title: Emergence of daptomycin non-susceptibility in colonizing vancomycin-resistant Enterococcus faecium isolates during daptomycin therapy.
abstract: Infections due to vancomycin-resistant enterococci (VRE) are of significant importance in high-risk populations, and daptomycin is a bactericidal antibiotic to treat multidrug-resistant VRE in these patients. The emergence of daptomycin non-susceptibility invasive VRE during daptomycin therapy is a major clinical issue. Here the hypothesis was tested that systemic daptomycin therapy also induces the emergence of daptomycin non-susceptible (DNS-) isolates in colonizing VRE populations. 11 vancomycin-resistant Enterococcus faecium strain pairs recovered from rectal swabs were available for analysis. All initial isolates exhibited daptomycin MICs within the wild type MIC distribution of E. faecium (MIC≤4 mg/L). In follow-up isolates from five patients a 4-16-fold daptomycin MIC increase was detected. All patients carrying DNS-VRE received daptomycin (14-28 days) at 4 mg/kg body weight, while two patients in whom no DNS-VRE emerged were only treated with daptomycin for 1 and 4 days, respectively. Comparative whole genome sequencing identified DNS-VRE-specific single nucleotide polymorphisms (SNP), including mutations in cardiolipin synthase (Cls), and additional SNPs in independent genes potentially relevant for the DNS phenotype. Mutations within cls were also identified in three additional, colonizing DNS-VRE. Of these, at least one strain was transmitted within the hospital. In none of the VRE isolates tested, pre-existing or de novo mutations in the liaFSR operon were detected. This is the first report documenting the emergence of DNS-VRE in colonizing strains during daptomycin treatment, putting the patient at risk for subsequent DNS-VRE infections and priming the spread of DNS-VRE within the hospital environment.
authors.affiliation: Klinik für Stammzelltransplantation, Universitätsklinikum Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Lellek
authors.affiliation: Institut für Medizinische Mikrobiologie, Virologie und Hygiene, Universitätsklinikum Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
authors.forename: Gefion C
authors.initials: GC
authors.lastname: Franke
authors.affiliation: Institut für Medizinische Mikrobiologie, Virologie und Hygiene, Universitätsklinikum Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Ruckert
authors.affiliation: Institut für Medizinische Mikrobiologie, Virologie und Hygiene, Universitätsklinikum Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Wolters
authors.affiliation: Klinik für Stammzelltransplantation, Universitätsklinikum Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Wolschke
authors.affiliation: Institut für Medizinische Mikrobiologie, Virologie und Hygiene, Universitätsklinikum Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Christner
authors.affiliation: Institut für Medizinische Mikrobiologie, Virologie und Hygiene, Universitätsklinikum Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Büttner
authors.affiliation: Bioinformatics Service Facility, Universitätsklinikum Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
authors.forename: Malik
authors.initials: M
authors.lastname: Alawi
authors.affiliation: Klinik für Stammzelltransplantation, Universitätsklinikum Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
authors.forename: Nicolaus
authors.initials: N
authors.lastname: Kröger
authors.affiliation: Institut für Medizinische Mikrobiologie, Virologie und Hygiene, Universitätsklinikum Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. Electronic address: rohde@uke.de.
authors.forename: Holger
authors.initials: H
authors.lastname: Rohde
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics; D017576:Daptomycin / Q000494:pharmacology* / Q000627:therapeutic use; D004361:Drug Tolerance; D016984:Enterococcus faecium / Q000187:drug effects* / Q000302:isolation & purification; D005243:Feces / Q000382:microbiology; D016680:Genome, Bacterial; D016908:Gram-Positive Bacterial Infections / Q000382:microbiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D020641:Polymorphism, Single Nucleotide; D065507:Vancomycin-Resistant Enterococci / Q000187:drug effects* / Q000302:isolation & purification
chemical_list: D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D017576:Daptomycin
keywords: Bone marrow transplantation; Comparative genome sequencing; Daptomycin resistance; Vancomycin-resistant enterococci