Activity of combinations of antistaphylococcal antibiotics with fusidic acid against staphylococcal biofilms in in vitro static and dynamic models [PublishAheadOfPrint]

Staphylococcal biofilms are a major cause of therapeutic failure, especially when caused by multiresistant strains. Oral fusidic acid is currently being re-developed in the US for skin and skin structure and orthopedic infections, in which biofilms play a major role. The aim of this study was to examine the activity of fusidic acid alone or combined with other anti-staphylococcal drugs against biofilms made by a reference strain and five clinical isolates of Staphylococcus aureus or Staphylococcus epidermidis in in vitro static or dynamic models (microtiter plates and CDC reactor) exposed to clinically-relevant concentrations. In microtiter plates, antibiotics alone were poorly active, with marked differences among strains. At concentrations mimicking free-drug human C_max, combination of fusidic acid with linezolid, daptomycin or vancomycin resulted in increased activity against 4-5 strains and combination with doxycycline, rifampin, or moxifloxacin, increased activity against 1-3 strains only. In the CDC reactor, biofilms were grown under constant flow and antibiotic concentrations decreased over time according to human elimination rates. A bactericidal effect was obtained when fusidic acid was combined with daptomycin or linezolid, but not with vancomycin. The higher tolerance of biofilms to antibiotics in the CDC reactor is probably attributable to the more complex architecture they adopt when growing under constant flow. Because biofilms grown in the CDC reactor are considered more similar to those developing in vivo, the data support further testing of combinations of fusidic acid with daptomycin or linezolid in models pertinent to chronic skin and skin structure or orthopedic infections.

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