We hypothesized that dosing vancomycin to achieve trough concentrations of >15 mg/liter overdoses many adults compared to area under the concentration-time curve (AUC)-guided dosing. We conducted a 3-year, prospective study of vancomycin dosing, plasma concentrations, and outcomes. In year 1, nonstudy clinicians targeted trough concentrations of 10 to 20 mg/liter (infection dependent) and controlled dosing. In years 2 and 3, the study team controlled vancomycin dosing with BestDose Bayesian software to achieve a daily, steady-state AUC/MIC ratio of ≥400, with a maximum AUC value of 800 mg · h/liter, regardless of trough concentration. For Bayesian estimation of AUCs, we used trough samples in years 1 and 2 and optimally timed samples in year 3. We enrolled 252 adults who were ≥18 years old with ≥1 available vancomycin concentration. Only 19% of all trough concentrations were therapeutic versus 70% of AUCs ( < 0.0001). After enrollment, median trough concentrations by year were 14.4, 9.7, and 10.9 mg/liter ( = 0.005), with 36%, 7%, and 6% over 15 mg/liter ( < 0.0001). Bayesian AUC-guided dosing in years 2 and 3 was associated with fewer additional blood samples per subject (3.6, 2.0, and 2.4; = 0.003), shorter therapy durations (8.2, 5.4, and 4.7 days; = 0.03), and reduced nephrotoxicity (8%, 0%, and 2%; = 0.01). The median inpatient stay was 20 days among nephrotoxic patients versus 6 days ( = 0.002). There was no difference in efficacy by year, with 42% of patients having microbiologically proven infections. Compared to trough concentration targets, AUC-guided, Bayesian estimation-assisted vancomycin dosing was associated with decreased nephrotoxicity, reduced per-patient blood sampling, and shorter length of therapy, without compromising efficacy. These benefits have the potential for substantial cost savings. (This study has been registered at ClinicalTrials.gov under registration no. NCT01932034.).

No abstract

This paper presents several new open-loop guidance methods for spacecraft swarms composed of hundreds to thousands of agents with each spacecraft having modest capabilities. These methods have three main goals: preventing relative drift of the swarm, preventing collisions within the swarm, and minimizing the propellant used throughout the mission. The development of these methods progresses by eliminating drift using the Hill-Clohessy-Wiltshire equations, removing drift due to nonlinearity, and minimizing the J2 drift. In order to verify these guidance methods, a new dynamic model for the relative motion of spacecraft is developed. These dynamics include the two main disturbances for spacecraft in Low Earth Orbit (LEO), J2 and atmospheric drag. Using this dynamic model, numerical simulations are provided at each step to show the effectiveness of each method and to see where improvements can be made. The main result is a set of initial conditions for each spacecraft in the swarm which provides the trajectories for hundreds of collision-free orbits in the presence of J2. Finally, a multi-burn strategy is developed in order to provide hundreds of collision-free orbits under the influence of atmospheric drag. This last method works by enforcing the initial conditions multiple times throughout the mission thereby providing collision-free trajectories for the duration of the mission.