Assessment of MODS and Personalized Exposures of Antibiotics

摘要

ABSTRACT Multiple organ dysfunction syndrome (MODS) affects as many 57% of critically ill children, with mortality rates as high 67% in those infected. The long-term goal of this proposal, Antibiotics in MODS: PersonaLizing Exposures (AMPLE), is to leverage the well-established infrastructure from our PARADIGM study (R01HD095976) to identify optimal antibiotic dosing strategies for this highly understudied, high-risk population. Infection is a common occurrence in children with MODS, either as an inciting insult or as a result of a new, nosocomial infection. However, management of children with MODS and infection is complicated by the development of immune paralysis (IP), which has deleterious effects on immune function. Unfortunately, antibiotic management strategies and how they should be modified as a function of host immune status are key knowledge gaps in pediatric MODS. Timely attainment of target antibiotic concentrations is a crucially important, modifiable intervention to increase survival in these children, yet we currently have limited data on antibiotic pharmacokinetics (PK) in children with MODS with which to develop personalized dosing strategies. We will quantify antibiotic PK in 400 subjects enrolled in the PARADIGM study, an ongoing, NIHfunded, 22- center, prospective study of the epidemiology and risk factors for IP in 1,400 children with MODS. The objectives of this application are to use samples and clinical data from PARADIGM subjects to characterize the variability of concentrations for the antibiotics most commonly used in pediatric MODS; to investigate the relationships between antibiotic target attainment and outcomes in pediatric MODS with and without IP; and to develop model-based dosing approaches that rapidly achieve and maintain target antibiotic concentrations. The central hypothesis of this proposal is that precision, PK-driven antibiotic dosing strategies can be developed that adequately account for organ dysfunction and immune function in children with MODS. We propose to pursue the following AIMs: 1) To create and evaluate sophisticated population PK models for the 6 most commonly used antibiotics in pediatric MODS. 2) To define antibiotic target windows outside of which children with MODS (with and without immunoparalysis) who are being treated for infection are at increased risk for death and prolonged organ failure. 3) To use simulations to identify dosing strategies that achieve and maintain antibiotic concentrations within defined therapeutic windows. The proposed studies will answer the following key questions about the pharmacology of pediatric MODS: 1) What proportion of children are under- or over- exposed using the current standard dosing approaches?, 2) How does MODS impact antibiotic PK and outcomes in children?, 3) How does IP impact necessary target concentrations in pediatric MODS? This research is expected to be significant as it will result in first-of-its kind data that are a crucial and a necessary step toward developing Precision Antibiotic Dosing strategies for children with MODS.