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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 21; pp. 11703 - 11714
• Main Authors: Chilambi, Gayatri Shankar, Nordstrom, Hayley R., Evans, Daniel R., Ferrolino, Jose A., Hayden, Randall T., Marón, Gabriela M., Vo, Anh N., Gilmore, Michael S., Wolf, Joshua, Rosch, Jason W., Van Tyne, Daria
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 26.05.2020
• Subjects: Antibiotic resistance; Antibiotics; Biofilms; Biological Sciences; Blood; Capsular polysaccharides; Carbohydrate metabolism; Carbohydrates; Chemotherapy; Colonization; Daptomycin; Enterococcus faecium; Genomes; Hematology; Hematopoietic stem cells; Immunological tolerance; Infections; Intestine; Linezolid; Lysozyme; Malignancy; Multidrug resistance; Mutation; Patients; Pediatrics; Polysaccharides; Sorbitol; Stem cell transplantation; Stem cells; Transcription; Transplantation; Vancomycin; functional genomics; vancomycin-resistant enterococci; pediatric infectious diseases
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1917130117

Patients with hematological malignancies or undergoing hematopoietic stem cell transplantation are vulnerable to colonization and infection with multidrug-resistant organisms, including vancomycin-resistant Enterococcus faecium (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 gutR 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 E. faecium capsular polysaccharide (cps) biosynthetic locus, with different mutations arising independently in distinct genetic backgrounds. Isolates with cps 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.