Development and Evaluation of CRRT-Specific Precision Dosing Models to Optimize Beta-Lactam Treatment for Patients with Hospital-Acquired Pneumonia

Project Abstract Hospital-acquired pneumonia (HAP) caused by antibiotic-resistant pathogens such as Klebsiella aerogenes, Klebsiella pneumoniae, and Pseudomonas aeruginosa are responsible treatment failure and mortality rates up to 50% and 30%, respectively. Meropenem is a mainstay for the treatment of HAP, but antibiotic resistance continues to erode its clinical efficacy. Importantly, the efficacy of beta-lactams depends on achieving adequate pharmacokinetic-pharmacodynamic (PK/PD) exposures; however, many patients with HAP experience inadequate PK/PD because of changes in PK caused by critically illness. Precision Dosing strategies can overcome PK variability caused by critical illness, but Precision Dosing requires robust models; such models for critically ill patients who develop kidney injury and require continuous renal replacement therapy (CRRT) are currently lacking for HAP patients. Without Precision Dosing models to help guide antibiotic dosing, these vulnerable patients will continue to experience high rates of treatment failure and death. Whereas the status quo treatment of HAP patients requiring CRRT uses population-based dosing schemes, our proposal will innovate Precision Dosing (i.e., individualized) strategies for patients with HAP. We will leverage the infrastructure of the Successful Clinical Response In Pneumonia Therapy (SCRIPT) Systems Biology Center to robustly address the unmet needs of patients on CRRT. Our long-term goal is to develop Precision Dosing strategies that overcome PK variability caused by severe illness. The project objective is to utilize the infrastructure, samples, and data collected in SCRIPT to develop Precision Dosing models for HAP. Our central hypothesis is: (1) CRRT leads to variability in beta-lactam PK with standard "one-size-fits all" HAP dosing regimens which (2) increases the risk of clinical treatment failure in HAP, (3) requiring Precision Dosing schemes. The rationale for our study is that Precision Dosing is needed for CRRT patients with HAP and that these approaches must be translated clinically. In Aim 1, we will develop and qualify Precision Dosing models for meropenem in CRRT. In Aim 2, we will describe meropenem PK/PD target attainment in plasma and in the lung for patients requiring CRRT. In Aim 3, we will create a web-based dosing calculator for translation to practice. Our study will have a positive clinical impact by providing clinicians with the tools necessary to ensure that each patient's dosing is optimized. This research is significant because it addresses a critical unmet need for optimized therapy. Upon completion, our study will have robustly characterized alveolar PK in CRRT patients, filling a gap in the rigor of prior research. We will have translated our Precision Dosing model predictions into actionable dosing regimens, which is innovative as no such calculators exist. Our Precision Dosing calculator will be evaluated in a future R01-funded randomized controlled trial.