Nikolaou, MichaelTam, Vincent H.Altman, Rachel2021-02-112021-02-112019https://hdl.handle.net/10657/7518Background: Evolving bacterial resistance presents a rising challenge to public health. One mechanism of resistance, the production of drug degrading enzymes, is traditionally treated with a combination of active first line antibiotic and enhancing inhibitor. The conventional testing method currently used to guide treatment with these combinations has deficiencies. Objective: To develop a robust computational tool that will help identify the most effective treatment options. Methods: A clinical strain of Klebsiella pneumoniae expressing CTX-M15 was studied. Piperacillin (an antibiotic) susceptibility testing was performed at varying concentrations of avibactam (an enzyme inhibitor). The susceptibility results were modeled against the changing inhibitor concentrations to produce a dynamic model of susceptibility. Accounting for fluctuating antibiotic concentrations in the body, an integrated metric (% T > MICi) was used to assess the potential effectiveness of various drug combination dosing regimens. Results: Piperacillin susceptibility was well characterized as a function of avibactam (r2 = 98). A range of % T > MICi (from 67.5% to 83.1%) was simulated by the computational model using escalating doses of piperacillin every 8 hours. These simulations will be experimentally validated in a preclinical infection model in the future. Conclusions: Integrating changing drug concentration levels in the body with a dynamic measure of susceptibility will likely provide a more comprehensive picture of how a bacterial infection might respond to a given drug combination. If validated, this computational model in combination with a revised testing method would help doctors to choose the best available treatment for the patient.en-USThe author of this work is the copyright owner. UH Libraries and the Texas Digital Library have their permission to store and provide access to this work. Further transmission, reproduction, or presentation of this work is prohibited except with permission of the author(s).Poster