Impact of High-Level Daptomycin Resistance in the Streptococcus mitis Group on Virulence and Survivability during...

Area of Science:

• Infectious Diseases
• Microbiology
• Pharmacology

Background:

• Viridans group streptococci, particularly the Streptococcus mitis/oralis group, are leading causes of infective endocarditis.
• These bacteria exhibit a tendency for beta-lactam resistance and can rapidly develop high-level daptomycin (DAP) resistance.
• Understanding the fitness and therapeutic implications of daptomycin resistance is crucial for managing endocarditis.

Purpose of the Study:

• To compare the relative fitness of daptomycin-susceptible (DAP^s) and daptomycin-resistant (DAP^r) *S. mitis/S. oralis* strains in experimental endocarditis.
• To evaluate bacterial survival in target organs (vegetations, kidneys, spleen) under coinfection and daptomycin-gentamicin therapy.
• To assess the fitness cost associated with daptomycin resistance acquisition.

Main Methods:

• An experimental endocarditis model was established using a parental DAP^s *S. mitis/S. oralis* strain and its derived DAP^r variant.
• Relative fitness was assessed via coinfection challenges in target organs without antibiotic therapy.
• Bacterial survivability was evaluated during daptomycin-gentamicin treatment in the coinfection model.

Main Results:

• The DAP^r variant showed comparable virulence to the DAP^s strain in individual challenges.
• In coinfection without therapy, the DAP^s strain outcompeted the DAP^r variant in all organs, especially kidneys and spleen.
• Daptomycin-gentamicin therapy eradicated the DAP^s strain but the DAP^r variant persisted in all tissues.

Conclusions:

• Acquisition of daptomycin resistance in *S. mitis/S. oralis* incurs an intrinsic fitness cost.
• Despite the fitness cost, daptomycin resistance confers complete protection against synergistic daptomycin-gentamicin therapy.
• These findings highlight the complex interplay between resistance, fitness, and therapeutic efficacy in bacterial endocarditis.