A high-dose of rifampin is necessary to achieve optimal bone penetration and may improve treatment outcomes for patients with Staphylococcus aureus orthopedic implant-associated infections, according to results of a study published in Science Translational Medicine.
In this study, researchers integrated findings from both human and animal studies using a bidirectional process. They administered a chemically identical radiolabeled analog of rifampin and performed positron emission tomography (PET) with CT imaging on prospectively enrolled patients with confirmed S aureus bone infection (n=3) or without orthopedic infection (n=12). Results showed that the bone to plasma area under the concentration-time curve (AUC) ratio was 0.14 (IQR, 0.09-0.19).. To facilitate further studies with a mouse model of S aureus orthopedic implant infection, the researchers used PET-based pharmacokinetic modeling to predict rifampin concentration-time profiles in bone.
Among mice, treatment with high-dose rifampin (35 mg/kg) once daily was found to significantly increase bone concentrations compared with a standard dose (10-15 mg/kg) once daily (2 mg/L vs <0.2 mg/L) and also achieved increased bacterial killing (85%; P <.05) and biofilm disruption. Compared with the recommended 6-week course of standard-dose rifampin, a 4-week course of high-dose rifampin with vancomycin was noninferior (risk difference, -6.7; 90% CI, -20 to 6.9), ameliorated antimicrobial resistance (0% vs 38%; P =.04), and mitigated adverse bone remodeling (P <.01) in mice.
The researchers performed whole-genome sequencing and found that mice treated with high-dose rifampin had a decreased selection of bacterial mutations conferring rifampin resistance or mutations in genes potentially linked to resistance.
Study limitations included testing high-dose rifampin against a single community-acquired strain of methicillin-resistant S aureus and testing only rifampin combination treatment with either vancomycin or linezolid. Other limitations included its small sample size, starting treatment 14 days after infection to allow for biofilm formation, and significant comorbidities among the study patients.
According to the researchers, “these results should be the basis of future clinical studies to evaluate the efficacy of high-dose rifampin–containing regimens for S aureus orthopedic implant–associated infections.”
Disclosure: Some authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
Gorden O, Lee DE, Liu B, et al. Dynamic PET-facilitated modeling and high-dose rifampin regimens for Staphylococcus aureus orthopedic implant-associated infections. Sci Transl Med. Published online December 1, 2021. doi: 10.1126/scitranslmed.abl6851