Integration of modeling and simulation into hospital-based decision support systems guiding pediatric pharmacotherapy

<p>Abstract</p> <p>Background</p> <p>Decision analysis in hospital-based settings is becoming more common place. The application of modeling and simulation approaches has likewise become more prevalent in order to support decision analytics. With respect to clinical decision making at the level of the patient, modeling and simulation approaches have been used to study and forecast treatment options, examine and rate caregiver performance and assign resources (staffing, beds, patient throughput). There us a great need to facilitate pharmacotherapeutic decision making in pediatrics given the often limited data available to guide dosing and manage patient response. We have employed nonlinear mixed effect models and Bayesian forecasting algorithms coupled with data summary and visualization tools to create drug-specific decision support systems that utilize individualized patient data from our electronic medical records systems.</p> <p>Methods</p> <p>Pharmacokinetic and pharmacodynamic nonlinear mixed-effect models of specific drugs are generated based on historical data in relevant pediatric populations or from adults when no pediatric data is available. These models are re-executed with individual patient data allowing for patient-specific guidance via a Bayesian forecasting approach. The models are called and executed in an interactive manner through our web-based dashboard environment which interfaces to the hospital's electronic medical records system.</p> <p>Results</p> <p>The methotrexate dashboard utilizes a two-compartment, population-based, PK mixed-effect model to project patient response to specific dosing events. Projected plasma concentrations are viewable against protocol-specific nomograms to provide dosing guidance for potential rescue therapy with leucovorin. These data are also viewable against common biomarkers used to assess patient safety (e.g., vital signs and plasma creatinine levels). As additional data become available via therapeutic drug monitoring, the model is re-executed and projections are revised.</p> <p>Conclusion</p> <p>The management of pediatric pharmacotherapy can be greatly enhanced via the immediate feedback provided by decision analytics which incorporate the current, best-available knowledge pertaining to dose-exposure and exposure-response relationships, especially for narrow therapeutic agents that are difficult to manage.</p

Structure-based prediction of anti-infective drug concentrations in the human lung epithelial lining fluid

Pharmacolog

Phytochemical Investigation and Bioactivity Assessment of Medicinal Plant from Northern Nigeria

Boswellia dalzielii (Burseraceae) has ethnopharmacological importance and is claimed to have anti-infection and immunomodulatory effects. In the Northern part of Nigeria, a region with a tropical dry climate, an aqueous infusion of this plant is used in the treatment of infections and tumours. The traditional formulation method was mimicked under laboratory conditions, and the effect of temperature and the impact of endophytic microbes present in aqueous infusion of B. dalzielii was also investigated. Activity-guided fractionation against Staphylococcus aureus and its methicillin-resistant strain resulted in the identification of two antibacterial compounds namely gallic acid and pyrogallol. The Minimum Inhibitory Concentration for pyrogallol and gallic acid against S. aureus growth are 508 and 753 μM, while against MRSA growth are 254 and 2032 μM, respectively. A growth Inhibition assay showed the activity of gallic acid as bacteriostatic, and pyrogallol as bacteriocidal against tested microorganisms. Interestingly, the bacteriocidal compound was found to arise by conversion of gallic acid by the endophyte Enterobacter cloacae. In addition, Pantoea spp was also isolated from the bark of B. Dalzielii. The sequences of both E. cloacae and Pantoea spp are deposited in the GenBank nucleotide database under the accession number MH764584 and MH764583, respectively. Similarly, activity-guided fractionation of B. Dalzielii bark against breast cancer cell line (MCF7) using MTT cytotoxicity assay resulted in the identification of a cytotoxic compound, catechol, and the half maximal effective concentration (EC50) observed was 86μM. The growth inhibition effect of catechol was observed to be time- and concentration- dependent. Endophytic Klebsiella pneumonia species (strain A and B) were shown to be responsible for bioconversion of protocatechuic acid to catechol. In addition, Pantoea agglomerans was also isolated from the bark of B. dalzielii. The sequences of Klebsiella pneumonia A, Klebsiella pneumonia B and Pantoea agglomerans are deposited in the GenBank nucleotide database under the accession number MH762022, MH762023 and MH762024, respectively. All isolated compounds were identified using HPLC, TLC, NMR, FTIR and HRMS.TETFUN

Antituberculosis Drug Repurposing: A New Hope for Tackling Multi-Challenging TB in Timely Manner

Tuberculosis still stands as the world’s leading infectious disease as 1/4th of the world’s population harbors Latent TB infection (LTBI) > 10 million develops active TB and ~ 1.5 million people die per year. Approximately 4,65,000 people fell ill with multidrug or rifampicin-resistant tuberculosis (MDR/RR-TB)/year. This deadly TB scenario demands new TB drug regimens to tackle global infection reservoir, and worldwide spread of drug resistance and DS TB. Successful entry of single new drug into market is much complicated mission owing to time, cost, efficacy, and safety issues. Therefore, drug repurposing seems one reliable hope to meet the challenges of modern TB drug discovery timely, as it starts with examining market acclaimed drugs against other diseases for their efficacies against tuberculosis avoiding several lengthy and costly steps required for new molecules. Several drugs have been identified, which show potential for TB treatment. There is need for careful consideration of various trial designs to ensure that TB phase III trials are initiated for fruitful development of new TB treatment regimens. TB drug repurposing will not only give fast track novel drugs but will also serve to identify new targets for future development in cost-effective manner

Feature Paper in Antibiotics for 2019

There has been much speculation about a possible antibiotic Armageddon; this would be the result of having untreatable post-operative infections, and similarly untreatable complications after chemotherapy. The now famous “O’Neill Report” (https://amr-review.org/) suggests that more people could die from resistant bacterial infections by 2050 than from cancer. We are still learning about all the subtle drivers of antibiotic resistance, and realizing that we need a single “whole of health” co-ordinated policy. We ingest what we sometimes feed to animals. There do not seem to be any new classes of antibiotics on our horizon. Perhaps something that has been around “forever” will come to our rescue—bacteriophages! Nevertheless, we have to do things differently, use antibiotics appropriately, for the correct indication, for the correct duration and with the correct dose, and with that, practice good antibiotic stewardship. Whilst by no means comprehensive, this book does cover some of the many topics of antibiotic stewardship. It also addresses some of the older antibiotics, some new combinations, and even some new agents. Last, and by no means least, there are two excellent articles on bacteriophages