Activity of antibiotic combinations towards intracellular small colony variants of Staphylococcus aureus in a model of THP-1 macrophages

Abstract number: P1059

Nguyen H.A., Denis O., Vergison A., Tulkens P.M., Struelens M.J., Van Bambeke F.

Objectives: In a model of human THP-1 macrophages intracellular infection, small colony variants (SCV)s of S. aureus have been shown to be poorly susceptible to most antibiotics (ICAAC 2007, A1437), except ORI, MXF or RIF (-2 log CFU in 24 or 72 h). In the present study, we have examined whether combining these drugs could further enhance intracellular efficacy in comparison with conventional associations (RIF-OXA, RIF-VAN, RIF-FA) as comparators.

Methods: We used a stable thymidine-auxotrophic mecA negative SCV of S. aureus isolated from a cystic fibrosis (CF) patient. MICs were determined in MH broth after 48 h incubation. Intracellular activities were measured as the change in post-phagocytosis inoculum [delta log CFU] after 24 h or 72 h of incubation with antibiotics at extracellular concentrations corresponding to their respective serum peak concentration (Cmax) when administered at standard doses.

Results: Combination of RIF with OXA, VAN, FA, or MXF was indifferent (same activity as RIF alone at 24 h, slight reduction at 72 h). In contrast, combination of ORI with RIF or MXF resulted in synergistic effects both at 24 h and 72 h (higher activity than observed for the most active drug given alone), with RIF-ORI reaching the limit of detection at 72 h.

Conclusion: The data suggest that combining oritavancin with other bactericidal antibiotics may prove useful for eradicating intracellular SCVs, and plead for the further evaluation of such combinations in in vivo pertinent models of recurrent staphylococcal infections that imply SCVs.