title: Impact of High-Level Daptomycin Resistance in the Streptococcus mitis Group on Virulence and Survivability during Daptomycin Treatment in Experimental Infective Endocarditis.
abstract: Among the viridans group streptococci, theStreptococcus mitisgroup is the most common cause of infective endocarditis. These bacteria have a propensity to be β-lactam resistant, as well as to rapidly develop high-level and durable resistance to daptomycin (DAP). We compared a parental, daptomycin-susceptible (DAPs)S. mitis/S. oralisstrain and its daptomycin-resistant (DAPr) variant in a model of experimental endocarditis in terms of (i) their relative fitness in multiple target organs in this model (vegetations, kidneys, spleen) when animals were challenged individually and in a coinfection strategy and (ii) their survivability during therapy with daptomycin-gentamicin (anin vitrocombination synergistic against the parental strain). The DAPrvariant was initially isolated from the cardiac vegetations of animals with experimental endocarditis caused by the parental DAPsstrain following treatment with daptomycin. The parental strain and the DAPrvariant were comparably virulent when animals were individually challenged. In contrast, in the coinfection model without daptomycin therapy, at both the 106- and 107-CFU/ml challenge inocula, the parental strain outcompeted the DAPrvariant in all target organs, especially the kidneys and spleen. When the animals in the coinfection model of endocarditis were treated with DAP-gentamicin, the DAPsstrain was completely eliminated, while the DAPrvariant persisted in all target tissues. These data underscore that the acquisition of DAPrinS. mitis/S. oralisdoes come at an intrinsic fitness cost, although this resistance phenotype is completely protective against therapy with a potentially synergistic DAP regimen.
authors.affiliation: Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Garcia-de-la-Maria
authors.affiliation: LA Biomedical Research Institute, Torrance, California, USA.|Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Y Q
authors.initials: YQ
authors.lastname: Xiong
authors.affiliation: Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Pericas
authors.affiliation: Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, Spain.
authors.forename: Y
authors.initials: Y
authors.lastname: Armero
authors.affiliation: Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Moreno
authors.affiliation: LA Biomedical Research Institute, Torrance, California, USA.|Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: N N
authors.initials: NN
authors.lastname: Mishra
authors.affiliation: Anti-Infective Research Laboratory, Wayne State University, Detroit, Michigan, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Rybak
authors.affiliation: University of Texas School of Medicine, Houston, Texas, USA.
authors.forename: T T
authors.initials: TT
authors.lastname: Tran
authors.affiliation: University of Texas School of Medicine, Houston, Texas, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Arias
authors.affiliation: Veterans Affairs Medical Center and the University of California, San Francisco, California, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Sullam
authors.affiliation: LA Biomedical Research Institute, Torrance, California, USA.|Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Bayer
authors.affiliation: Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, Spain jmmiro@ub.edu.
authors.forename: J M
authors.initials: JM
authors.lastname: Miro
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D017576:Daptomycin / Q000627:therapeutic use*; D024881:Drug Resistance, Bacterial / Q000235:genetics; D004359:Drug Therapy, Combination; D004697:Endocarditis, Bacterial / Q000188:drug therapy* / Q000382:microbiology; D005839:Gentamicins / Q000627:therapeutic use*; D006801:Humans; D008826:Microbial Sensitivity Tests; D011817:Rabbits; D013290:Streptococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D034361:Streptococcus mitis / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity
chemical_list: D000900:Anti-Bacterial Agents; D005839:Gentamicins; D017576:Daptomycin
keywords: Streptococcus mitis group; daptomycin; experimental endocarditis; fitness; gentamicin; high-level daptomycin resistance; virulence