Evolution of vancomycin-resistant Enterococcus faecium during colonization and infection in immunocompromised pediatric patients

Abstract

<jats:p>Patients with hematological malignancies or undergoing hematopoietic stem cell transplantation are vulnerable to colonization and infection with multidrug-resistant organisms, including vancomycin-resistant<jats:italic>Enterococcus faecium</jats:italic>(VREfm). Over a 10-y period, we collected and sequenced the genomes of 110 VREfm isolates from gastrointestinal and blood cultures of 24 pediatric patients undergoing chemotherapy or hematopoietic stem cell transplantation for hematological malignancy at St. Jude Children’s Research Hospital. We used patient-specific reference genomes to identify variants that arose over time in subsequent gastrointestinal and blood isolates from each patient and analyzed these variants for insight into how VREfm adapted during colonization and bloodstream infection within each patient. Variants were enriched in genes involved in carbohydrate metabolism, and phenotypic analysis identified associated differences in carbohydrate utilization among isolates. In particular, a Y585C mutation in the sorbitol operon transcriptional regulator<jats:italic>gutR</jats:italic>was associated with increased bacterial growth in the presence of sorbitol. We also found differences in biofilm-formation capability between isolates and observed that increased biofilm formation correlated with mutations in the putative<jats:italic>E. faecium</jats:italic>capsular polysaccharide (<jats:italic>cps</jats:italic>) biosynthetic locus, with different mutations arising independently in distinct genetic backgrounds. Isolates with<jats:italic>cps</jats:italic>mutations showed improved survival following exposure to lysozyme, suggesting a possible reason for the selection of capsule-lacking bacteria. Finally, we observed mutations conferring increased tolerance of linezolid and daptomycin in patients who were treated with these antibiotics. Overall, this study documents known and previously undescribed ways that VREfm evolve during intestinal colonization and subsequent bloodstream infection in immunocompromised pediatric patients.</jats:p>

Bacterial evolution during human infection: Adapt and live or adapt and die

“…Because transmission does not happen between the bacterial populations at these more invasive sites of infection, beneficial traits must reevolve within each new patient. This process of evolution “on repeat” can be studied by sequencing pathogen genomes sampled from sites of colonization and infection within the same patient [ 76 ] or by sequencing the genomes of bacteria from outbreaks of a particular kind of infection [ 77 , 78 ]. One example of this is the enterococci, which are stable colonizers of the gastrointestinal tracts of land mammals [ 79 ].…”

CRISPR-based antimicrobials to obstruct antibiotic-resistant and pathogenic bacteria

“…The overuse of antibiotics in both medical and agricultural settings has facilitated the emergence of multidrug-resistant (MDR) bacteria [ 2 ]. Furthermore, many antibiotics lack specificity, indiscriminately killing pathogenic and nonpathogenic bacteria and contributing to antibiotic-associated infections [ 3 , 4 ]. This highlights the critical need for novel therapeutics that circumvent existing modes of drug resistance while adding specificity [ 5 ].…”

Evolution of Acinetobacter baumannii in Clinical Bacteremia Patients

“…Variants have been shown to be enriched in genes involved in carbohydrate metabolism, and phenotypic analysis has revealed associated differences in carbohydrate utilisation among isolates. 37 Another research has utilised whole-genome sequencing to characterise E. faecium associated with stool carriage and bloodstream infection in patients. A comparative genomic analysis of related isolates in stool and blood of the same patient has failed to reveal adaptive mutations associated with invasive disease.…”