8 research outputs found
Microbubble Cavitation Restores Staphylococcus Aureus Antibiotic Susceptibility in Vitro and in a Septic Arthritis Model
Treatment failure in joint infections is associated with fibrinous, antibiotic-resistant, floating and tissue-associated Staphylococcus aureus aggregates formed in synovial fluid (SynF). We explore whether antibiotic activity could be increased against Staphylococcus aureus aggregates using ultrasound-triggered microbubble destruction (UTMD), in vitro and in a porcine model of septic arthritis. In vitro, when bacterially laden SynF is diluted, akin to the dilution achieved clinically with lavage and local injection of antibiotics, amikacin and ultrasound application result in increased bacterial metabolism, aggregate permeabilization, and a 4-5 log decrease in colony forming units, independent of microbubble destruction. Without SynF dilution, amikacin + UTMD does not increase antibiotic activity. Importantly, in the porcine model of septic arthritis, no bacteria are recovered from the SynF after treatment with amikacin and UTMD-ultrasound without UTMD is insufficient. Our data suggest that UTMD + antibiotics may serve as an important adjunct for the treatment of septic arthritis
Targeted Release of Tobramycin from a pH-Responsive Grafted Bilayer Challenged with S. aureus
A stimuli-responsive, controlled
release bilayer for the prevention of bacterial infection on biomaterials
is presented. Drug release is locally controlled by the pH-responsiveness
of the bilayer, comprised of an inner poly(acrylic acid) (PAA) monolayer
grafted to a biomaterial and cross-linked with an outer chitosan (CH)
brush. Tobramycin (TOB) is loaded in the inner PAA in part to minimize
bacteria resistance. Because biofilm formation causes a decrease in
local pH, TOB is released from PAA and permeates through the CH, which
is in contact with the biofilm. Antibiotic capacity is controlled
by the PAA thickness, which depends on PAA brush length and the extent
of cross-linking between CH and PAA at the bilayer interface. This
TOB-loaded, pH-responsive bilayer exhibits significantly enhanced
antibacterial activity relative to controls
Targeted Release of Tobramycin from a pH-Responsive Grafted Bilayer Challenged with S. aureus
A stimuli-responsive, controlled
release bilayer for the prevention of bacterial infection on biomaterials
is presented. Drug release is locally controlled by the pH-responsiveness
of the bilayer, comprised of an inner poly(acrylic acid) (PAA) monolayer
grafted to a biomaterial and cross-linked with an outer chitosan (CH)
brush. Tobramycin (TOB) is loaded in the inner PAA in part to minimize
bacteria resistance. Because biofilm formation causes a decrease in
local pH, TOB is released from PAA and permeates through the CH, which
is in contact with the biofilm. Antibiotic capacity is controlled
by the PAA thickness, which depends on PAA brush length and the extent
of cross-linking between CH and PAA at the bilayer interface. This
TOB-loaded, pH-responsive bilayer exhibits significantly enhanced
antibacterial activity relative to controls
Role of Phenol-Soluble Modulins in Formation of Staphylococcus aureus Biofilms in Synovial Fluid.
Staphylococcus aureus is a leading cause of prosthetic joint infections, which, as we recently showed, proceed with the involvement of biofilm-like clusters that cause recalcitrance to antibiotic treatment. Here we analyzed why these clusters grow extraordinarily large, reaching macroscopically visible extensions (\u3e1 mm). We found that while specific S. aureus surface proteins are a prerequisite for agglomeration in synovial fluid, low activity of the Agr regulatory system and subsequent low production of the phenol-soluble modulin (PSM) surfactant peptides cause agglomerates to grow to exceptional dimensions. Our results indicate that PSMs function by disrupting interactions of biofilm matrix molecules, such as the polysaccharide intercellular adhesin (PIA), with the bacterial cell surface. Together, our findings support a two-step model of staphylococcal prosthetic joint infection: As we previously reported, interaction of S. aureus surface proteins with host matrix proteins such as fibrin initiates agglomeration; our present results show that, thereafter, the bacterial agglomerates grow to extremely large sizes owing to the lack of PSM expression under the specific conditions present in joints. Our findings provide a mechanistic explanation for the reported extreme resistance of joint infection to antibiotic treatment, lend support to the notions that Agr functionality and PSM production play a major role in defining different forms of S. aureus infection, and have important implications for antistaphylococcal therapeutic strategies