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 ␤-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 10 6 -and 10 7 -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.

VraSR and Virulence Trait Modulation during Daptomycin Resistance in Methicillin-Resistant Staphylococcus aureus Infection

“…In addition, if they are exposed to antimicrobial agents, they are able to generate metabolic and/or genetic changes that promote survival when exposed to a certain drug while sustaining the infection within the host (18). The correlation between resistance to several antibiotics and virulence has been demonstrated previously in different bacterial species (34, 36, 45, 46). In the present study, we analyzed how DAP resistance impacted the pathogenicity of clinically derived MRSA strains obtained from cases of DAP treatment failure.…”

“…These results were consistent with the results reported by Cameron et al (45), in which clinical and in vitro DAP r strains were less virulent but more persistent in vivo than their DAP s progenitor strains. Similarly, DAP r Streptococcus mitis strains have been shown to display reduced in vitro and in vivo virulence in an endovascular infection model; the parental DAP- susceptible strain outcompeted the DAP r variant in all target organs (46). One explanation for the lowered virulence of DAP r staphylococcal strains could be that bacteria are more likely to prefer to sustain a chronic persistent infection instead of invasive acute infections once they acquire resistance.…”

Daptomycin Dose-Ranging Evaluation with Single-Dose versus Multidose Ceftriaxone Combinations against Streptococcus mitis /oralis in an Ex Vivo Simulated Endocarditis Vegetation Model

“…Lastly, in general, alterations in CM fluidity have been closely related to resistance to killing by calcium-DAP and other cationic peptides among DAP-R Gram-positive pathogens (1)(2)(3)(4)(5)(6)(7)(8). These phenotypes are believed to link to an altered ability of DAP to interact with and/or insert within target CMs at extremes of CM order.…”

“…These phenotypes are believed to link to an altered ability of DAP to interact with and/or insert within target CMs at extremes of CM order. It is presumed that there are certain CM order set points for the optimal interaction of target CMs with cationic peptides such as calcium-DAP, rendering strains more or less susceptible to such agents (1)(2)(3)(4)(5)(6)(7)(8). The DAP-R 351 (but not the DAP-R SF100) variant demonstrated significant increases in CM fluidity compared to that of its DAP-S parental strain.…”

“…and also exhibit in vitro vancomycin tolerance (3,(6)(7)(8)(9). The mechanism of ␤-lactamresistance in these isolates relates to a reduction of antibiotic affinity to target penicillin-binding proteins (10).…”