Optimisation of alternative antibiotic dosing regimens for maximal antibacterial activity and suppression of emergence of resistance

Abstract

Infections caused by extended-spectrum beta-lactamase (ESBL)producing Enterobacterales, e.g., Escherichia coli and Klebsiella pneumoniae can be severe and often deadly in critically-ill patients in intensive care units (ICUs). Achieving target antibiotic concentrations to increase bacterial killing and suppress the emergence of resistance is a highly desirable aim of therapy. However, achieving these endpoints can be challenging in these patients with conventional dosing regimens because of variable pathophysiology affecting antibiotic dosing requirements and because the concentrations that suppress emergence of resistance are not well defined. Beta-lactams are the most commonly used to empirical agents in ICU patients. These antibiotics exhibit timedependent bacterial killing, therefore, prolonged infusion (i.e., extended/continuous infusion) I acknowledge that copyright of all material contained in my thesis resides with the copyright holder(s) of that material. Where appropriate I have obtained copyright permission from the copyright holder to reproduce material in this thesis and have sought permission from coauthors for any jointly authored works included in the thesis. v Publications included in this thesis Sumi CD, Heffernan AJ, Lipman J, Roberts JA, Sime FB. What antibiotic exposures are required to suppress the emergence of resistance for gram-negative bacteria? A systematic review. Clin Pharmacokinet. 2019.