Efficacy of linezolid in monotherapy q12h versus q8h versus combined with daptomycin in the treatment of experimental endocarditis caused by methicillin-resistant and glycopeptide-intermediate Staphylococcus aureus strains

Daptomycin is a bactericidal antibiotic, highly effective against MRSA. Linezolid, though bacteriostatic, is effective in MRSA pneumonia and has excellent meningeal penetration. Therefore, the combination of both antibiotics can be required in some patients with disseminated MRSA infections. This study aimed to evaluate the in vitro activity of linezolid plus daptomycin against MRSA and glycopeptide-intermediate Staphylococcus aureus (GISA) strains and to determine the efficacy of linezolid monotherapy administered every 12 h versus every 8 h versus the combination of linezolid-q12h plus daptomycin against MRSA and GISA experimental endocarditis (EE). In vitro time-kill studies were performed using standard (105 cfu/L) and high (109 cfu/mL) inoculum of six MRSA strains, including one GISA strain. MRSA-277 and GISA-700788 were selected for the EE model. Animals were treated with linezolid-q12h (600 mg/kg/12 h), linezolid-q8h (600 mg/kg/8 h), daptomycin (6 mg/kg/day) or daptomycin plus linezolid-q12h mimicking human-like serum levels. Linezolid-q8h and linezolid-q12h showed similar activity in MRSA-277 EE (P = 0.15). Against GISA-700788 endocarditis, linezolid-q8h was more effective than linezolid-q12h (P < 0.001). Daptomycin monotherapy was very effective against MRSA-277 and GISA-700788 EE, sterilizing 70% and 60% of valvular vegetations, respectively. Daptomycin plus linezolid-q12h was similarly effective at 60% and 56%, respectively. This combination showed neither in vitro nor in vivo antagonism, and daptomycin-non-susceptible strains were not recovered. Increasing linezolid to 600 mg/8 h might be useful as initial treatment in clinical practice. If required, the combination of daptomycin plus linezolid-q12h could be a suitable option in MRSA/GISA bacteraemia/endocarditis.