Design principles of collateral sensitivity-based dosing strategies

Nature Communications, vol. 12, pp. 5691

Abstract

Collateral sensitivity (CS)-based antibiotic treatments, where increased resistance to one antibiotic leads to increased sensitivity to a second antibiotic, may have the potential to limit the emergence of antimicrobial resistance. However, it remains unclear how to best design CS-based treatment schedules. To address this problem, we use mathematical modelling to study the effects of pathogen- and drug-specific characteristics for different treatment designs on bacterial population dynamics and resistance evolution. We confirm that simultaneous and one-day cycling treatments could supress resistance in the presence of CS. We show that the efficacy of CS-based cycling therapies depends critically on the order of drug administration. Finally, we find that reciprocal CS is not essential to suppress resistance, a result that significantly broadens treatment options given the ubiquity of one-way CS in pathogens. Overall, our analyses identify key design principles of CS-based treatment strategies and provide guidance to develop treatment schedules to suppress resistance.

Authors 5

1. Linda B. S. Aulin corresponding Aachen Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands. l.b.s.aulin@lacdr.leidenuniv.nl

   Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands

2. Apostolos Liakopoulos Aachen Institute of Biology, Leiden University

   Leiden University

   Affiliation as printed

   Institute of Biology, Leiden University, Leiden, The Netherlands

3. Piet H. van der Graaf Aachen Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Certara, Canterbury, UK

   Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands

4. Daniel E. Rozen Aachen Institute of Biology, Leiden University

   Leiden University

   Affiliation as printed

   Institute of Biology, Leiden University, Leiden, The Netherlands

5. J. G. Coen van Hasselt corresponding Aachen Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands. coen.vanhasselt@lacdr.leidenuniv.nl

   Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands