Evaluation of intraosteoblastic activity of dalbavancin against Staphylococcus aureus in an ex vivo model of bone cell infection

Objectives: Long-acting lipoglycopeptides are promising therapeutic options in Staphylococcus aureus bone and joint infections (BJIs). This study evaluated the ability of dalbavancin to eradicate the intraosteoblastic reservoir of S. aureus, associated with BJI chronicity. Methods: Osteoblastic cells were infected with a standardized inoculum of the S. aureus reference strain HG001 and incubated for 24h with dalbavancin, vancomycin or rifampicin using the MIC, 10xMIC, 100xMIC and/or the intraosseous concentrations reached using standard therapeutic doses (i.e. vancomycin, 10mg/L; rifampicin, 2mg/L; and dalbavancin, 6mg/L). The remaining intracellular bacteria were quantified by plating cell lysates. Results: MICs of dalbavancin, vancomycin and rifampicin were 0.125, 1 and 0.004mg/L, respectively. Dalbavancin significantly reduced the intracellular inoculum of S. aureus starting at a concentration equal to the MIC, with a significant dose effect, ranging from a reduction of 31.4% (95% CI=17.6%-45.2%) at MIC to 51.6% (95% CI=39.8%-63.4%) at 100xMIC compared with untreated cells. Of note, dalbavancin was the only molecule to significantly reduce the intraosteoblastic inoculum at low concentration (MIC). At intraosseous concentrations, dalbavancin reduced the intracellular inoculum by 49.6% (95% CI=45.1%-54.1%) compared with untreated cells (P<0.001), with no significant difference compared with vancomycin (38.1%; 95% CI=19.2%-57.0%; P=0.646), and was less efficient than rifampicin (69.0%; 95% CI=63.2-74.8; P<0.001). Conclusions: Dalbavancin was able to decrease the intraosteoblastic S. aureus inoculum by 50% at intraosseous concentrations reached during standard human therapeutic dosing, with no difference compared with vancomycin, and remained less efficient than rifampicin. However, it was the only molecule significantly active at low concentration.