Comparison of Vancomycin Area-Under-the-Curve Dosing Versus Trough Target-Based Dosing in Obese and Nonobese Patients With Methicillin-Resistant Staphylococcus aureus Bacteremia.

Background: A vancomycin target of area under the curve to minimum inhibitory concentration (AUC:MIC) ratio ≥400 is recommended for treatment of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Objective: To evaluate vancomycin total daily dose (TDD) achieving trough targets versus a calculated strategy achieving AUC targets based on body mass index (BMI). Methods: A retrospective cohort study was performed within a large hospital network. Patients with MRSA bacteremia were eligible if they received vancomycin with a steady-state trough (15-20 mg/L). Cockcroft-Gault was used to estimate creatinine clearance, calculating vancomycin clearance and AUC. Patients were stratified by BMI (less than/greater than 30 kg/m2). The primary outcome was vancomycin TDD for the trough-based strategy compared with an AUC-dosing strategy. Results: A total of 119 patients were included, including 51 (42.9%) and 68 (57.1%) patients with high- and low-BMI, respectively. The TDD for trough-based dosing (2390.76 ± 1224.59 mg) differed significantly from AUC-based dosing (1985.07 ± 616.18 mg) across the cohort (P = 0.0014). For patients with high BMI, there was a significant difference (P < 0.0001) in TDD between trough (2637.25 ± 1327.89 mg) versus AUC (1918.71 ± 625.89 mg) strategies. No difference in TDD between dosing strategies was observed among low-BMI patients. Across all patients, 46 (38.7%) experienced acute kidney injury (AKI); high-BMI patients experienced higher rates of AKI compared with low-BMI patients (54.9 vs 26.5%; P = 0.002). Conclusions and Relevance: An AUC-based dosing strategy may reduce vancomycin TDD required for MRSA bacteremia compared with trough-based dosing, particularly for patients with higher BMI.

A simple and accurate rule-based modeling framework for simulation of autocrine/paracrine stimulation of glioblastoma cell motility and proliferation by L1CAM in 2-D culture.

BACKGROUND: Glioblastoma multiforme (GBM) is a devastating brain cancer for which there is no known cure. Its malignancy is due to rapid cell division along with high motility and invasiveness of cells into the brain tissue. Simple 2-dimensional laboratory assays (e.g., a scratch assay) commonly are used to measure the effects of various experimental perturbations, such as treatment with chemical inhibitors. Several mathematical models have been developed to aid the understanding of the motile behavior and proliferation of GBM cells. However, many are mathematically complicated, look at multiple interdependent phenomena, and/or use modeling software not freely available to the research community. These attributes make the adoption of models and simulations of even simple 2-dimensional cell behavior an uncommon practice by cancer cell biologists. RESULTS: Herein, we developed an accurate, yet simple, rule-based modeling framework to describe the in vitro behavior of GBM cells that are stimulated by the L1CAM protein using freely available NetLogo software. In our model L1CAM is released by cells to act through two cell surface receptors and a point of signaling convergence to increase cell motility and proliferation. A simple graphical interface is provided so that changes can be made easily to several parameters controlling cell behavior, and behavior of the cells is viewed both pictorially and with dedicated graphs. We fully describe the hierarchical rule-based modeling framework, show simulation results under several settings, describe the accuracy compared to experimental data, and discuss the potential usefulness for predicting future experimental outcomes and for use as a teaching tool for cell biology students. CONCLUSIONS: It is concluded that this simple modeling framework and its simulations accurately reflect much of the GBM cell motility behavior observed experimentally in vitro in the laboratory. Our framework can be modified easily to suit the needs of investigators interested in other similar intrinsic or extrinsic stimuli that influence cancer or other cell behavior. This modeling framework of a commonly used experimental motility assay (scratch assay) should be useful to both researchers of cell motility and students in a cell biology teaching laboratory.