Intraosteoblastic activity of daptomycin in combination with oxacillin and ceftaroline against MSSA and MRSA

J Antimicrob Chemother. 2017 Dec 1;72(12):3353-3356. doi: 10.1093/jac/dkx314.

Abstract

Background: The Staphylococcus aureus intracellular reservoir is associated with bone and joint infection (BJI) chronicity. As daptomycin is increasingly prescribed in BJI, strategies for improving its reduced intracellular activity should be promoted.

Objectives: Based on the known in vitro synergy of daptomycin with β-lactams, the aim of the present study was to evaluate the intracellular activity of these combinations in an ex vivo osteoblast infection model.

Methods: Osteoblastic cells infected with an MRSA strain or its isogenic MSSA counterpart were incubated for 24 h with daptomycin, oxacillin or ceftaroline alone or in combination using usual intraosseous therapeutic concentrations. Intracellular bacteria were quantified by plating cell lysates. MICs for MSSA and MRSA were determined using the chequerboard method at pH 5 to mimic conditions expected within lysosomes, the foremost S. aureus intracellular location.

Results: Daptomycin failed to reduce the intracellular MSSA inoculum, and was weakly active against MRSA compared with untreated cells (-27.6%; P < 10-3). Oxacillin and ceftaroline revealed significant intracellular activity, including oxacillin against MRSA-infected cells (-43.2%; P < 10-3). The daptomycin/oxacillin combination was significantly more active against intracellular MSSA and MRSA compared with daptomycin and oxacillin alone (-44.4% and -57.2%, respectively; P < 0.05). In contrast, daptomycin/ceftaroline was not more efficient than ceftaroline alone. Interestingly, oxacillin MICs for MRSA decreased in vitro from >256 to 0.023 mg/L when the pH decreased from 7 to 5, and chequerboards showed an additive effect of the daptomycin/oxacillin combination against MRSA at pH 5.

Conclusions: In acidic intracellular conditions, oxacillin enhances daptomycin activity against the intraosteoblastic reservoir of S. aureus, including MRSA.

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Cell Line
  • Cephalosporins / pharmacology*
  • Colony Count, Microbial
  • Daptomycin / pharmacology*
  • Drug Synergism*
  • Humans
  • Methicillin Resistance
  • Microbial Viability / drug effects
  • Osteoblasts / microbiology*
  • Oxacillin / pharmacology*
  • Staphylococcus aureus / drug effects*

Substances

  • Anti-Bacterial Agents
  • Cephalosporins
  • T 91825
  • Daptomycin
  • Oxacillin