients with residual schizophrenia. All three metabolite concentration values in the ACC were significantly reduced in this group. These findings are consistent with the hypothesis that excito-toxicity during the acute phase of illness leads to reduced glutathione and glutamate in the residual phase of the illness

Effect of Impaired Renal Function on the Pharmacokinetics of Tomopenem (RO4908463/CS-023), a Novel Carbapenem▿

The objective of this study was to assess the impact of impaired renal function on the pharmacokinetics of tomopenem (RO4908463/CS-023), a novel carbapenem antibiotic, and its major metabolite in humans. Thirty-two subjects were enrolled in an open-label, two-center study. Subjects were evenly assigned to one of four groups, based on creatinine clearance ranges of ≥80, 50 to 79, 30 to 49, and <30 ml/min. The drug was given as a single 1,500-mg constant-rate intravenous infusion over 60 min. There were no safety concerns with increasing renal dysfunction. Renal impairment had a significant impact on exposure of both tomopenem and its metabolite. Mean (± standard deviation) areas under the curve for tomopenem increased with decreasing renal function, from 191 ± 35.2 to 1,037 ± 238 μg·h/ml. The maximum concentration of drug in plasma (Cmax) increased with a maximum difference of 44% between the severe and normal groups. In contrast, the corresponding increase in Cmax of the metabolite was much higher, at 174%. Total body clearance was linearly correlated with creatinine clearance (R2 = 0.97; P < 0.0001). Renal clearance for tomopenem decreased with increasing severity of disease, with mean values decreasing from 4.63 ± 0.89 to 0.59 ± 0.19 liters/h. The results of this study indicated a strong correlation between the creatinine clearance and total clearance of tomopenem. While renal impairment appeared to have a significant effect on the pharmacokinetics of tomopenem, an even greater effect was seen on the elimination of the inactive metabolite

Improved detection following neuro-eye therapy in patients with post-geniculate brain damage

Damage to the optic radiation or the occipital cortex results in loss of vision in the contralateral visual Weld, termed partial cortical blindness or hemianopia. Previously, we have demonstrated that stimulation in the Weld defect using visual stimuli with optimal properties for blindsight detection can lead to increases in visual sensitivity within the blind Weld of a group of patients. The present study was aimed to extend the previous work by investigating the eVect of positive feedback on recovery of visual sensitivity. Patients’ abilities for detection of a range of spatial frequencies within their Weld defect were determined using a temporal two-alternative forced-choice technique, before and after a period of visual training (n = 4). Patients underwent Neuro-Eye Therapy which involved detection of temporally modulated spatial grating patches at speciWc retinal locations within their Weld defect. Three patients showed improved detection ability following visual training. Based on our previous studies, we had hypothesised that should the occipital brain lesion extend anteriorly to the thalamus, little recovery would be expected. Here, we describe one such case who showed no improvements after extensive training. The present study provides further evidence that recovery (a) can be gradual and may require a large number of training sessions (b) can be accelerated using positive feedback and (c) may be less likely to take place if the occipital damage extends anteriorly to the thalamus

Structural and neurochemical correlates of individual differences in gamma frequency oscillations in human visual cortex

Neuronal oscillations in the gamma frequency range play an important role in stimulus processing in the brain. The frequency of these oscillations can vary widely between participants and is strongly genetically determined, but the cause of this variability is not understood. Previous studies have reported correlations between individual differences in gamma frequency and the concentration of the inhibitory neurotransmitter, gamma‐aminobutyric acid (GABA), as well as with age and primary visual cortex (V1) area and thickness. This study assessed the relationships between all of these variables in the same group of participants. There were no significant correlations between gamma frequency and GABA+ concentration, V1 area or V1 thickness, although the relationship with GABA+/Cr approached significance. Considering age as a covariate further reduced the strength of all correlations and, in an additional dataset with a larger age range, gamma frequency was strongly inversely correlated with age but not V1 thickness or area, suggesting that age modulates gamma frequency via an additional, as yet unknown, mechanism. Consistent with other recent studies, these findings do not demonstrate a clear relationship between gamma frequency and GABA+ concentration. Further investigation of additional variables and the interactions between them will be necessary in order to more accurately determine predictors of the frequency of gamma oscillations

Abnormal salience signaling in schizophrenia: the role of integrative beta oscillations

Aberrant salience attribution and cerebral dysconnectivity both have strong evidential support as core dysfunctions in schizophrenia. Aberrant salience arising from an excess of dopamine activity has been implicated in delusions and hallucinations, exaggerating the significance of everyday occurrences and thus leading to perceptual distortions and delusional causal inferences. Meanwhile, abnormalities in key nodes of a salience brain network have been implicated in other characteristic symptoms, including the disorganization and impoverishment of mental activity. A substantial body of literature reports disruption to brain network connectivity in schizophrenia. Electrical oscillations likely play a key role in the coordination of brain activity at spatially remote sites, and recent, evidence implicates beta band oscillations in long-range integrative processes. We used magnetoencephalography (MEG) and a task designed to disambiguate responses to relevant from irrelevant stimuli to investigated beta oscillations in nodes of a network implicated in salience detection and previously shown to be structurally and functionally abnormal in schizophrenia. Healthy participants, as expected, produced an enhanced beta synchronisation to behaviourally relevant, as compared to irrelevant, stimuli, while patients with schizophrenia showed the reverse pattern: a greater beta synchronisation in response to irrelevant than to relevant stimuli. These findings not only support both the aberrant salience and disconnectivity hypotheses, but indicate a common mechanism that allows us to integrate them into a single framework for understanding schizophrenia in terms of disrupted recruitment of contextually appropriate brain networks