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Updated: Nov 25, 2025
Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection
Published on: October 25, 2013
Daptomycin treatment impacts resistance in off-target populations of vancomycin-resistant Enterococcus faecium
Clare L Kinnear1, Elsa Hansen2, Valerie J Morley2
1Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan, United States of America.
Abstract:
The antimicrobial resistance crisis has persisted despite broad attempts at intervention. It has been proposed that an important driver of resistance is selection imposed on bacterial populations that are not the intended target of antimicrobial therapy. But to date, there has been limited quantitative measure of the mean and variance of resistance following antibiotic exposure. Here we focus on the important nosocomial pathogen Enterococcus faecium in a hospital system where resistance to daptomycin is evolving despite standard interventions. We hypothesized that the intravenous use of daptomycin generates off-target selection for resistance in transmissible gastrointestinal (carriage) populations of E. faecium. We performed a cohort study in which the daptomycin resistance of E. faecium isolated from rectal swabs from daptomycin-exposed patients was compared to a control group of patients exposed to linezolid, a drug with similar indications. In the daptomycin-exposed group, daptomycin resistance of E. faecium from the off-target population was on average 50% higher than resistance in the control group (n = 428 clones from 22 patients). There was also greater phenotypic diversity in daptomycin resistance within daptomycin-exposed patients. In patients where multiple samples over time were available, a wide variability in temporal dynamics were observed, from long-term maintenance of resistance to rapid return to sensitivity after daptomycin treatment stopped. Sequencing of isolates from a subset of patients supports the argument that selection occurs within patients. Our results demonstrate that off-target gastrointestinal populations rapidly respond to intravenous antibiotic exposure. Focusing on the off-target evolutionary dynamics may offer novel avenues to slow the spread of antibiotic resistance.
Insights
Intravenous daptomycin use drives resistance in gastrointestinal Enterococcus faecium populations. This off-target selection increases antimicrobial resistance, highlighting a new strategy to combat the crisis.
Area of Science:
- Microbiology
- Evolutionary Biology
- Infectious Diseases
Background:
- Antimicrobial resistance (AMR) is a global health crisis, with resistance selection in non-target bacterial populations proposed as a key driver.
- Quantitative data on resistance evolution in off-target sites following antibiotic exposure remains limited.
- Enterococcus faecium is a significant nosocomial pathogen, and daptomycin resistance is emerging despite standard interventions.
Purpose of the Study:
- To investigate the hypothesis that intravenous daptomycin administration selects for daptomycin resistance in gastrointestinal carriage populations of E. faecium.
- To quantitatively measure the mean and variance of daptomycin resistance in off-target E. faecium populations.
- To explore the evolutionary dynamics of daptomycin resistance within patients over time.
Main Methods:
- A cohort study comparing daptomycin-exposed patients to a control group exposed to linezolid.
- Isolation and phenotypic testing of E. faecium from rectal swabs to assess daptomycin resistance.
- Whole-genome sequencing of E. faecium isolates from a subset of patients.
Main Results:
- Daptomycin resistance in E. faecium from rectal swabs was 50% higher in daptomycin-exposed patients compared to controls (n=428 clones, 22 patients).
- Greater phenotypic diversity of daptomycin resistance was observed in the daptomycin-exposed group.
- Temporal analysis revealed variable resistance dynamics, including long-term maintenance and rapid reversion to sensitivity after treatment cessation.
Conclusions:
- Intravenous daptomycin treatment exerts significant off-target selection pressure on gastrointestinal E. faecium populations.
- The rapid evolutionary response of these off-target populations underscores their role in AMR.
- Targeting off-target evolutionary dynamics presents a potential novel strategy to mitigate the spread of antibiotic resistance.
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