Modified Antibiotic Adjuvant Ratios Can Slow and Steer the Evolution of Resistance: Co-amoxiclav as a Case Study

Author:

Allen Richard C.1ORCID,Brown Sam P.23

Affiliation:

1. Institute of Integrative Biology, ETH Zürich, Zürich, Switzerland

2. School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia, USA

3. Center for Microbial Dynamics and Infection, Georgia Institute of Technology, Atlanta, Georgia, USA

Abstract

As antibiotic resistance spreads, a promising approach is to restore the effectiveness of existing drugs via coadministration with adjuvants that inhibit resistance. However, as for monotherapy, antibiotic-adjuvant therapies can select for a variety of resistance mechanisms, so it is imperative that adjuvants be used in a sustainable manner. We test whether the rate of resistance evolution can be decoupled from treatment efficacy using co-amoxiclav, a clinically important combination of the β-lactam amoxicillin and β-lactamase inhibitor clavulanate. Using experimental evolution and a simple theoretical model, we show that the current co-amoxiclav formulation with a high proportion of amoxicillin rapidly selects for resistance via increased β-lactamase production. On the other hand, formulations with more clavulanate and less amoxicillin have similar efficacies yet prevent the selective benefit of increased β-lactamase. We suggest that by blocking common paths to resistance, treatment combinations with the adjuvant in excess can slow the evolution of resistance.

Funder

Human Frontier Science Program

Cystic Fibrosis Foundation

UK Research and Innovation | Natural Environment Research Council

Publisher

American Society for Microbiology

Subject

Virology,Microbiology

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