Development of a Mouse Model for Preclinical Screening of Investigational Drugs Against Pseudomonas Aeruginosa

A. OBJECTIVES: Infections with Pseudomonas aeruginosa are a growing problem in clinics worldwide and the bacteria are quickly developing resistance to current antibiotics. Therefore, the need for novel antibiotics to combat these infections is becoming dire. In support of these efforts, we have recently developed a robust mouse model to test investigational drugs against multidrug-resistant (MDR) P. aeruginosa with support from the NIAID [1]. Our goals here are to improve the ability of this model to predict whether an investigational drug will be efficacious in humans through two main objectives: 1. To validate this model against multiple P. aeruginosa isolates with different drug resistance profiles by establishing the LD50 and natural history for each isolate. 2. To establish dosing parameters for two control antibiotics using PK/PD analysis/models so that these antibiotics can be used as controls/comparators to better gauge the efficacy of novel investigational drugs against P. aeruginosa. Together, these goals will provide an optimized platform to support the evaluation of novel antibacterial drugs against P. aeruginosa pulmonary infection to increase the predictive capacity of preclinical evaluation for translation into the clinic. B. RESEARCH AREA ADDRESSED: The goals outlined in the proposal are directly in line with those of the FDA’s Advancing of Regulatory Science Plan and fall within Research Area 2.4: Facilitate Antibacterial Drug Development and Address Antibacterial Drug Resistance, and specifically within the priority area 2.4.2: Advance the science of in-vitro, animal model, and/or pharmacokinetic studies to facilitate antibacterial drug development, including studies focused on drug development for special populations such as patients with unmet need, children and patients with renal or hepatic dysfunction. C. MILESTONES AND DELIVERABLES: 1. Established median lethal doses and natural history of infection for four clinically relevant P. aeruginosa isolates in the neutropenic mouse model. 2. Established dosing regiments that recapitulate human simulated doses for two antibiotics that will be used as controls during future preclinical screening of novel investigational drugs. 3. 23 Monthly Technical Progress Reports as described in Reporting Requirements. 4. One Final Report as described in the Reporting Requirements. 5. 24 Monthly (or other agreed upon delivery schedule) Invoices as described in the Reporting Requirements.