Modified antibiotic adjuvant ratios can slow and steer the evolution of resistance: co-amoxiclav as a case study

Abstract

As the spread of antibiotic resistance outstrips the introduction of new antibiotics, reusing existing antibiotics is increasingly important. One promising method is to combine antibiotics with synergistically acting adjuvants that inhibit resistance mechanisms, allowing drug killing. Here we use co-amoxiclav (a commonly used and clinically important drug combination of the {beta}-lactam antibiotic amoxicillin and the {beta}-lactamase inhibitor clavulanate) to ask whether treatment efficacy and resistance evolution can be decoupled via component dosing modifications.\n\nA simple mathematical model predicts that different ratios of these two drug components can produce distinct evolutionary responses despite similar initial levels of control. We test this hypothesis by selecting Escherichia coli with a plasmid encoded {beta}-lactamase (ESBL CTX-M-14), against different proportions of amoxicillin and clavulanate. Consistent with our theory, we found that while resistance evolved under all conditions, the component ratio influenced both the rate and mechanism of resistance evolution. Specifically, we found that the current clinical practice of high amoxicillin to clavulanate ratios resulted in the most rapid failure due to the evolution of gene dosing responses. Increased plasmid copy number allowed E. coli to increase {beta}-lactamase dosing and effectively titrate out the low quantities of clavulanate, restoring amoxicillin resistance. In contrast, we found high clavulanate ratios were more robust - plasmid copy number did not increase, although porin or efflux resistance mechanisms were found, as in all drug ratios. Our results indicate that by changing the ratio of adjuvant to antibiotic we can slow and steer the path of resistance evolution. We therefore suggest the use of increased clavulanate dosing regimens to slow the rate of resistance evolution.