Leveraging the Dynamic in Vitro Hollow Fiber Infection Model in Determining Optimal Clinical Dose of β-Lactam and β-Lactamase Inhibitor Combinations.

Abstract

Infectious disease is one of the top ten leading causes of death worldwide (WHO, 2017). Emergence of new mechanisms of antibiotic resistance continually rises and spreads globally, becoming one of the major global health threats. Without new antibiotics being successfully developed, we are getting closer to a post-antibiotic era where a simple cut can become life-threatening. Significant amounts of time and money are invested on these new drug candidates, however, very few make it to the market, often due to poor PK/PD properties recognized after the failure of lengthy, expensive clinical testing. The aim of this study is to help assess the use of a dynamic in vitro PK/PD system, to help predict successful clinical dose, PK/PD target and regimen that would help reduce the development of resistance. In vitro and in vivo PK/PD models have previously been utilized to help characterize potential drug candidates and their PK/PD properties that would help streamline drug development in its early stages or preventing them from entering development in the first place (Meihbom 2002). The Hollow Fiber system is a robust in vitro PK/PD model that has a potential in helping predict proper clinical doses. The system can be useful in identifying the drug exposure and dosing frequency that will result in an improved therapeutic outcome.