Right Dose, Right Now: Development of AutoKinetics for Real Time Model Informed Precision Antibiotic Dosing Decision Support at the Bedside of Critically Ill Patients

• Main Authors: Luca F. Roggeveen, Tingjie Guo, Ronald H. Driessen, Lucas M. Fleuren, Patrick Thoral, Peter H. J. van der Voort, Armand R. J. Girbes, Rob J. Bosman, Paul Elbers
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2020-05-01
• Series: Frontiers in Pharmacology
• Subjects: clinical decision support; precision medicine; antibiotic dosing; sepsis; TDM (therapeutic drug monitoring)
• Online Access: https://www.frontiersin.org/article/10.3389/fphar.2020.00646/full

IntroductionAntibiotic dosing in critically ill patients is challenging because their pharmacokinetics (PK) are altered and may change rapidly with disease progression. Standard dosing frequently leads to inadequate PK exposure. Therapeutic drug monitoring (TDM) offers a potential solution but requires sampling and PK knowledge, which delays decision support. It is our philosophy that antibiotic dosing support should be directly available at the bedside through deep integration into the electronic health record (EHR) system. Therefore we developed AutoKinetics, a clinical decision support system (CDSS) for real time, model informed precision antibiotic dosing.ObjectiveTo provide a detailed description of the design, development, validation, testing, and implementation of AutoKinetics.MethodsWe created a development framework and used workflow analysis to facilitate integration into popular EHR systems. We used a development cycle to iteratively adjust and expand AutoKinetics functionalities. Furthermore, we performed a literature review to select and integrate pharmacokinetic models for five frequently prescribed antibiotics for sepsis. Finally, we tackled regulatory challenges, in particular those related to the Medical Device Regulation under the European regulatory framework.ResultsWe developed a SQL-based relational database as the backend of AutoKinetics. We developed a data loader to retrieve data in real time. We designed a clinical dosing algorithm to find a dose regimen to maintain antibiotic pharmacokinetic exposure within clinically relevant safety constraints. If needed, a loading dose is calculated to minimize the time until steady state is achieved. Finally, adaptive dosing using Bayesian estimation is applied if plasma levels are available. We implemented support for five extensively used antibiotics following model development, calibration, and validation. We integrated AutoKinetics into two popular EHRs (Metavision, Epic) and developed a user interface that provides textual and visual feedback to the physician.ConclusionWe successfully developed a CDSS for real time model informed precision antibiotic dosing at the bedside of the critically ill. This holds great promise for improving sepsis outcome. Therefore, we recently started the Right Dose Right Now multi-center randomized control trial to validate this concept in 420 patients with severe sepsis and septic shock.