Novel modeling framework to guide design of optimal dosing strategies for β-lactamase inhibitors

The scarcity of new antibiotics against drug-resistant bacteria has led to the development of inhibitors targeting specific resistance mechanisms, which aim to restore the effectiveness of existing agents. However, there are few guidelines for the optimal dosing of inhibitors. Extending the utility of mathematical modeling, which has been used as a decision support tool for antibiotic dosing regimen design, we developed a novel mathematical modeling framework to guide optimal dosing strategies for a beta-lactamase inhibitor. To illustrate our approach, MK-7655 was used in combination with imipenem against a clinical isolate of Klebsiella pneumoniae known to produce KPC-2. A theoretical concept capturing fluctuating susceptibility over time was used to define a novel pharmacodynamic index (time above instantaneous MIC [T>MIC(i)]). The MK-7655 concentration-dependent MIC reduction was characterized by using a modified sigmoid maximum effect (E(max))-type model. Various dosing regimens of MK-7655 were simulated to achieve escalating T>MIC(i) values in the presence of a clinical dose of imipenem (500 mg every 6 h). The effectiveness of these dosing exposures was subsequently validated by using a hollow-fiber infection model (HFIM). An apparent trend in the bacterial response was observed in the HFIM with increasing T>MIC(i) values. In addition, different dosing regimens of MK-7655 achieving a similar T>MIC(i) (69%) resulted in comparable bacterial killing over 48 h. The proposed framework was reasonable in predicting the in vitro activity of a novel beta-lactamase inhibitor, and its utility warrants further investigations.     

Diurnal sedative changes during intensive care: Impact on liberation from mechanical ventilation and delirium*

OBJECTIVE:: To determine whether benzodiazepine and propofol doses are increased at night and whether daytime and nighttime sedative doses are associated with delirium, coma, and delayed liberation from mechanical ventilation. DESIGN:: Single-center, prospective cohort study nested within the Awakening and Breathing Controlled randomized trial. SETTING:: Saint Thomas Hospital in Nashville, TN, from 2004 to 2006. PATIENTS:: Adult patients receiving mechanical ventilation for >12 hrs with continuous recording of hourly sedation dosing. INTERVENTIONS:: We measured hourly doses of benzodiazepine and propofol exposure during the daytime (7 AM to 11 PM) and nighttime (11 PM to 7 AM) for 5 days. We quantified nighttime dose increases by subtracting the average hourly daytime dose on the preceding day from subsequent average hourly nighttime dose. We used multivariable logistic regression to determine whether daytime and nighttime dose increases were independently associated with delirium, coma, and delayed liberation from mechanical ventilation. MEASUREMENTS AND MAIN RESULTS:: Among 140 patients, the median Acute Physiology and Chronic Health Evaluation II score was 27 (interquartile range 22-33). Among those receiving the sedatives, benzodiazepine and propofol doses were increased at night on 40% and 41% of patient-days, respectively. Of 485 patient-days, delirium was present on 160 (33%) and coma on 206 (42%). In adjusted models, greater daytime benzodiazepine dose was independently associated with failed spontaneous breathing trial and extubation, and subsequent delirium (p < .02 for all). Nighttime increase in benzodiazepine dose was associated with failed spontaneous breathing trial (p < .01) and delirium (p = .05). Daytime propofol dose was marginally associated with subsequent delirium (p = .06). CONCLUSIONS:: Nearly half of mechanically ventilated intensive care unit patients received greater doses of sedation at night, a practice associated with failed spontaneous breathing trials, coma, and delirium. Over the first 5 days in our study, patients spent 75% of their time in coma or delirium, outcomes that may be reduced by efforts to decrease sedative exposure during both daytime and nighttime hours in the intensive care unit.     

Programmable valve shunts: are they really better?

Programmable valve shunts allows selection of opening pressure of shunt valve. In the presented article, a unique complication pertaining to programmable shunts has been discussed. A 5-year-old boy who had tectal plate low grade glioma with obstructive hydrocephalus was managed with Codman programmable ventriculoperitoneal shunt. There was a spontaneous change in the opening pressure of the shunt valve leading to shunt malfunction. Routinely used household appliances produce a magnetic field strong enough to cause change in the setting of shunt valve pressure and may lead to valve malfunction. Other causes of programmable valve malfunction also discussed.     

Independent component analysis of DTI reveals multivariate microstructural correlations of white matter in the human brain

It has recently been demonstrated that specific patterns of correlation exist in diffusion tensor imaging (DTI) parameters across white matter tracts in the normal human brain. These microstructural correlations are thought to reflect phylogenetic and functional similarities between different axonal fiber pathways. However, this earlier work was limited in three major respects: (1) the analysis was restricted to only a dozen selected tracts; (2) the DTI measurements were averaged across whole tracts, whereas metrics such as fractional anisotropy (FA) are known to vary considerably within single tracts; and (3) a univariate measure of correlation was used. In this investigation, we perform an automated multivariate whole-brain voxel-based study of white matter FA correlations using independent component analysis (ICA) of tract-based spatial statistics computed from 3T DTI in 53 healthy adult volunteers. The resulting spatial maps of the independent components show voxels for which the FA values within each map co-vary across individuals. The strongest FA correlations were found in anatomically recognizable tracts and tract segments, either singly or in homologous pairs. Hence, ICA of DTI provides an automated unsupervised decomposition of the normal human brain into multiple separable microstructurally correlated white matter regions, many of which correspond to anatomically familiar classes of white matter pathways. Further research is needed to determine whether whole-brain ICA of DTI represents a novel alternative to tractography for feature extraction in studying the normal microstructure of human white matter as well as the abnormal white matter microstructure found in neurological and psychiatric disorders.