Staphylococcus aureus (SA), the predominant pathogen in human osteomyelitis, is known to persist by forming intracellular reservoirs, including in bone cells, promoting decreased antibiotic susceptibility. However, there are no evidence-based treatment guidelines for intracellular SA infections in osteomyelitis. We addressed this by systematically reviewing the literature and testing candidate antibiotics in a clinically relevant in vitro assay.
A systematic review was conducted for the efficacy of antibiotics against intracellular SA infections relevant to osteomyelitis. Mostly, osteoblasts and macrophages have been used to test immediate short-term activity against intracellular SA, with a high variability in methodologies. Some extant evidence supports that rifampicin, oritavancin, linezolid, moxifloxacin and oxacillin may be effective intracellular treatments. For potentially useful antibiotics identified, the minimal inhibitory concentration (MIC) against 11 clinical osteomyelitis SA-isolates was determined. We tested those further, which are reported to reach a higher concentration in bone than their respective MIC. Thus, rifampicin, oxacillin, linezolid, levofloxacin, oritavancin and doxycycline were tested in human SaOS2-osteocyte infection models of acute (1d) or chronic (14d) infection for the ability to reduce intracellular SA numbers at 1x/4x/10x the MIC for 1d or 7d in each model.
Of the antibiotics tested to date, rifampicin linezolid and levofloxacin showed to be effective treatments for osteomyelitic intracellular SA infection, while oxacillin and doxycycline have proved ineffective. The combined approach of a systematic review and disease-relevant in vitro screening will potentially inform as to the best approach for treating osteomyelitis where intracellular SA infection is confirmed or suspected.