Abstract
ABSTRACTLinezolid and daptomycin resistance among Enterococccus faecium (Efm) isolates, while rare, is a major challenge for clinicians who are often limited to broad-spectrum or combination antibiotic therapies for management. Combination therapy with a beta-lactam has been reported, but limited clinical evidence exists to support its use. We describe the clinical management of a prolonged Efm intraabdominal (IA) infection and subsequent bacteremia, along with observed multidrug resistance development and use of serial whole genome sequencing to better understand resistance mechanisms. Combination antimicrobial therapy with daptomycin (DAP) and ceftaroline (CPT) was used to treat the patient’s catheter-associated daptomycin-, linezolid-, vancomycin-resistant Efm (DLVRE) bloodstream infection. In vitro antimicrobial testing of this DLVRE revealed only minor synergy between daptomycin and ceftaroline; However, the patient’s bacteremia cleared following initiation of combination therapy in conjunction with catheter removal. Sequencing of the patient’s DLVRE revealed multiple genomic mutations which explain both linezolid and daptomycin resistance and the presence of a plasmid containing known resistance determinants for vancomycin. Daptomycin resistance was attributed to the presence of chromosomal mutations in liaS (Thr120Ala), liaR (Trp73Cys), and cls (Asp13Ile), while linezolid resistance was attributed to the presence of the G2576T variant allele in some of 23S rRNA gene copies. Sequential whole genome sequencing of two additional bacterial isolates from the same patient revealed protracted colonization with a single DLVRE clone and suggested the development of bacterial subpopulations. Pairing clinical isolate susceptibilities with whole genome sequencing should be encouraged in clinical practice to better inform antimicrobial management in cases of multidrug resistance.
Publisher
Cold Spring Harbor Laboratory