Systematic design of pulse dosing to eradicate persister bacteria: The case of fluoroquinolones

Abstract

A small fraction of infectious bacteria use persistence as a strategy to survive exposure to antibiotics. Pulse dosing of antibiotics, if designed well, has long been considered a potentially effective strategy towards eradication of such bacterial pathogens. In a recent study, we developed a method to systematically design optimal pulse dosing regimens for rapid eradication of persisters with $\beta$-lactam antibiotics, and validated the effectiveness of that method experimentally. In this paper, we extend that method for fluoroquinolones. This is because, in contrast to $\beta$-lactams, fluoroquinolones impart different dynamic behavior on treated bacteria, by inducing persister formation and by triggering a non-negligible post-antibiotic effect. Pulse dosing designed according to the proposed method demonstrated rapid bacterial population reduction compared to constant dosing, underscoring the potential of optimal pulse dosing for efficient use of fluoroquinolone antibiotics. In addition, model fitting and parameter estimation also highlighted differences in persister mechanisms between fluoroquinolones and β-lactams. Overall, our study demonstrates that pulse dosing strategies can be effectively designed with the proposed method, using simple formulas and data derived from basic experiments.