Staphylococcal biofilms are a major cause of therapeutic failure, especially when caused by multiresistant strains. Oral
fusidic acid is currently being redeveloped in the United States for skin, 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 antistaphylococcal drugs against biofilms made by a reference strain and five clinical isolates of Staphylococcus aureus or Staphylococcus epidermidis in in vitro static and dynamic models (microtiter plates and a CDC reactor) exposed to clinically relevant concentrations. In microtiter plates,
antibiotics alone were poorly active, with marked differences among strains. At concentrations mimicking the free-
drug human maximum concentration of
drug in serum (Cmax), the combination of
fusidic acid with
linezolid,
daptomycin, or
vancomycin resulted in increased activity against 4 to 5 strains, while the combination with
doxycycline,
rifampin, or
moxifloxacin increased activity against 1 to 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, skin structure, or orthopedic
infections.