Clinical prevalence of collateral sensitivity: a systematic exploration of multicentre antimicrobial surveillance data

Abstract

Background

Collateral effects arise when resistance to one antibiotic alters the susceptibility of a bacterial strain to another antibiotic, resulting in either increased (collateral sensitivity) or decreased (collateral resistance) susceptibility. Collateral sensitivity-based antibiotic treatment offers a promising strategy against antibiotic resistance. To date, the clinical occurrence of collateral sensitivity between bacterial strains and species remains to be further evaluated. Our study aims to evaluate the occurrence patterns of collateral sensitivity in clinical settings.

Methods

For this systematic exploration of multicentre antimicrobial surveillance data, we analysed large-scale antimicrobial resistance surveillance data from three datasets, covering over 5 million minimum inhibitory concentration (MIC) measurements across 86 antibiotics and 30 pathogen species, to identify collateral effect interactions. Pairwise and three-way collateral effects were quantified to assess species-wide trends in both collateral sensitivity and collateral resistance within individual pathogen species. Additionally, we compared the prevalence of collateral sensitivity between and within antibiotic classes. By comparing collateral sensitivity occurrence across species, we identified collateral sensitivity interactions conserved across several pathogens.

Findings

We found a low occurrence of collateral sensitivity in clinical strains, with 364 of 12 024 species-antibiotic pairs (3·0%) affected, compared to 5044 cases (42·0%) of collateral resistance. Most collateral sensitivity interactions involved antibiotics from different classes, except for β-lactams, which showed 41 (34·2%) of 120 occurrences of intraclass collateral sensitivity. We identified six collateral sensitivity pairs that were conserved across four bacterial species, including several highly virulent pathogens belonging to the ESKAPEE group. Three of these conserved collateral sensitivity pairs were associated with a higher MIC towards colistin. Only one three-way collateral sensitivity interaction was shared across four pathogen species. The collateral effect network generated in this study is available via a web application, enabling further data exploration and supporting future research on antibiotic collateral effects.

Interpretation

Several collateral sensitivity interactions were conserved across several clinically relevant pathogens. The identified collateral sensitivity pairs can be considered for the development and application of collateral sensitivity-based antibiotic therapies to prevent and reverse antimicrobial resistance.

Funding

The Longfonds foundation and the Dutch Ministry of Health, Welfare, and Sport.