Staphylococcus aureus under antibiotic pressure (vancomycin and rifampin) - whole genome sequencing

Staphylococcus aureus is a major human pathogen causing serious orthopedic implant associated infections. Combination treatment with rifampin (10-15 mg/kg/day), which has potent, dose-dependent sterilizing activity, is recommended to treat S. aureus orthopedic implant associated infections. Rifampin, however, has limited bone penetration. In this study a mouse model of S. aureus orthopedic implant infection was utilized. Administration of high-dose rifampin (human equipotent to 35 mg/kg/day, shown to be safe in humans) substantially increased bone concentrations (2 mg/L versus <0.2 mg/L with standard-dosing) in mice. Importantly, 4-weeks of high-dose rifampin with vancomycin was non-inferior to the recommended 6-weeks of standard-dose rifampin with vancomycin in mice (risk difference: -6.7% favoring high-dose rifampin regimen). Additionally, high-dose rifampin treatments ameliorated antimicrobial resistance (0% versus 38%; P=0.04) and mitigated adverse bone remodeling (P<0.01). Whole-genome bacterial sequencing demonstrated that administration of high-dose rifampin in mice reduced selection of mutations in genes related to rifampin resistance (rpoB) or bacterial persistence (lysM, sdhB and clfB). These data suggest that administration of high-dose rifampin is needed to achieve optimal bone concentrations, which could shorten and improve treatments for S. aureus orthopedic implant infections