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, 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 (DAP^s) S. mitis/S. oralis strain and its daptomycin-resistant (DAP^r) 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 DAP^r variant was initially isolated from the cardiac vegetations of animals with experimental endocarditis caused by the parental DAP^s strain following treatment with daptomycin. The parental strain and the DAP^r 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 DAP^r 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 DAP^s strain was completely eliminated, while the DAP^r variant persisted in all target tissues. These data underscore that the acquisition of DAP^r 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.

Keywords: Streptococcus mitis group; daptomycin; experimental endocarditis; fitness; gentamicin; high-level daptomycin resistance; virulence.

FIG 1

(A) Results of time-kill experiments for DAP^s strain S.MIT/ORALIS-351 incubated with DAP plus GEN at concentrations of 0.5× MIC and 1× MIC for both antibiotics. (B) Results of time-kill experiments for the DAP^r variant incubated with DAP plus GEN at concentrations of 64 μg/ml and 128 μg/ml for DAP and 4 μg/ml and 8 μg/ml for GEN. The numbers in the keys are concentrations (in micrograms per milliliter).