Daptomycin treatment impacts resistance in off-target populations of vancomycin-resistant Enterococcus faecium

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.

Oral cholestyramine prevents enrichment of diverse daptomycin-resistance mutations in intestinal Enterococcus faecium

“…Treatment then imposes selection, which can enrich for these resistant clones. This process of resistance emergence has been observed in hospital patients— E. faecium isolated from patient perirectal swabs are more resistant following daptomycin treatment, and genomic data suggests that this resistance arises de novo within patients [4]. Here, we observe the same process in a mouse model.…”

“…These treatments rely on antibiotic antagonists, which bind to or inactivate antibiotics locally in the intestines. Daptomycin is an especially attractive antibiotic target, because daptomycin resistance emerges easily and often in the gut through point mutations, as shown here in our mouse model and in patient data [4]. Additionally, cholestyramine is an attractive drug to repurpose as an adjuvant, because it is an FDA-approved drug that has been in use with minimal side effects for over 50 years [30,31], and it could inexpensively be repurposed to prevent the spread of resistance.…”

“…After incubation, cell densities were measured by OD600 absorbance in a plate reader. OD values were fitted to a Hill function to determine the computed MIC (MIC c ), the concentration at which the Hill function crossed a cutoff two standard deviations above the mean of the negative control wells, as described previously [4].…”

Genomic Surveillance of Vancomycin-Resistant Enterococcus faecium Reveals Spread of a Linear Plasmid Conferring a Nutrient Utilization Advantage

“…This led to a first observation: a variant of the persistent clone with decreased daptomycin susceptibility spread among 17 patients during the outbreak of 2018. In the first place, this variant was likely selected within host, either during treatment of one of the sampled individuals or in the off-target carriage population of any unsampled individual, as suggested by Kinnear et al ( 51 ). However, while within-host evolution of variants with decreased daptomycin susceptibility is commonly reported, their clonal spread is rarely observed ( 52 – 54 ).…”

Daptomycin-Resistant Enterococcus Bacteremia Is Associated With Prior Daptomycin Use and Increased Mortality After Liver Transplantation

“…Pre–liver transplant colonization with VRE has been associated with higher rates of post–liver transplant VRE infection as well as increased length of stay, morbidity, and mortality when compared with noncolonized recipients [ 6 , 7 , 43 , 44 ]. Recent data have shown that daptomycin resistance can develop in screening fecal cultures and that the development of daptomycin resistance is 50% higher in those exposed to daptomycin [ 45 , 46 ]. However, to date, there are limited data focusing on infection prevention strategies in DRE-colonized and -infected liver transplant patients.…”