Ryan K. Shields, PharmD, MS, has been awarded funding in the amount of $431,417 for a two-year grant by the National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) entitled, “Use of site-specific pharmacokinetics to optimize antibiotic combinations and prevent the emergence of resistance against CRE.” This proposal was submitted in response to the competitive funding opportunity entitled NIH Exploratory/Developmental Research Grant Program (Parent R21) under funding opportunity number PA-19-053.
Carbapenem-resistant Enterobacteriaceae (CRE) continues to be a global public health threat and priority for antimicrobial development efforts. Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (KPC-Kp) is the predominant pathogen; however, prevalence rates have decreased in endemic regions resulting in a more diverse CRE landscape that includes both KPC and non-KPC-producing pathogens. The emergence of CR Enterobacter cloacae constitutes a second CRE epidemic in the U.S., while rates of CR E. coli continue to rise. Antibiotic combination therapy is a common strategy to treat CRE infections; however, regimens have not been shown to improve patient outcomes or prevent the emergence of resistance.
Ceftazidime-avibactam (CAZ-AVI), meropenem-vaborbactam (MER-VAB), and imipenem-relebactam (IMI-REL) are new antibiotic agents with similar, but distinct characteristics against carbapenem-resistant Enterobacteriaceae (CRE). Resistance due to mutations in β-lactamase or porin genes has already been described against some isolates. The primary objectives of this project are to understand mechanisms by which CRE develop resistance to CAZ-AVI, MER-VAB, and IMI-REL, and to identify strategies that effectively suppress the emergence of resistance.
This results of this study will generate timely, clinically-relevant data that provides new information on optimized treatment regimens in the face of a rapidly changing CRE landscape. Dr. Shields will define novel mechanisms of resistance, and use these data to better define the therapeutic niche of each newly-approved, CRE-active agent.