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NIH grant 1R21AI200425-01: Tailoring Bacteriophage Therapy for Optimized Management of Pulmonary Infections
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Gauri G Rao. Award: $518302.
Start: 2026-09-25T00:00:00.
Pseudomonas aeruginosa is a leading cause of hospital-acquired infections, including
pneumonia and bacteremia, and is increasingly resistant to multiple antibiotics. The limited
effectiveness of current treatments underscores the urgent need for alternative strategies.
Bacteriophages (phages), viruses that infect and kill bacteria, offer a promising therapeutic
option, particularly for multidrug-resistant (MDR) P. aeruginosa.
The Pittsburgh Phage Program, based at the University of Pittsburgh, has provided phage
therapy to 35 patients with MDR P. aeruginosa infections under compassionate use. However,
clinical outcomes have varied, ranging from full recovery to no response. These treatments
were administered without knowledge of phage pharmacokinetics (PK), pharmacodynamics
(PD), or resistance dynamics, limiting their reproducibility and optimization.
This proposal aims to fill existing gaps in knowledge regarding the optimal use of phage therapy
by identifying key factors that influence phage efficacy and resistance, and by developing a
model-based framework to guide phage-antibiotic combination therapy design. Using clinical P.
aeruginosa-phage pairs, we will conduct in vitro and in vivo PK/PD studies to inform rational
phage cocktail design. Aim 1 will characterize phage PK in uninfected mice and use these data
to develop a physiologically based PK (PBPK) model to analyze the impact of phage exposure
on bacterial killing in an in vitro static time-kill system. Aim 2 will evaluate model-informed
phage regimens in murine and rat lung infection models and expand the model using host-
bacteria-phage interaction data. Aim 3 will use whole genome sequencing to characterize
phage resistance and identify therapeutic combinations that sustain bacterial killing or drive the
population to evolutionary states that are more clinically favorable due to trade-offs in fitness or
antibiotic resistance.
The proposed work will establish a foundation for rational phage therapy design and support its
transition from compassionate use to broader clinical application, particularly for drug-
resistant P. aeruginosa infections.document fetched 2026-10-04 02:43