Staphylococcus aureus (SA), the predominant pathogen in human osteomyelitis, is known to persist by forming intracellular reservoirs, including in bone cells (Schwarz et al., 2019, Yang et al., 2018, Krauss et al., 2019, Gao et al., 2020, Bosse et al., 2005), promoting decreased antibiotic susceptibility. However, there are no evidence-based treatment guidelines for intracellular SA infections in osteomyelitis. We sought to address this by systematically reviewing the literature and, testing a selection of antibiotic treatments in a clinically relevant in vitro assay.
We conducted a systematic review of the literature to determine the current evidence for the efficacy of antibiotics against intracellular SA infections relevant to osteomyelitis. For the antibiotics identified as potentially useful, we determined their minimal inhibitory concentration (MIC) against 11 clinical osteomyelitis SA- isolates. We selected those for further testing reported able to reach a higher concentration in the bone than the identified MIC against the majority of strains. Thus, rifampicin, oxacillin, linezolid, levofloxacin, oritravancin and doxycycline were tested in human SaOS-2-osteocyte infection models (Gunn et al., 2021) of acute (1d) or chronic (14d) infection to clear intracellular SA. Antibiotics were tested at 1x/4x/10x the MIC for the duration of 1d or 7d in each model.
A systematic review found that osteoblasts and macrophages have mostly been used to test immediate short-term activity against intracellular SA, with a high variability in methodology. Some extant evidence supports that rifampicin, oritravancin, linezolid, moxifloxacin and oxacillin may be effective intracellular treatments. Importantly, these have lower MICs against multiple clinical isolates than their respective clinically-achievable bone concentrations. However, in a clinically relevant in vitro model only rifampicin showed to be an effective treatment for osteomyelitic intracellular SA infections.
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.