Estimating the association of antimicrobial resistance genes with minimum inhibitory concentration in Escherichia coli: an observational study.
BACKGROUND: Surveillance and prediction of antibiotic resistance in Escherichia coli relies on curated databases of genes and mutations. We aimed to quantify the effect of acquiring specific genetic elements on minimum inhibitory concentrations (MICs) for particular antibiotic-species combinations, addressing the current scarcity of such data in existing databases. METHODS: For this observational study, we evaluated a collection of E coli isolates with linked whole-genome sequencing and MIC data, originating from human urinary or bloodstream infections obtained from the Oxford University Hospitals National Health Service Foundation Trust in Oxfordshire, UK. We used multivariable interval regression models to estimate the change in MIC (with 95% CIs) for specific antibiotics associated with the acquisition of antibiotic resistance genes and associated mutations in the National Center for Biotechnology Information AMRFinder database, with and without an adjustment for population structure. We then tested the ability of these models to predict MIC and binary resistance or susceptibility using leave-one-out cross-validation. FINDINGS: We evaluated 2875 E coli isolates obtained during 2013-2018 and 2020. Although most ARGs and resistance mutations (89 [80%] of 111) were associated with an increased MIC, a much smaller number (27 [24%] of 111) was found to be putatively independently resistance-conferring (ie, associated with an MIC above the European Committee on Antimicrobial Susceptibility Testing breakpoint) when acquired in isolation. We found evidence of differential effects of acquired ARGs and resistance mutations between different generations of cephalosporin antibiotics and showed that sub-breakpoint variation in MIC can be linked to genetic mechanisms of resistance. 20 697 (83·3%; range 52·9-97·7 across all antibiotics) of 24 858 MICs were correctly exactly predicted and 23 677 (95·2%; 87·3-97·7) of 24 858 MICs were predicted to within one doubling dilution. INTERPRETATION: Quantitative estimates of the independent effect of the acquisition of ARGs on MIC add to the interpretability and utility of existing databases. Compared with approaches using machine learning models, the use of these estimates yields similar or better performance in the prediction of antibiotic resistance phenotype with more readily interpretable results. The methods outlined here could be readily applied to other antibiotic-pathogen combinations. FUNDING: The National Institute for Health and Care Research (NIHR) and the Medical Research Council (MRC).