Abstract
Aim
Leading etiology of Bone and Join infections (BJI), Staphylococcus aureus (SA) is responsible for difficult-to-treat infections mainly because of three persistence factors: (i) biofilm formation, (ii) persistence within bone cells and (iii) switch to the small colony variant (SCV) phenotype. The impact of rifampin on these mechanisms gave it a prominent place in orthopedic device-associated BJI. However, resistance emergence, intolerance and drug interactions cause significant concerns. In this context, other rifamycins – namely rifapentine and rifabutin – have poorly been evaluated, particularly toward their ability to eradicate biofilm-embedded and intracellular reservoirs of SA.
Method
This study aimed at comparing the intracellular activities of and SCV induction by rifampin, rifabutin and rifapentine in an in vitro model of osteoblast infection. Four concentrations were tested (0.1xMIC, MIC, 10xMIC, 100xMIC) against three SA strains (6850 and two clinical isolates involved in recurrent BJI)
Results
Each rifamycin had a similar intracellular activity, decreasing by 50% the intracellular inoculum from a concentration equal to MIC. Rifabutin was more efficient at low concentrations, with a reduction of 19.9% at 0.1MIC. At all concentrations, a 1.5-fold increase in cellular viability was observed for all molecules. A dose-dependent induction of intracellular SCVs was observed, which was significantly lower for rifabutin than rifampicin at 10MIC (p<0.0001).
Conclusions
Each rifamycin was efficient to eradicate intraosteoblastic SA reservoir, one bacterial phenotype in recurrent's BJI. Rifabutin was more efficient at low concentration, suggesting an important intracellular accumulation. This can be explained by its oil/water coefficient of partition 100 time superior than other rifamycins. Using rifabutin at lower concentration, limiting adverses effect and the emergence of SCVs, could be an interesting therapeutic alternative in BJI's treatment. The comparison of rifamycin ability to eradicate biofilm-embedded SA, another chronicity and relapse factor, is an ongoing work.
