1. Antimicrob Agents Chemother. 2018 Jun 26;62(7). pii: e00598-18. doi:
10.1128/AAC.00598-18. Print 2018 Jul.

Activities of Combinations of Antistaphylococcal Antibiotics with Fusidic Acid
against Staphylococcal Biofilms in In Vitro Static and Dynamic Models.

Siala W(1), Rodriguez-Villalobos H(2), Fernandes P(3), Tulkens PM(1), Van Bambeke

Author information: 
(1)Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute,
Université catholique de Louvain, Brussels, Belgium.
(2)Laboratoire de microbiologie, Cliniques universitaires Saint-Luc, Université
catholique de Louvain, Brussels, Belgium.
(3)Cempra, Inc., Chapel Hill, North Carolina, USA.
(4)Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute,
Université catholique de Louvain, Brussels, Belgium

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

Copyright © 2018 American Society for Microbiology.

DOI: 10.1128/AAC.00598-18 
PMID: 29712650