Evaluation of intraosteoblastic activity of dalbavancin against Staphylococcus aureus in an ex vivo model of bone cell infection
Authors: Chauvelot Pierre , Dupieux-Chabert Céline , Abad Lélia , Souche Aubin , Ferry Tristan , Josse Jérôme , Laurent Frédéric , Valour Florent ,   the Lyon BJI Study Group, Ferry Tristan , Ferry Tristan , Valour Florent , Perpoint Thomas , Miailhes Patrick , Ader Florence , Roux Sandrine , Becker Agathe , Triffault-Fillit Claire , Conrad Anne , Pouderoux Cécile , Benech Nicolas , Chauvelot Pierre , Chabert Paul , Braun Evelyne , Chidiac Christian , Lustig Sébastien , Servien Elvire , Batailler Cécile , Gunst Stanislas , Schimdt Axel , Malatray Matthieu , Sappey-Marinier Eliott , Michel-Henry Fessy , Viste Anthony , Jean-Luc Besse , Chaudier Philippe , Louboutin Lucie , Ode Quentin , Van Haecke Adrien , Mercier Marcelle , Belgaid Vincent , Walch Arnaud , Martres Sébastien , Trouillet Franck , Heery Yannick , Barrey Cédric , Mojallal Ali , Brosset Sophie , Hanriat Camille , Person Philippe CÉruse , Fuchsmann Carine , Daveau Clémentine , Blanc Jacques , Gleizal Arnaud , Daurade Mathieu , Bourlet Jérôme , Aubrun Frédéric , Dziadzko Mikhail , Macabéo Caroline , Laurent Frederic , Beraut Laetitia , Roussel-Gaillard Tiphaine , Dupieux-Chabert Céline , Kolenda Camille , Josse Jérôme , Craighero Fabien , Boussel Loic , Pialat Jean-Baptiste , Morelec Isabelle , Tod Michel , Gagnieu Marie-Claude , Goutelle Sylvain , Mabrut Eugénie 
Published: August 2021

Abstract

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 24 h with dalbavancin, vancomycin or rifampicin using the MIC, 10×MIC, 100×MIC and/or the intraosseous concentrations reached using standard therapeutic doses (i.e. vancomycin, 10 mg/L; rifampicin, 2 mg/L; and dalbavancin, 6 mg/L). The remaining intracellular bacteria were quantified by plating cell lysates.

Results
MICs of dalbavancin, vancomycin and rifampicin were 0.125, 1 and 0.004 mg/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 100×MIC 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 &lt; 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 &lt; 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.