Among the viridans group streptococci, the Streptococcus mitis group 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. oralis strain 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 (an in vitro combination synergistic against the parental strain). The DAPr variant was initially isolated from the cardiac vegetations of animals with experimental
endocarditis caused by the parental
DAPs strain following treatment with
daptomycin. The parental strain and the DAPr variant 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 DAPr variant in all target organs, especially the kidneys and spleen. When the animals in the
coinfection model of
endocarditis were treated with DAP-
gentamicin, the
DAPs strain was completely eliminated, while the DAPr variant persisted in all target tissues. These data underscore that the acquisition of DAPr in S. mitis/S. oralis does come at an intrinsic fitness cost, although this resistance phenotype is completely protective against
therapy with a potentially synergistic DAP regimen.